Journal articles on the topic 'Genesis 32–33 (Bible)'

AbstractThe patriarch Jacob is an involuntary migrant. Jacob lives as an asylum seeker from Esau’s threat of violence and then as a refugee under Laban’s protection. Eventually, Jacob returns ‘home’ to Canaan, but he finds there a society totally different than the one he remembers or imagines. Jacob resembles involuntary migrants from other cultures in all of these ways. The experiences of other involuntary migrants can and should, therefore, guide interpretation of this narrative. This article, therefore, exegetes the texts concerning Jacob in Genesis 25-33 by utilising findings from the social-scientific study of involuntary migration, James C. Scott’s work on subaltern resistance, and studies on the role of trickster narratives in the Hebrew Bible. By generating new interpretive solutions to perennially problematic passages and showing the prominence of the experience of involuntary migration in Genesis, this article outlines an important new hermeneutical approach relevant not only for this text but also for a large number of texts in the Hebrew Bible concerned with involuntary migration.

AbstractIt is general consensus that Malachi 3:23-24 is a redactional insertion to the book of Malachi. Scholars have argued that the insertion creates a closure either to the book of Malachi or to a larger corpus in the Hebrew Bible (e.g. the Law and the Prophets). In this article, I will present evidence that draws this consensus into question. I will examine a pattern of scriptural reuse found throughout the book of Malachi that is also found in Malachi 3:24. I will demonstrate that throughout Malachi and in Malachi 3:24, elements of Genesis 31-33 are reused. Based on this observation, I will compare the scribal mechanics and hermeneutic employed in the incorporation of the reused texts into the Malachi corpus with those used in Malachi 3.24. I will argue that there are enough similarities in the employed mechanics and hermeneutic to conclude that Malachi 3:24 is not a redactional insertion.

The points of contact between Genesis 27 and 32–33 have inspired significant commentary through the years, much of which has revolved around the question of whether the latter should be understood as the fulfillment of Isaac's pronouncements over Jacob and Esau in the former. This essay highlights the role of the displaced firstborn Esau in these narratives, suggesting that a reading which is attentive to the unchosen brother can offer fresh perspective for thinking about some of the complexities surrounding blessing and fulfillment in the Jacob Cycle.

The aim of the work is to develop forensic criteria for differentiation of hemorrhages of traumatic and non-traumatic genesis by digital Mueller matrix (MM) polarization microscopy of histological sections of human brain substance (HBS).Material and methods. Native histological preparations of HBS from 32 corpses with ischemic stroke (1 group), 35 corpses with hemorrhages of traumatic origin (2 groups), 33 corpses with hemorrhages in HBS of non-traumatic genesis (3 group) and 30 corpses caused by acute coronary insufficiency (4 control group). The method of research is azimuthal-invariant MM microscopy of circular dichroism (CD) of histological sections of the brain.Results. The results of studies of the coordinate and statistical structure of maps of the size of values at the points of digital microscopic images of histological sections of HBS of the dead of all groups revealed a coordinate-inhomogeneous structure of all distributions of the size of the CD of microscopic images of histological sections of the dead of all groups. Probable distributions that characterize MM invariants CD maps of histological sections of brain samples from all groups have a small scatter of values of the statistical moment of the 2nd order, as well as significant values of statistical moments of the 3rd and 4th orders.Conclusion. The efficiency of using the Mueller-matrix mapping method in diagnosing of hemorrhage genesis in the brain substance in the differentiation of the set of samples of control and experimental groups reaches a satisfactory level - 77% - 78%.

Aim. To study and comparatively analyze the integral stiffness of arterial system in healthy subjects and in patients with hypertensive heart disease, hypothyroidism associated with arterial hypertension and rheumatoid arthritis associated with arterial hypertension. Methods. The study included 32 healthy volunteers and 178 patients with arterial hypertension, including 63 patients with hypertensive heart disease of 1-3 degree, 82 patients with hypothyroidism associated with arterial hypertension, 33 patients with rheumatoid arthritis associated with arterial hypertension. All patients underwent echocardiography; modulus of volume elasticity (MVE), pulse pressure, mean arterial pressure (MAP), total peripheral vascular resistance (TPVR), and MVE/TPVR ratio were calculated. The stiffness of arterial system was considered the main component if MVE/TPVR ratio exceeded 1; if MVE/TPVR ≤1, TPVR was considered the leading component. Results. Patients with arterial hypertension had higher rates of stiffness of arterial system in comparison with control group by MVE and pulse pressure. In control group, 87.5% persons had prevalence of TPVR, and in 12.5% arterial stiffness prevailed. In 77.8% of patients with hypertensive heart disease prevalence of TPVR was found, and in 22.2% arterial stiffness prevailed. In patients with combination of rheumatoid arthritis and hypertension arterial stiffness prevailed, while patients with combination of hypothyroidism and hypertension had higher TPVR. Conclusion. All patients with combination of rheumatoid arthritis and hypertension had arterial stiffness prevailing over TPVR. In patients with hypothyroidism associated with arterial hypertension TPVR prevailed over arterial stiffness.

The creation of the universe, according to the Holy Bible has actually done as said in Genesis 1-2. However, there are some people who are still struggling in order to search for the reason to question the process of how is this universe actually began, so that they will look for scientific consideration to find the “theoretical justification” over the biblical truth. This writing aims to give an answer to the gap theory in Genesis 1:1-2. The author, through the study Genesis 1:1-2, the result of this study concluded as follows. First, there is no exegesis background that is strong enough for gap theory to give an assumption that there was an unmeasurably period of time or age in the creation of the universe. Second, a biblical statement, “In the beginning God created the heavens and the earth ... for in six days the LORD made heaven and the earth” (Gen. 1:1; Ex. 20:11) is an ultimate fact of God’s power and majesty in creating the earth from nothing to existence with His Word (creatio ex Nihilo). Third, the doctrine of world’s creation must be the foundation of faith that is tested in the authority of God’s words (2 Tim. 3:16) and the entire creation of God which become the medium of scientifical activity in the history of humanity must be according to the biblical perspective. Fourth, The statement of Genesis 1:1 appears to be refutation toward various scientific theories and human’s philosophic perspective that are opposite the biblical truth (Gen. 1-2, Ps. 33:4-9).Pernyataan Alkitab tentang penciptaan alam semesta sebenarnya sudah tuntas sebagaimana dikemukakan dalam Kejadian 1-2. Namun ada saja orang yang berusaha mencari alasan untuk mempertanyakan proses terjadinya alam semesta ini, sehingga mencoba mencari pertimbangan ilmiah untuk menemukan “pembenaran teoritis” atas kebenaran Alkitab. Tulisan ini bertujuan untuk memberi jawab terhadap teori celah (gap theory) dalam Kejadian 1:1-2, melalui studi biblika penulis mengemukakan argumentasi paham teori celah, dalam kajian metode induktif terhadap studi teks Kejadian 1:1-2. Hasil studi ini disimpulkan bahwa: Pertama, bahwa tidak ada dasar eksegesis yang kuat bagi teori celah untuk memberi ruang bagi asumsi adanya rentang waktu periode atau zaman yang tak terukur dalam proses penciptaan semesta. Kedua, pernyataan Alkitab, “Pada mulanya Allah menciptakan langit dan bumi ... dalam waktu enam hari lamanya” (Kej. 1:1, Kel. 20:11) adalah suatu fakta Alkitab yang tak terbantahkan sebagai tindakan kemahakuasaan dan keagungan Allah menciptakan dunia dari yang tidak ada menjadi ada dengan firman-Nya (creatio ex nihilo). Ketiga, doktrin penciptaan harus menjadi landasan iman Kristen yang diuji dalam otoritas Firman Allah yang berkuasa (2 Tim. 3:16) serta dunia ciptaan Allah dan segala isinya menjadi arena kegiatan ilmiah dalam lintasan sejarah manusia haruslah berdasarkan perspektif Alkitab. Keempat, pernyataan penciptaan Kejadian 1:1 merupakan sanggahan terhadap berbagai teori ilmu pengetahuan dan pandangan filsafat manusia yang bertentangan dengan kebenaran Alkitab (Kej. 1-2, Mzm. 33:4-9).

Objective: the study is to determine the effectiveness of EEG-biofeedback training on β-rhythm for correcting voluntary attention in children 6 – 8 years of age with the consequences of perinatal CNS lesions of hypoxic-ischemic genesis. Materials and methods: a total of 120 children aged 6 – 8 years who included 30 children with cerebrastenic syndrome (I group) were examined; 58 children with hyperactivity and attention deficit syndrome (II group); 32 children with cerebral palsy, spastic diplegia (III group). EEG-biofeedback training on β-rhythm correction was carried out in an amount of 15 sessions lasting 20 – 30 minutes on the Kinesis machine (Neurot, Russia). Before and after the biofeedback therapy, a psychodiagnostic evaluation of the functions of voluntary attention on the Toulouse-Pieron scale was carried out (in the adaptation of LA Yasyukova, 2001). EEG recording was performed on an EEG 21/26 encephalograph Encephalan-131-03, modification 10 (Manufacturer: NPKF Medikom MTD, Russia). For statistical analysis of the obtained indicators before and after treatment, the significance criterion was used to compare the two proportions (fractions) under the assumption that the variables are distributed according to the normal law (package STATISTICS 6.0). Results: the effectiveness of EEG-biofeedback training on β-rhythm correction was revealed, as evidenced by a significant decrease in the number of children with isolated types of attention disorders in all groups of patients as well as with mixed disorders in the II group. Conclusion: аctivation of cortical processes, increasing the level of attention, memory and cognitive abilities of the psyche, when EEG-biofeedback training is included in the therapy complex, depend on the nature and severity of central nervous system lesions in children with various nosological forms of neurological pathology, which requires rethinking of therapeutic complex methods of correction and selection of personalized biofeedback training protocols, taking into account data on various types of metabolic and neurophysiological abnormalities in the head in children with different nosological forms of neurological disorders.

Endogenous vitamin D deficiency (low serum 25(OH)D3) is a necessary but insufficient requirement for the genesis of vitamin D-deficiency rickets and osteomalacia. The magnitude of the independent contributions of dietary factors to rachitic and osteomalacic risk remains uncertain. We reanalysed two weighed dietary surveys of sixty-two cases of rickets and osteomalacia and 113 normal women and children. The independent associations of four dietary variables (vitamin D, Ca, fibre and meat intakes) and daylight outdoor exposure with rachitic and osteomalacic relative risk were estimated by multivariate logistic regression. Meat and fibre intakes showed significant negative and positive associations respectively with rachitic and osteomalacic relative risk (RR; zero meat intake: RR 29·8 (95 % CI 4·96, 181), P<0·001; fibre intake: RR 1·53 (95 % CI 1·01, 2·32), P+0·043). The negative association of meat intakes with rachitic and osteomalacic relative risk was curvilinear; relative risk did not fall further at meat intakes above 60 g daily. Daylight outdoor exposure showed a significant negative association with combined relative risk (RR 0·33 (95 % CI 0·17, 0·66), P<0·001). Operation of the meat and fibre risk factors was related to sex, age and dietary pattern (omnivore/lactovegetarian), mainly determined by religious affiliation. The mechanism by which meat reduces rachitic and osteomalacic risk is uncertain and appears independent of revised estimates of meat vitamin D content. The meat content of the omnivore Western diet may explain its high degree of protection against nutritional rickets and osteomalacia from infancy to old age in the presence of endogenous vitamin D deficiency.

Abstract Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with poor outcome. We and others have previously demonstrated in a limited number of pPCL patients that novel agents and mainly bortezomib-based regimens (BBR) improve response rates and survival; in addition, two recent prospective studies have confirmed the efficacy of lenalidomide-dexamethasone and BBR respectively, followed by autologous transplantation (ASCT) in pPCL; however, the prognostic impact of the induction therapy was not evaluated in both studies. Herein, we explored the clinical characteristics and the impact of current treatments and biological markers on the outcome of an extended cohort of primary PCL (pPCL) patients treated upfront with novel agents, outside clinical trials. We analyzed the medical records of 50 patients with pPCL (M/F: 25:25; median age 65.5 years, range: 32-86 years; IgG: 19, IgA: 9, light-chain only: 14, IgD: 2, non-secretory: 6; ISS1: 5, ISS2: 16, ISS3: 29) out of 2711 myeloma patients (1.8%), registered in the Greek Myeloma study group database, between 2000-2015. Eastern Cooperative Group (ECOG) performance status was ≥2 in 52% of patients; 77% of patients presented with lytic bone disease and 11% with bone or soft tissue palsmacytomas. Bence-Jones protein was present in 68% of patients; 53% of patients had abnormal lactate dehydrogenase (LDH); 28% had hypercalcemia and 68% had hemoglobin <10 g/dL; fluorescent in situ hybridization (FISH) or conventional karyotype were available in 32/50 (64%) patients; high risk features were present in 65% of patients; 60% of patients had CD56(-) peripheral blood plasma cells; 49/50 patients received therapy: Thirty-eight out of 49 (77.5%) patients received BBR, one patient was treated with the combination of melphalan, prednisone and thalidomide and 10 patients with conventional chemotherapy (C/T); 14/38 (37%) of patients treated with BBR and one patient treated with C/T underwent ASCT consolidation; one patient received in addition an allogeneic transplantation; 48/49 treated patients were evaluated for response: 38/48 patients (79%) achieved objective response (≥PR) and 35% displayed at least very good partial response (≥vgPR), including 17% complete responses (CR). Achievement of ≥vgPR significantly correlated with BBR followed by ASCT (p=0.02). Median time to response was 2 months (range 1-11). After a median follow up of 61 months (95% CI: 34.5-87.4), 38 (76%) patients have died (disease progression: 18, infection: 16, other causes: 4) and 12 patients remain alive. Early mortality (≤1 month) occurred in 3/38 (6%) deceased patients; 31/38 patients who responded in induction treatment progressed; 27/31 patients who progressed received 2nd line treatment (lenalidomide-based: 7, BBR: 16, C/T: 4). Progression-free survival was 12 months (95% CI: 8.5-15.4) and it was marginally longer in patients treated with BBR+ASCT vs. others (18 months vs. 10 months, p=0.07). Median OS was 17 months (95% CI: 13-21 months) and it was double in patients treated with BBR+ASCT compared to others (33 months vs. 16 months); median survival after PCL progression was only 7 months (95% CI: 3-11 months). In the univariate analysis, performance status, LDH, induction treatment with BBR, or treatment with BBR+ASCT and quality of response (≥vgPR vs. <vgPR) were independent prognostic factors for OS. In the multivariate analysis quality of response and LDH were the only significant predictors for OS (p<0.05). The median OS for patients who achieved ≥vgPR was 39 months (95% CI: 22-55) vs. 13 months (95% CI: 9-17) for those achieved <vgPR (p=0.02, HzR: 0.46). The median OS for patients with LDH ≥300 U/L was 11 months (95% CI: 7-15 months) vs. 24 months (95% CI: 8-40 months) for those with LDH <300U/L (p=0.03, HzR: 0.5). These real-world data, based on the largest reported national multicenter series of pPCL patients to-date, support that treatment with BBR plus ASCT is the best currently available option that offers deep and durable responses and reduces early mortality in this setting. Quality of response and high LDH were the strongest independent prognostic factors for OS. We conclude that pPCL requires an aggressive upfront therapeutic approach with a bortezomib-based regimen followed by ASCT that would lead to maximum response and eventually to prolonged OS. Disclosures Katodritou: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Terpos:Celgene: Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Delimpasi:Janssen: Honoraria; Genesis: Honoraria; Amgen: Honoraria. Kotsopoulou:Genesis: Honoraria. Kyrtsonis:Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Roche: Honoraria; Amgen: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Honoraria. Kastritis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Genesis: Consultancy, Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Renal disease in monoclonal gammopathies (MGs) is associated with several different pathologies with prognostic and treatment implications. In symptomatic MM, cast nephropathy is a leading cause of renal dysfunction and acute renal failure (ARF) but in patients with other MGs the diagnoses may be diverse and monoclonal gammopathy of renal significance (MGRS) is well described. Renal biopsy is required in such cases in order to establish the diagnosis, especially if selective Bence Jones proteinuria is absent. MGs are more frequent in the elderly, in which renal diseases are also common, associated with underlying co-morbidities (diabetes, hypertension etc). However, although common, there is limited data on the frequency of monoclonal immunoglobulin (MIg)-unrelated pathologies in patients with a known MG presenting with renal dysfunction. Thus, we evaluated the frequency of non-MIg related renal pathologies in patients with known MGs, in a series of consecutive patients from a single referral center (Department of Clinical Therapeutics, Athens , Greece). We reviewed our database and identified 79 patients with known MGs that had a renal biopsy for evaluation of renal dysfunction, and which was performed after the diagnosis of MG. We excluded patients in which renal biopsy was performed before the diagnosis of the MG. At the time of renal biopsy, median age was 69 years (range 39-84), 63% were males, 28% had diabetes, 72% hypertension, 22.5% CAD, 7% an autoimmune disease ; 45% had known symptomatic MM (N=36) and 55% a prior diagnosis of MGUS or SMM. Median eGFR was 33 ml/min/1.73 m2 (range 4-110), 15% required dialysis, median proteinuria was 3.1 gr/d and was >0.5 gr/d in 93%. Abnormal FLC ratio was present in 69.5%, median dFLC level was 85 mg/L and 62% had dFLC>50 mg/L. In urine protein electrophoresis (PEP), median albumin proportion was 40% (range 3-100%) and median urine monoclonal protein was 2% (range 0-97%) of the total urine protein. Reasons leading to renal biopsy included proteinuria (with <50% creatinine increase) in 61% and ARF (with or without proteinuria) in 39%. Renal pathology revealed a MIg-related diagnosis in 68%, which included cast nephropathy in 13%, MIDD in 25%, AL amyloidosis in 25% and other MGRS in 5%. A non MIg-related diagnosis was established in 32%, and included diabetic nephropathy in 5%, hypertension-associated in 14%, single cases of IgA nephropathy, chinese herb nephropathy, obesity-related GN and in 8% was drug related. Among MM patients, 26/36 were on therapy when renal biopsy was performed, 19/36 (53%) were in hematologic remission. Notably, in 11/19 (58%) of MM patients in remission, renal pathology was not related to MIg vs 6/17 (35%) of those not in remission or at the time of MM diagnosis. Factors that were associated with MIg-related pathology included serum albumin <3 gr/dl (88% vs 60%, p=0.007), proteinuria >1.7 gr/d (82% vs 48%, p=0.004), a positive UIFE (75% vs 33%, p=0.039), urine monoclonal protein >100 mg/d (68% vs 25%, p=0.003), dFLC > 50 mg/L (76% vs 37%, p=0.003) and abnormal FLC ratio (78% vs 53%, p=0.044). The presence of other co-morbidities (diabetes, hypertension, history of CAD, history of autoimmune disease) or the presence of hematuria or the reason leading to renal biopsy (proteinuria or ARF) were not associated with a diagnosis of non MIg-related renal pathology. In multivariate analysis, only urine monoclonal protein >100 mg/d (HR:7.95, 95% CI 1.3-47, p=0.024) was independently associated with a diagnosis of MIg-related pathology. If parameters of urine PEP (urine monoclonal protein, urine IFE) were not included in the analysis, then total proteinuria >1.7 gr/d (HR: 4.5, 95% CI 1.1-18, p=0.036) and dFLC>50 mg/L (HR:5.8, 95% CI 1.15-29, p=0.033) were the only independent predictors. By using these two parameters 7% of those without any vs 30% with any of the two vs 63% with both factors had a MIg related renal pathology. In conclusion, among patients with known monoclonal gammopathies and renal dysfunction, 32% had a non MIg-related diagnosis, which had implications in their management. Urine protein electrophoresis can help identify those at higher probability of MIg-related renal disease and should be evaluated in all patients with MGs; otherwise, dFLC > 50 mg/L and proteinuria >1.7 gr/d can be used. Renal dysfunction should not attributed to the underlying MIg without careful consideration of the other parameters and of a renal biopsy. Disclosures Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Gavriatopoulou:Genesis: Honoraria, Other: Travel expenses; Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses. Terpos:Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Janssen: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.

Abstract Background: The initial therapies for multiple myeloma have changed significantly in the recent years with routine incorporation of combinations containing IMiDs and proteasome inhibitors. However, patients with MM invariably relapse after their initial treatment and undergo successive therapies for continued control of their disease. The increasing access to new therapies for treatment of relapsed disease has led to improved survival of patients with MM. Many recent phase 3 trials have studied the impact of new agents on outcome of patients with MM who are relapsing after the initial lines of therapy for relapsed disease. However, the natural history of relapsed myeloma earlier in the course of relapsed disease has not been studied in detail. Patients and methods: We designed a global, multicenter, retrospective study to examine the current treatment approaches for initial relapses in MM and patient outcomes following application of successive treatment regimens. Patients with multiple myeloma who experience a first relapse between January 1, 2007 and December 31, 2011 were identified at participating sites. Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses up to and including the third relapse will be obtained from the clinical records. The first date of treatment with an anti-myeloma regimen for first disease relapse was termed time zero (T0). Results: Three hundred and fifteen patients were enrolled; median age at diagnosis was 59 years (range: 35 - 86), 59% were male. Patients were enrolled from North America (33%), Europe (35%) or Asia (32%). The patients were diagnosed between 1997 and 2011 and the median time to T0 from diagnosis was 23.9 months (range: 0.8 - 131.9 months). An IMiD (thalidomide or lenalidomide), bortezomib or alkylator (melphalan or cyclophosphamide) was part of the initial therapy in 63%, 36% and 51% of patients, respectively; 93 (33%) patients had stem cell transplantation as part of initial treatment. The median follow up from the study entry was 56 months; 117 were alive at the time of data extraction. A second line, third line and fourth line of treatment were recorded in 307, 163 and 84 patients respectively. An IMiD (thalidomide, lenalidomide, or pomalidomide), proteasome inhibitor (bortezomib or carfilzomib) or alkylator (melphalan or cyclophosphamide) was part of the therapy for first relapse in 50%, 59% and 33% of patients, respectively. The responses to the regimens after T0, the TTNT, PFS and OS to each line of therapy are provided in the Table. Conclusion: The current study provides an assessment of the current treatment approaches used for initial treatment of MM and the salvage treatment options utilized. The study again demonstrates the progressively shorter duration of disease control with each successive treatment regimen, reflecting ongoing development of drug resistance. The overall survival of over 3 years from the time of therapy for first relapse highlights the impact of the newer therapies that have been introduced for this disease. Table. Treatment outcomes after initial relapse Endpoint 2nd line therapyN=307 3rd line therapyN=163 4th line therapyN=84 Partial response or better Median in Months (95% Confidence Interval) Overall Survival 36.1 (30.2, 42.4) 18.4 (14.5, 26.8) 12.6 (10.4, 19.0) Progression-Free Survival 13.4 (11.8, 15.8) 8.3 (6.5, 11.2) 6.4 (5.0, 8.1) Time to Next Treatment 15 (12,17) 9.8 (7.4, 12.0) 6.6 (5.8, 8.7) Figure 1. Figure 1. Disclosures Kumar: Onyx: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dimopoulos:Novartis: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Leleu:Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; TEVA: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pierre Fabre: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy.

Achenbach, R 2005. Pentateuch, Hexateuch und Enneateuch. Eine Verhältnisbestimmung, ZAR 11:122–154. Albertz, R 2007. Die kanonische Anpassung des Johuabuches. Ein Neubewertung seiner sog.”Priesterschriftelike Texte”, in Römer and Schmid 2007:199–217. Aurelius, E 2003. Zukunft jenseits des Gerichts: Eine redaktionsgeschichltliche Studie zumEnneateuch. BZAW 319. Berlin: de Gruyter. Barrick, W B & Spencer, J R (eds) 1984. In the shelter of Elyon: essays on ancient Palestinian life in honour of GW Ahlström. JSOTSup 31. Sheffield: JSOT Press. Becker U, 2006. Endredaktionelle Kontextvernetzungen des Josua-Buches, in Witte, Schmid, Prechel and Gertz 2006:139–161. Bieberstein, K 1995. Josua-Jordan-Jericho. Archäologie, Geschichte und Theologie der Landnahmeerzählungen Josua 1–6. OBO. Friborg: Universitätsverlag, Göttingen: Vandenhoeck & Ruprecht. Blum, E 1990. Studien zur Komposition des Pentateuch. BZAW 189. Berlin/New York: de Gruyter. _______ 1997. Die Kompositionelle Knoten am Übergang von Josua zu Richter: Ein Entflechtungsvorschlag, in Lust and Vervenne 1997:181–212. _______ 2006. The literary connection between the books of Genesis and Exodus and the end of the book of Joshua, in Dozeman and Schmid 2006:80–106. _______ 2011. Pentateuch-Hexateuch-Enneateuch, in Dozeman , Römer and Schmid 2011:43–71. Carr, D M 1996. Reading the fractures of Genesis. Historical and literary approaches. Louisville: Westminster John Knox. _______ 2006. What is required to identify pre-Priestly narrative connections between Genesis and Exodus? in Dozeman and Schmid 2006:159–180. _______ 2012. The Moses story: literary and historical reflections, HeBAI 1–2:7–36. Dozeman, T B & Schmid, K (eds) 2006. Farewell to the Yahwist? The composition of the Pentateuch in recent European discussion. SBL Symposium Series 34. Atlanta: SBL. Dozeman, T B, Römer, T C & Schmid, K (eds) 2011. Pentateuch, Hexateuch, or Enneateuch. Identifying literary works in Genesis through Kings. SBL 8. Atlanta: SBL. Du Pury, A, Römer, T C & Macchi, J P (eds) 2000. Israel constructs its history. Deuteronomistic historiography in recent research. Sheffield: Sheffield Academic Press. Edenburg, C & Pakkala, J (eds) 2013. Is Samuel amongst the Deuteronomists? Current views on the place of Samuel in a Deuteronomistic History. Atlanta: SBL. Eisffeldt, O 1964. Einleitung in das Alte Testament. Tübingen: Mohr. Frevel, C 2000. Mit Blick auf das Land die Schöpfung erinnern. Zum Ende der Priestergrundschrift. HBS 23. Freiburg/New York: Herder. _______ 2011. Die Wiederkehr der Hexateuchperspektive. Eine Herausforderung für die These vom Deuteronomistischen Geschictswerk, in Stipp 2011:13–53. Frey, J, Schattner-Rieser, U & Schmid, K (eds) 2012. Die Sameritaner und die Bibel: Historische und literarische Wechselwirkungen zwischen biblischen und Sameritanischen Traditionen. Studia Judaica/Studia Samaritana 7. Berlin/New York. Fritz, V 1994. Das Buch Josua. Hat 1/7. Tübingen: Mohr Siebeck. Garciá-Martinez, F (ed.) 1998. Perspectives in the study of the Old Testament and early Judaism: a symposium in honour of Adam S. van der Woude on the occasion of his 70th Birthday. VTSup 73. Leiden: Brill. Gertz, J C 2000. Tradition und Redaktion in der Exoduserzählung. Untersuchungen zur Endredaktion des Pentateuch. FRLANT 186. Göttingen: Vandenhoeck& Ruprecht. Görg, M 1991. Josua. NEB 26. Würzburg: Echter Verlag. Gunkel, H 1910. Genesis. 3rd ed. GHK 1. Göttingen: Vandenhoeck & Ruprecht. Hjelm, I 2000. The Samaritans and early Judaism: a literary analysis. JSOTSup 303. Sheffield: Sheffield Academic Press. Keel, O 1973. Das Vergaben der “Fremder” Götter in Genesis xxxv 4b, VT 23:305–336. Knauf, E A 2000. Does Deuteronomsitic Historiography (DH) exist? in du Pury , Römer and Macchi 2000:388–398. _______ 2007. Buchschlüsse im Josuabuch, in Römer and Schmid 2007:217–224. _______ 2008. Josua. ZBKAT 6. Zurich: Theologisher Verlag. Knoppers, G N & McConville, J G (eds) 2000. Reconsidering Israel and Judah: recent studies on the Deuteronomistic History. SBTS 8. Winona Lake: Eisenbrauns. Köckert, M 1988. Vätergott und Väterverheisssungen. Eine Auseinandersetzung mit Albrecht Alt und seine Erben. FRLANT 142. Göttingen: Vandenhoeck & Ruprecht. Konkel, M 2008. Sünde und Vergebung:Eine Rekontruktion der Redaktionsgeschichte der hinterein Sinaiperikope (Ex 32–34). Vor dem Hintergrund aktueller Pentateuchmodelle. FAT 88. Tübingen: Mohr. Koopmans, W T 1990. Joshua 24 as poetic narrative. JSOTSup 93. Sheffield: JSOT Press. Kratz, R G 2000. Die Komposition der erzählender Bücher des Alten Testaments: Grundwissen der Bibelkritik. UTB 215.Göttingen: Vandenhoeck & Ruprecht. Levin, C 1993. Der Jahwist. FRLANT 157.Göttingen: Vandenhoeck& Ruprecht. Lipschits, O, Knoppers, G N & Albertz, R (eds) 2007. Judah and the Judeans in the fourth century B.C.E. Winona Lake: Eisenbrauns. Lust, J & Vervenne, M (eds) 1997. Deuteronomy and Deuteronomistic literature. BETL 133. Leuven: Peeters. Mckenzie, S L & Römer, T C (eds) 2000. Rethinking the foundations: historiography in the ancient world and the Bible. Essays in honour of John Van Seters. Berlin/New York: de Gruyter. Nelson, R D 1997. Joshua: a commentary. Louisville: Westminster John Knox. Nentel, J 2000. Trägerschaft und Intentionen des deuteronomistischen Geschichtswerks: Untersuchungen zu Refelexionreden: Jos1; 23; 24; 1 Sam12 und 1 Kön 8. BZAW 297. Berlin: de Gruyter. Nihan, C 2012. The literary relationship between Deuteronomy and Joshua: a reassessment, in Schmid and Person 2012:79–114. _______ 2013. 1 Sam 8 and 12 and the Deuteronomsitic edition of Samuel, in Edenburg and Pakkala 2013: 225–274. Na`man, N 2000. The law of the altar in Deuteronomy and the cultic site near Shechem, in Mckenzie and Römer 2000:141–161. Noll, K L and Schramm, B (eds) 2010. Raising a faithful exegete: essays in honour of Richard Nelson. Winona Lake: Eisenbrauns. Noort, E 1997. The traditions of Ebal and Gerizim: theological positions in the book of Joshua, in Vervenne and Lust 1997:161–180. _______ 1998. Zu Stand und Perspektiven: Der Glaube Israels zwischen Religionsgeschichte und Theologie, der Fall Josua 24, in Garciá-Martinez 1998:82–108. Noth, M 1943. Überlieferungsgeschichtliche Studien. Tübingen: Niemeyer. _______ 1953. Das Buch Josua. 2nd ed. HAT 7. Tübingen: Mohr Siebeck. O’Brien, M A 1989. The Deuteronomistic History hypothesis: a reassessment. OBO 92. Fribourg: Éditions. Universitaires/Göttingen: Vandenhoeck& Ruprecht. Otto, E 1999. Bruckensläge in der Pentateuchsforschung, TRU 64:84–99. _______ 2000. Das Deuteronomium im Pentateuch und Hexateuch. Studien zur Literaturgeschichte von Pentateuch und Hexateuch im Lichte des Deuteronomiumrahmens. FAT 30. Tübingen: Mohr Siebeck. Otto, E & Achenbach, R (eds) 2004. Das Deuteronomium zwischen Pentateuch undDeuteronomistischem Geschictswerk. FRLANT 206. Göttingen: Vandenhoeck & Ruprecht. Perlitt, L 1968. Bundestheologie im Altes Testament. Neukirchen-Vluyn: Neukirchener Verlag. _______ 1994. Priesterschrift in Deuteronomium34? VT 59:475–494. Popovich, M 2009. Conquest of the land, loss of the land. Where does Joshua 24 belong?, in von Ruiten and de Vos 2009:87–98. Rofé, A 2000. Ephraimite versus Deuteronomistic History, in Knoppers & McConville 2000:462–474. Römer, T C 2010. Book-endings in Joshua and the question of the so-called Deuteronomistic History, in Noll and Schramm 2010:85–99. Römer, T C & Brettler, M Z 2000. Deuteronomy 34 and the case for a Persian Hexateuch, JBL 119/3:401–419. Römer, T C and Schmid, K (eds) 2007. Les dernières rédactions du Pentatueque, de l` Hexateuge,et de l` Henneatuege. BETL 203. Leuven: Peeters. Rösel, H N 1980. Die Überleitungen vom Josua-ins Richterbuch, VT 30:342–350. Schmid K, 1999. Erzväter und Exodus: Untersuchungen zur doppelten Begründing der Ursprünge Israels innerhalb der Geschichtsbücher des Alten Testaments. WMANT 81. Neukirchen-Vluyn: Neukirchener Verlag. _______ 2007. The late Persian formation of the Torah: observations on Deuteronomy 34, in Lipschits, Knoppers & Albertz 2007:236–245. _______ 2012. Die Sameritaner und die Judaër. Die biblische Diskussion um ihr Verhältnis in Josua 24, in Frey, Schattner-Rieser & Schmid 2012:21–49. Schmid, K & Person, R (eds) 2012. Deuteronomy in the Pentateuch, Hexateuch, and the Deuteronomistic History. Tübingen: Mohr Siebeck. Schmidt, L 2009. P in Deuteronomium 34, VT 59:475–494. Schmitt, G 1964. Der Landtag von Sichem. Stuttgart: Calwer Verlag. Schmitt, H C 2004. DTN 34 als Verbindingstuck zwischen Tetrateuch und Dtr. Geschictswerk, in Otto and Achenbach 2004:181–192. Smend, R 1970. Das Gesetz un die Völker, in Wolff 1970:494–504. Sperling, S D 1987. Joshua 24 re-examined. HUCA 58:119–136. Steuernage, l C 1923. Das Buch Josua. GHK 1,3 (2). Göttingen: Vandenhoeck & Ruprecht. Stipp, H J (ed.) 2011. Das deuteronomistische Geschichtswerk. ÖBS 39. Frankfurt am Main: Peter Lang. Van Seters, J 1984. Joshua 24 and the problem of tradition in the Old Testament, in Barrick and Spencer 1984:139–158. _______ 2003. Deuteronomy between Pentateuch and Deuteronomistic History, HTS 59/3:947–956. Vervenne, M & Lust, J (eds) 1997. Deuteronomy and Deuteronomistic literature. FS C.H.W Brekelmans. BETL 133. Leuven: Peeters. Von Ruiten, J and de Vos, C (eds) 2009. The land of Israel in Bible, history and theology: studies in honour of Ed Noort. VTSup 124. Leiden: Brill. Weimar, P 2008. Studien zur Priesterschrift. FAT 56. Tübingen: Mohr Siebeck. Westermann, C 1994. Die Geschictsbücher des Alten Testaments: Gab es ein deuteronomsitisches Geschichtswerk? TB Altes Testament 87. Gütersloh: Gütersloher Verlag. Witte, M 1998. Die biblische urgeschichte. Redaktions-und Theologiegeschichtliche Beobachtungen zu Genesis 1,1–11:26. BZAW 265. Berlin: de Gruyter. Witte M, Schmid K, Prechel, D & Gertz, J C (eds) 2006. Die deuteronomistischenGeschichtswerke: Redaktions- und religionsgeschichtliche Perspektiven zur “Deuteronomismus”-Diskussion in Tora und vorderen Propheten. BZAW 365. Berlin: de Gruyter. Wolff, H W (ed.) 1970. Probleme biblischer Theologie: Gerard von Rad zum 70. Geburtstag. Munich: Kaiser Verlag. Würthwein, E 1994a. Erwägungen zum sog. Deuteronomistischen Geschichtswerk: eine Skizze, in Würthwein 1994b:1–11. Würthwein, E 1994b. Studien zum deuteronomistischen Geschichtswerk BZAW227. Berlin: de Gruyter, Zakovitch, Y 1980. The object of the narrative of the burial of the foreign gods at Shechem, BeTM 25:300–337. Zenger, E 2004. Einleitung in das Alte Testament. 5th ed. Stuttgart: Kohlhammer.

Introduction: Skeletal-related events (SREs) that include pathological fractures, spinal cord compression (SCC) and need for radiotherapy or surgery to the bone are frequent complications of multiple myeloma (MM). Although the incidence of SREs at diagnosis is well-documented, there is limited information for the natural history of SREs during treatment with novel agents. Thus, we evaluated the SRE rate in MM patients who received frontline and second line therapy with proteasome inhibitors (PIs) or immunomodulatory drug (IMiD)-based therapies and explored possible correlations with disease or genetic features and type of treatment. Methods: MM patients who received frontline therapy in our center (Department of Clinical Therapeutics, University of Athens, Greece), between 2007-2017, were included in this analysis. Patients had a whole-body skeletal survey using either conventional radiography (WBXR) or low-dose CT (WBLDCT) at diagnosis and then at the time of relapse or whenever clinically indicated. Magnetic Resonance Imaging (MRI) of the spine and pelvis at diagnosis was recorded when available. SNPs in genes that are involved in bone destruction in osteoporosis were also evaluated: LRP5 (rs4988321), GC vitamin D (rs4588), TNFRSF11A (rs3018362), DKK1 (rs1569198), RANKL (rs9594759), OPG (rs6469804) and ERS1 (rs1038304). Results: In total, 620 consecutive patients with symptomatic MM (316M/304F, median age: 65 years) were studied. The median follow-up was 54 months. At diagnosis, osteolytic disease was present in 408 (66%) patients. MRI was available in 390 patients: 149 (38%) patients had focal, 139 (36%) diffuse, 81 (21%) normal and 21 (5%) variegated pattern of marrow involvement. SREs were observed in 271 (44%) patients at diagnosis: 213 (34%) presented with pathological fractures (183 with vertebral fractures, 18 with rib fractures and 15 with long bone fractures; 32 patients had both vertebral and long bone or rib fractures), while 34 (5.5%) patients needed surgery to bone, 45 (7.2%) radiotherapy and 31 (5%) patients presented with SCC. The incidence of SREs was higher in patients with osteolytic lesions (76.4% vs. 12.4%, p<0.0001) or abnormal MRI pattern (49% vs. 11.3%, p<0.0001) at diagnosis. No correlation was found between the presence of SREs at diagnosis and a specific SNP of those studied. Frontline therapy with IMiD-based regimens was given in 38% of patients; 27% patients received bortezomib-based regimens and 28% both IMiD and bortezomib-based therapies (VTD or VRD); 7% received only conventional chemo. Bisphosphonates (BPs) were given to 465 patients (75%) at diagnosis; the vast majority (91%) received zoledronic acid. The remaining 155 patients did not receive upfront BPs, mainly due to renal insufficiency. During first line treatment, 39 (6.3%) patients developed a SRE: 25/341 (7.3%) on bortezomib- (including combos with an IMiD) and 14/235 (6%) on IMiD-based regimens. At the time of first relapse, 4.5% of patients presented with new fractures and 12% required local radiotherapy to bone (SRE rate: 16.5%). The rate of SREs at first progression was much higher in patients who did not receive upfront BPs (92.3% vs. 7.7%). There was no difference in the incidence of SREs at first relapse between patients who received PI- vs. non-PI-based regimens as first line therapy (54.2% vs. 45.8%, p=0.544). During second line therapy, 12.2% of patients developed a SRE, with no difference regarding the second line therapy (PI- or IMiD-based regimens). In total, 126 (20.3%) patients developed at least one SRE, during the course of the first and second line of therapy; this was more common in those who presented with an SRE at diagnosis (33% vs 12%; p<0.03). Conclusions: Our data, which constitutes one of the few systematic reports on the incidence and characteristics of SREs in the era of novel agents, indicate that SREs remain a significant complication in MM. Despite high response rates after first line therapy and the broad use of BPs, more than 20% of patients develop a new SRE during the first and second line treatment or at the time of first relapse. Importantly, patients who do not receive BPs due to renal impairment develop very frequently SREs, suggesting an unmet need in this setting. More effective frontline therapies or more potent bone-targeted agents (denosumab or anti-sclerostin drugs) may manage to further reduce the SREs rate in MM patients, especially in those who cannot receive BPs. Disclosures Terpos: Celgene: Honoraria; Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria. Kastritis:Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria. Gavriatopoulou:Amgen: Honoraria; Takeda: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Dimopoulos:Sanofi Oncology: Research Funding.

Abstract Renal failure (RF) is a common severe complication of symptomatic myeloma and may be severe enough to require extrarenal dialysis in approximately 1-5% of newly diagnosed patients. Severe RF is associated with high risk of early death and increased morbidity. Immediate effective anti-myeloma therapy and vigorous supportive care are the cornerstones of management. The use of high cutoff hemodialysis to rapidly reduce the load of nephrotoxic light chains seems to offer limited additional benefit in patients requiring dialysis when treated with bortezomib-based therapies (Cook M et al EHA 2016, Abs P270). However, outside clinical trials, there are limited data focusing on the management and outcomes of NDMM patients requiring dialysis. Thus, we analyzed the outcomes of consecutive newly diagnosed patients with RF requiring dialysis, who were managed and treated in a single center. Between 1995 and 2016, 50 patients (6.2% of 796 consecutive NDMM) who were treated in the Department of Clinical Therapeutics (Athens, Greece) presented with severe RF requiring dialysis. The analysis included all patients who received at least one dose of any therapy. All patients received similar supportive care and dialysis with regular filters. The median age of patients requiring dialysis was 69 years (37-88), 68% were >65 years of age. At presentation 92% had Hb <10 g/dl, 5 (10%) had platelet count <100x109/l, 12 (24%) had hypeprcalcemia (Ca ≥11.5 mg/dl) and 24 (48%) had elevated LDH (≥250 IU/l). All patients had elevated β2-microglobulin (median 21.7 mg/L, range 6-60 mg/l) and all were ISS stage 3. High risk cytogenetics (N=40) were present in 38% and per R-ISS, 75% were R-ISS-3 and 25% R-ISS-2. Myeloma was light chain only in 42%, IgA in 26%, IgG in 30% and IgD in 1 patient (2%); light chain was κ in 38 (64%) and λ in 18 (36%). Among patients who retained urine flow at presentation, median 24h Bence Jones proteinuria was 2.2 gr (range 0.1-8.8 gr). Among patients with available FLCs, median level of involved free light chain (iFLC) was 9080 mg/l (range 119-201000 mg/l). Treatment was bortezomib-based in 41 (82%) patients: 11 (22%) had bortezomib + dexamethasone (VD), 21 (42%) VD + cyclophosphamide (VCD), 8 (16%) VD + thalidomide (VTD), 1 (2%) VD + doxorubicin (PAD). Nine (18%) patients received non-bortezomib containing regimens: 5 (10%) thalidomide plus high dose dexamethasone and 4 (8%) VAD with high dose dexamethasone. Twenty-five (50%) patients became dialysis independent at a median time of 158 days from start of therapy (range 4-336 days). Age ≤65 years was associated with higher probability (75% vs 38%) and shorter time to dialysis independence (51 vs 336 days; p=0.027); no other baseline factors were associated with dialysis independence in univariate analysis. Among patients treated with bortezomib, three-drug combinations (n=30) vs VD alone (N=11) were associated with higher probability of dialysis independence (57% vs 27%; p=0.06). Among patients who became dialysis independent 12 received VCD, 4 VTD, one PAD, 3 VD, 2 MDT, 2 VAD and one T-VAD. Median follow up for all patients was 33 months and median survival was 29 months. Early mortality (within 2 months from start of therapy) was 16%, mostly due to infectious complications. On intent to treat, 64% achieved ≥PR (CR: 6%, VGPR: 32%, PR: 26%); among patients who survived >2 months, ≥PR was achieved by 76%. At 2-month landmark, patients who achieved ≥PR within the first 2 months had higher dialysis independence rates (68% vs 27%, p=0.004). Becoming dialysis independent was associated with a significant improvement in survival (median OS of 63 vs 22 months of patients who remained on dialysis; p=0.002), even after exclusion of early deaths. Notably, the survival of patients who discontinued dialysis was similar to that of the rest of patients (57 months). High dose melphalan (HDM) followed by autologous stem cell transplantation was performed in five patients while on dialysis. Four of them (80%) become dialysis independent approximately one month after HDM. In conclusion, about 6% of NDMM present with renal failure requiring dialysis but half of them can become dialysis independent after bortezomib-based therapy, without the use of special filters, especially if they achieve a rapid myeloma response. VD-based triplets increase the probability of renal response over VD alone and independence from dialysis is associated with a significant improvement in prognosis. Disclosures Dimopoulos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:Celgene: Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Abstract Expression of CD25 on blasts of AML patients has been shown to hold independent prognostic value for both survival and response to induction therapy. Patients with MDS-related AML have generally higher CD25 expression from de novo AML patients, but though there is paucity of a serviceable biomarker of outcome in MDS patients treated with azacytidine, the prognostic value of CD25 has not yet been investigated. Bone marrow samples of 61 patients with intermediate-2/high risk IPSS, high/very high WPSS and low blast count AML were obtained before and 15 days (D15) after the initiation of treatment. All patients received azacytidine in a non clinical trial setting at an initial dose of 75mg/m2 SC for 7 days on 28-day cycles. CD25 expression was assessed by 4-color flow cytometry on total CD34+ blasts, committed progenitors (Lin-CD38+CD34+) and leukemic stem cells (LSC, Lin-CD38-CD34+). Positivity was defined as a CD25 expression of ≥ 20%. Statistical comparisons were done by ÷2, one-way ANOVA and paired or unpaired t-test as appropriate, and survival with Kaplan-Meier analysis and log-rank test. Overall survival (OS) was defined as the time from azacytidine initiation to death from any cause and event-free survival (EFS) as the time from diagnosis to disease progression, relapse or death. Multivariate survival analysis was based on Cox’s proportional hazards model using a backward stepwise selection procedure with entry and removal criteria of p=0.05 and p=0.10, respectively. As shown in table 1 the cohorts of CD25- and CD25+ patients were well balanced for most known predictive factors and characteristics, except sex. Compared to CD25+ patients the CD25- ones have significantly longer OS (16.2 vs 8.8 months, respectively, p=0.04) and EFS (12.8 vs 6.66 months, p=0.04) in univariate analysis. Multivariate analysis confirmed the independent predictive power of CD25 for OS and EFS (p=0.006 and p=0.009, respectively), whereas heavy transfusion requirements (p=0.003 and p=0.002) and age>75 (p=0.02 and p=0.02) were also independent predictors. The average expression of CD25 in CD34+ blasts of all patients was 21.6%±24%. Compared to committed progenitors, LSCs displayed higher expression (19.4%±23.7% vs 24.1%±28.2%, respectively, p=0.027). Interestingly, on D15 CD25 was downregulated in LSCs (p=0.03) but remained stable in committed progenitors (p=0.8, n=18), indicating a particular sensitivity of the CD25+ subset of LSCs in azacytidine.Table 1Patient characteristics. N/A: not applicable/not available.CD25- (n=36)CD25+ (n=25)p-valueAge72,5 (53,4-83.5)72,9 (52-81.7)0.2 >6531(86%)17(68%) <655(14%)8(32%)Sex0.027 Male20(55%)21(84%) Female16(45%)4(16%)WHO classification0.28 RCMD2(5%)0(0%) RAEB-I0(0%)1(4%) RAEB-II17(47%)13(52%) CMML-II6(16%)7(28%) Low blast count - sAML11(30%)4(16%)Baseline blood counts Hemoglobin (g/dl)8,6(6.1-10.6)8,8(6.8-11.5)0.78 ANC(x 109/L)1,1(0.04-13.4)2,8(0.08-23)0.07 Platelets (x 109/L)66(9-383)50(11-181)0.42IPSS0.6 Intermediate-217(47%)9(36%) High8 (22%)6(24%) N/A11(31%)10(40%)WPSS0.22 High15(42%)8(32%) Very high6(16%)7(28%) N/A15(42%)10(40%)IPSS-R0.8 Intermediate3(8%)1(4%) High14(39%)8(32%) Very high17(48%)12(48%) N/A2(5%)6(24%)IPSS-R Cytogenetic risk0.72 Good18(50%)10(40%) Intermediate8(22%)6(24%) Poor5(14%)6(24%) Very poor4(11%)2(8%) N/A1(3%)1(4%)PB blasts0.5 Present19(53%)13(52%) Absent14(39%)11(44%) N/A3(8%)1(4%)BM blasts0.2 >15%18(50%)9(36%) ≤15%18(50%)16(54%)Transfusions ≥ 4 per month0.48 Yes23(4%)17(4%) No13(4%)8(4%)Response0.4 CR & PR12(33%)4(16%) Hematologic improvement5(14%)4(16%) Stable disease8(22%)5(20%) Failure11(31%)12(48%)Figure 1(A) OS and EFS according to CD25 positivity status. (B) OS and EFS according to transfusion requirements.Figure 1. (A) OS and EFS according to CD25 positivity status. (B) OS and EFS according to transfusion requirements. Collectively, our findings reveal an independent prognostic role for CD25 in MDS patients treated with azacytidine. In addition, the differential expression and epigenetic modulation of CD25 in the LSC compartment support the investigation of therapeutic strategies using monoclonal antibody targeting combined with epigenetic agents. Disclosures: Kotsianidis: Genesis Hellas: Honoraria, Research Funding. Spanoudakis:Genesis Hellas: Honoraria. Tsatalas:Genesis Hellas: Honoraria.

Background:There is a lack of real-life evidence on secukinumab effectiveness in psoriatic arthritis (PsA) patients.Objectives:To assess the real-life 6- and 12-month secukinumab retention rates and proportions of patients in remission/low disease activity (LDA) overall, and by prior biologic disease-modifying anti-rheumatic drug (bDMARD)/targeted synthetic (ts)DMARD use.Methods:Data from PsA patients treated with secukinumab in routine care from 13 countries in the European Spondyloarthritis (EuroSpA) Research Collaboration Network were pooled. Patients started secukinumab ≥12 months before date of datacut. Crude and LUNDEX adjusted (crude value adjusted for drug retention) 28-joint Disease Activity index for PSoriatic Arthritis (DAPSA28) and 28-joint Disease Activity Score with CRP (DAS28CRP) remission and LDA rates were calculated. Group comparisons between b/tsDMARD naïve, 1 prior and ≥2 prior b/tsDMARD users were done with ANOVA, Kruskal-Wallis, Chi-square or Kaplan-Meier analyses with log-rank test, as appropriate.Results:A total of 1543 PsA patients were included (Table 1). b/tsDMARD naïve patients had shorter time since diagnosis, higher baseline disease activity, a higher proportion were men and a higher proportion achieved remission. Overall 6/12-month secukinumab retention rates were 86%/74% and significantly higher in b/tsDMARD naïve patients at 12, but not 6 months (Table 2, Figure). Overall, crude 6- and 12-month DAPSA28≤4/DAS28CRP<2.6 were achieved by 13%/34% and 11%/39% of the patients, respectively.Table 1.All patients (n=1543)b/tsDMARD naïve (n=287)1 prior b/tsDMARD (n=333)≥2 prior b/tsDMARDs (n=923)p *Age (years), mean (SD)52 (11)49 (12.3)51 (11)53 (11)<0.001Male, %42%49%46%39%0.003Years since diagnosis, mean (SD)9 (8)7 (8)8 (7)10 (8)<0.001Current smokers, %19%21%22%18%0.23CRP (mg/L), median (IQR)5 (2-12)7 (2-19)4 (2-8)5 (2-11)<0.001DAPSA28, median (IQR)26 (18-37)28 (19-38)22 (13-32)27 (19-38)<0.001DAS28CRP, median (IQR)4.2 (3.3-5.0)4.4 (3.5-5.2)3.8 (2.6-4.5)4.2 (3.4-5.0)<0.001*Comparisons across number of prior b/tsDMARD were done with ANOVA, Kruskal-Wallis or Chi-square test, as appropriateTable 2.MonthsAll patients (n=1543)b/tsDMARD naïve (n=287)1 prior b/tsDMARD (n=333)≥2 prior b/tsDMARDs (n=923)p *Secukinumab retention rate, % (95%CI)686% (84-87%)89% (86-93%)85% (81-89%)85% (82-87%)0.111274% (72-76%)81% (76-86%)76% (71-80%)72% (69-75%)0.006DAPSA28≤4 Crude613%25%11%11%<0.001 LUNDEX11%22%9%9%<0.001 Crude1211%22%11%8%<0.001 LUNDEX7%17%7%5%0.001DAS28CRP<2.6 Crude634%51%33%30%<0.001 LUNDEX29%45%27%24%<0.001 Crude1239%55%41%34%<0.001 LUNDEX26%41%27%21%<0.001DAPSA28 >4 and ≤14 Crude633%42%32%30%0.04 LUNDEX27%37%27%25%0.02 Crude1235%48%36%32%0.009 LUNDEX24%36%24%20%0.004DAS28CRP ≤3.2 Crude652%69%53%47%<0.001 LUNDEX43%61%45%38%<0.001 Crude1255%72%55%50%<0.001 LUNDEX37%54%37%32%<0.001*Comparisons across number of prior b/tsDMARDs were done with Kaplan-Meier with log-rank test or Chi-Square test, as appropriateConclusion:In this real-life study of 1543 patients with PsA in 13 European countries 12-month secukinumab retention was high, and significantly higher for b/tsDMARD naïve patients. Overall, a higher proportion of bionaïve than previous b/tsDMARD users achieved remission, regardless of remission criteria.Acknowledgments:Novartis and IQVIA for supporting the EuroSpA RCNDisclosure of Interests:Brigitte Michelsen Grant/research support from: Research support from Novartis, Consultant of: Consulting fees Novartis, Stylianos Georgiadis Grant/research support from: Novartis, Daniela Di Giuseppe: None declared, Anne Gitte Loft Grant/research support from: Novartis, Consultant of: AbbVie, MSD, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, MSD, Novartis, Pfizer and UCB, Michael Nissen Grant/research support from: Abbvie, Consultant of: Novartis, Lilly, Abbvie, Celgene and Pfizer, Speakers bureau: Novartis, Lilly, Abbvie, Celgene and Pfizer, Florenzo Iannone Consultant of: Speaker and consulting fees from AbbVie, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, MSD, Speakers bureau: Speaker and consulting fees from AbbVie, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, MSD, Manuel Pombo-Suarez Consultant of: Janssen, Lilly, MSD and Sanofi., Speakers bureau: Janssen, Lilly, MSD and Sanofi., Heřman Mann: None declared, Ziga Rotar Consultant of: Speaker and consulting fees from Abbvie, Amgen, Biogen, Eli Lilly, Medis, MSD, Novartis, Pfizer, Roche, Sanofi., Speakers bureau: Speaker and consulting fees from Abbvie, Amgen, Biogen, Eli Lilly, Medis, MSD, Novartis, Pfizer, Roche, Sanofi., Kari Eklund Consultant of: Celgene, Lilly, Speakers bureau: Pfizer, Roche, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Maria Jose Santos Speakers bureau: Novartis and Pfizer, Björn Gudbjornsson Speakers bureau: Novartis and Amgen, Catalin Codreanu Consultant of: Speaker and consulting fees from AbbVie, Accord Healthcare, Alfasigma, Egis, Eli Lilly, Ewopharma, Genesis, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB, Speakers bureau: Speaker and consulting fees from AbbVie, Accord Healthcare, Alfasigma, Egis, Eli Lilly, Ewopharma, Genesis, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB, Sema Yilmaz: None declared, Johan K Wallman Consultant of: AbbVie, Celgene, Eli Lilly, Novartis and UCB Pharma, Cecilie Heegaard Brahe Grant/research support from: Novartis, Burkhard Moeller: None declared, Ennio Giulio Favalli Consultant of: Consultant and/or speaker for BMS, Eli-Lilly, MSD, UCB, Pfizer, Sanofi-Genzyme, Novartis, and Abbvie, Speakers bureau: Consultant and/or speaker for BMS, Eli-Lilly, MSD, UCB, Pfizer, Sanofi-Genzyme, Novartis, and Abbvie, Carlos Sánchez-Piedra: None declared, Lucie Nekvindova: None declared, Matija Tomsic: None declared, Nina Trokovic: None declared, Eirik kristianslund: None declared, Helena Santos Speakers bureau: AbbVie, Eli-Lilly, Janssen, Pfizer, Novartis, Thorvardur Love: None declared, Ruxandra Ionescu Consultant of: Consulting fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, Speakers bureau: Consulting and speaker fees from Abbvie, Eli-Lilly, Novartis, Pfizer, Roche, Sandoz, Yavuz Pehlivan: None declared, Gareth T. Jones Grant/research support from: Pfizer, AbbVie, UCB, Celgene and GSK., Irene van der Horst-Bruinsma Grant/research support from: AbbVie, Novartis, Eli Lilly, Bristol-Myers Squibb, MSD, Pfizer, UCB Pharma, Consultant of: AbbVie, Novartis, Eli Lilly, Bristol-Myers Squibb, MSD, Pfizer, UCB Pharma, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis

Abstract The aim of therapy in AL amyloidosis is to rapidly eliminate the production of toxic, amyloidogenic light chains by targeting the plasma cell clone. Especially for patients with advanced cardiac involvement, a rapid hematologic response may be critical, while, the depth of response is important in order to maximize the probability of organ response. Bortezomib with the addition of dexamethasone with either cyclophosphamide (CyBorD) or melphalan (BMDex) remain the most commonly used primary treatment. In myeloma multiple (MM) patients the combinations of bortezomib with an IMiD [thalidomide (VTD) or lenalidomide (VRD)] are very effective and widely used in newly diagnosed patients. In AL amyloidosis the tumor clone is usually of low burden without adverse prognostic features ; thus, the VRD regimen should be particularly effective. However, IMiDs have unique toxicity in patients with AL and their tolerability is poorer than in MM patients and lower doses of IMiDs are commonly used in AL patients. Here we report our experience with a VRD light regimen as primary therapy in consecutive patients with AL amyloidosis. From March 2017, 30 consecutive patients (28 evaluable at the day of this report) treated at the Department of Clinical Therapeutics, Athens, Greece, received bortezomib 1.3 mg/m2 on days 1, 8 & 15, with lenalidomide (starting at 5 to 15 mg, according to age, cardiac and renal function) on days 1-21 and dexamethasone 20 mg weekly, every 28 days for 8 cycles (VRD regimen). Standard and updated criteria for organ involvement and response evaluation and for hematologic response were used. A rigorous assessment following standard institutional protocol for efficacy and toxicity was followed. Among the 30 patients, 71% were males, median age was 65 years (range 46-84); 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000) and per Mayo stage 14%, 54% , 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement with a median eGFR of 59 ml/min/1.73 m2 (range 10-133), renal stage distribution was 13%, 53% and 33% (stages 1, 2 & 3) and no patient required dialysis at the time of initiation of VRD. So far 14 patients have completed the planned 8 cycles, 7 died prior to completion of planned therapy, 1 discontinued per physician's decision and 8 are still on therapy. The starting dose of lenalidomide was 5 mg in 26 (86%), 10 mg in 2 (7%) and 15 mg in 2 (7%) patients. After the first cycle of VRD, 32% patients achieved a VGPR and 29% a PR; after 3 months 76% of evaluable patients (N=17) had a VGPR and 24% a PR, while after 6 cycles ≥VGPR and PR rates (N=15 evaluable) were 94% and 6% respectively. Overall, on intent to treat, the best hematologic response was CR in 24%, VGPR in 48% and PR in 16%, for an ORR of 88% and ≥VGPR of 72%. Median follow up is 10 months and 6 and 12 month survival is 73% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). At 6 month landmark, organ responses were documented in 21% of patients (20% renal and 15% cardiac), but the follow up is still short. Hematologic toxicity was mild (≥Gr3 neutropenia: 4%, anemia: 7%, thrombocytopenia: 7%). Among non hematologic toxicities rash was common (Gr2: 29%, Gr3: 11%, Gr4: 4%); median time to development of rash was 118 days, in 2 patients lenalidomide was discontinued due to rash and in the rest it was continued with the addition of anti-histamines, low dose steroids with or without dose reductions of lenalidomide. Other common AEs included infections (≥Gr3: 11%), constipation (≥Gr3: 11%), neuropathy (Gr2: 18%). Thromboprophylaxis with aspirin was given in 46%, LMWH in 25%, NOACs in 14% and coumadin in 15%. A thromboembolic event (pulmonary embolism) occurred in only one patient with heavy nephrotic syndrome who was receiving LMWH prophylaxis. In total, 43% of patients required lenalidomide dose reduction, 28% discontinued lenalidomide before therapy completion, while, 29% required bortezomib dose reduction and 11% discontinued bortezomib before cycle 8. We conclude that VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy with toxicity that is manageable with appropriate interventions and thromboprophylaxis. Disclosures Kastritis: Prothena: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Genesis Pahrma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Abstract Introduction Waldenström's Macroglobulinemia (WM) is a rare indolent lymphoma with a low incidence of ~3 cases per million per year. There are few randomized trials and no well-established treatment standards in WM. Treatment landscapes for treatment-naïve and relapsed WM are heterogeneous and data on treatment choices and their outcome in patients (pts) outside clinical trials are lacking. The goal of this project was to generate data on epidemiologic/treatment patterns and efficacy outcomes for WM over a prolonged period of time (~10 yr) in a large pan-European effort. Methods In this observational chart review, physicians completed a retrospective electronic record for pts who fit the following inclusion criteria: confirmed WM, symptomatic disease at treatment initiation, front line treatment initiated between Jan 2000-Jan 2014, and availability of complete clinical/biologic evaluation at diagnosis/initial therapy. Study endpoints included initial/subsequent lines of treatment, progression-free survival (PFS), and overall survival (OS). The number of pt records per country was prespecified to balance the distribution between European countries. Results Of 454 pt records reviewed, cases were from France (n=92), United Kingdom (UK; n=72), Germany (n=66), Spain (n=60), Italy (n=56), Greece (n=25), Netherlands (n=25), Poland (n=21), Austria (n=19), and Czech Republic (n=16). Data were summarized across 5 lines of treatment for 454, 397, 160, 61, and 26 pts, respectively. Median age at initiation of front-line treatment was 65 yr (range, 29-89); 61% were male. The most common reasons for initiating treatment at diagnosis were constitutional symptoms (58%), cytopenias (72%; anemia [69%]), and IgM-related symptoms (57%). Choice of therapy varied with line of treatment; monotherapy fell from 31% in front-line to 20%/21% in 2nd/3rd-line ( Table 1). Combination therapy with antibody increased from 40% in front-line to 64%/56% in 2nd/3rd-line. Across all lines, rituximab followed by cyclophosphamide, and to a lesser extent, chlorambucil, fludarabine, vincristine, and bendamustine, were the most common agents, excluding steroids, that were used as monotherapy or in any combination with use varying between countries (Table 1). Median PFS decreased with successive lines of treatment (29 vs 23 vs 16 mo), (Figure 1) and varied by country and choice of agents (Table 1). Median OS was 123 mo, but significantly lower in pts ≥75 yr (75 mo) or with high-risk IPSSWM risk score (91 mo) and similar for pts with low/intermediate risk groups. Considerable country-specific OS differences were noted. Other malignancies were reported in 12% after diagnosis of WM. Conclusions The retrospective chart review of WM pts treated in Europe shows that constitutional symptoms and anemia are the most common reasons for initiating therapy. Rituximab was the most commonly used agent across all lines of treatment. Outside clinical trials, monotherapy is widely used even at first relapse with notable differences between countries. This large observational dataset will be an important tool to improve understanding of treatment practice and survival of WM pts in Europe outside of clinical trials, as well as unmet medical needs in the community. Table 1. Use of Monotherapy or Combination Regimens and Median PFS in Front -, 2nd -, and 3rd-Line Settings Overall and by Country Country Number of Cases, n Monotherapy, % Combination Therapy With Antibody†, % Combination Therapy Without Antibody, % Median PFS,Months (95% CI) Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Front line 2nd line 3rd line Overall 454 397 160 31 20 21 40 63 56 28 14 21 29.0 (25-31) 23.0 (20-26) 16.0 (10-18) France 92 86 43 62 26 16 24 66 70 14 8 14 28.5 (22-32) 30.0 (20-37) 16.0 (9-32) United Kingdom 72 64 19 18 22 21 19 55 42 63 23 37 31.5 (25-36) 20.0 (11-35) 13.0 (9-33) Germany 66 52 18 9 8 22 61 81 50 30 8 11 36.5 (29-44) 24.0 (16-29) 8.0 (3-16) Spain 60 58 21 43 28 38 38 59 52 18 12 5 18.0 (15-25) 16.0 (12-24) 11.0 (9-24) Italy 56 47 20 20 17 15 57 68 70 23 6 15 30.5 (20-39) 30.0 (18-42) 17.0 (4-21) Eastern European* 37 30 12 8 13 8 32 40 0 60 47 92 33.0 (26-38) 20.0 (16-26) 20.5 (4-38) Smaller European** 71 60 27 35 22 26 56 67 63 7 12 11 23.0 (18-29) 16.0 (13-25) 16.0 (7-26) * Includes Czech Republic and Poland **Includes Austria, Greece, and Netherlands † Antibodies other than rituximab, <1% Figure 1. Figure 1. Kaplan-Meier PFS Estimates by Line of Treatment Disclosures Buske: CELLTRION, Inc.: Consultancy, Honoraria. Sadullah:Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; NAPP: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; TEVA: Consultancy; Boehringer: Other: Travel, Accommodations, Expenses. Kastritis:Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Garcia-Sanz:Janssen: Honoraria, Other: Travel, Accommodations, Expenses; Takeda: Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Research Funding. Leleu:Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria. Willenbacher:Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; CTI: Consultancy, Other: Travel, Accommodations, Expenses. Hajek:Amgen: Honoraria; Celgene: Consultancy; Janssen: Consultancy. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Graef:Pharmacyclics LLC, an AbbVie Company: Employment, Membership on an entity's Board of Directors or advisory committees; AbbVie: Equity Ownership. Dimopoulos:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding.

Abstract Background The introduction of multiple novel agents and regimens for NDMM and relapsed/refractory MM (RRMM) has improved outcomes while increasing the complexity of treatment selection and disease management. The real-world effectiveness of many novel-agent-based regimens remains to be elucidated. INSIGHT MM (NCT02761187) is the largest global, prospective, observational MM study to date. It aims to understand global NDMM/RRMM disease and pt characteristics, treatment patterns, and clinical outcomes, as well as regional variations. Here we report data for 1056 NDMM pts enrolled from July 1, 2016 to April 27, 2018. Methods INSIGHT MM is enrolling ~4200 adult pts with NDMM/RRMM (1-3 prior therapies) from 15 countries; 9 in Europe (EU), 3 in Latin America (LA), the United States (US), and 2 in Asia. Pts will be followed prospectively for ≥5 yrs. Data are collected from hospital/clinic records at baseline (MM-specific disease characteristics, prior therapies) and every 3 mos (disease management, effectiveness, safety). Results At data cut-off, 1056 NDMM pts had been enrolled from 14 countries, including 495 (47%) from EU, 361 (34%) from the US, 112 (11%) from LA, and 88 (8%) from Taiwan. Median age at enrollment was 64 (range 32-89) yrs and 139 (13%) pts were aged >75 yrs (14%/12%/11%/13% in EU/US/Taiwan/LA); 57% of pts were male (60%/58%/61%/39% in EU/US/Taiwan/LA); 72%, 13%, and 8% were White/Caucasian, Asian, and Black/African American, respectively. Overall, 62% of pts were treated at academic centers and 38% in community settings. Based on accrual at data cut-off, regional differences were observed, with more pts treated at academic centers in EU/Taiwan (88%/91%) vs the US/LA (30%/25%). 87% of pts were treated outside of clinical trials (88%/82%/95%/98% in EU/US/Taiwan/LA). Bone pain (32%, including 33%/28%/40%/37% in EU/US/Taiwan/LA), weakness/fatigue (anemia; 11%, including 12%/10%/6%/18% in EU/US/Taiwan/LA), and kidney problems (5%, including 3%/3%/17%/2% in EU/US/Taiwan/LA) were the most common reasons for pts seeking care; 32% (36%/32%/22%/24% in EU/US/Taiwan/LA) were asymptomatic at diagnosis. At diagnosis, 27%/26%/31% of pts had physician-reported ISS Stage I/II/III MM, and 88% had ECOG PS 0-1; 8% of pts had hypercalcemia, 34% creatinine clearance <60 ml/min, 56% anemia, and 30% >3 bone lesions. The most common reasons for initiating therapy were the presence of CRAB criteria, e.g. bone involvement (54%) and anemia (37%). At start of treatment, fixed-duration therapy, treat-to-best-response, and treat-to-progression approaches were planned for 38%, 29%, and 31% of pts, respectively. The most frequently administered regimens are shown in the Table; 20%/66% of pts received a doublet/triplet. V-based regimens were the most frequently used. Regional differences in regimen selection are emerging: among IMiDs, T is most commonly prescribed in EU, Taiwan, and LA; R is more common in the US. After a median follow-up of 9.3 mos, 72 (7%) pts had discontinued the study, most often due to death (57%), consent withdrawal (14%), or change of treatment provider (11%). At data cut-off, data for 236 (22%) pts who received 1st-line ASCT were available (median age 60 yrs; 12%/63%/25% of pts aged <50/50-65/>65 yrs). Of these, 64% received ASCT at academic centers; 42% of pts each in EU and the US received ASCT vs 11% in Taiwan and 4% in LA. The most frequently administered regimens in ASCT-eligible (n=429) vs ASCT-ineligible (n=571) pts were VC±d (21% vs 21%), VR±d (19% vs 17%) and VT±d (17% vs 10%). At data cut-off, 115 NDMM pts had progressed to 2nd-line therapy; 99 pts received a PI with 1st-line therapy, of whom 33 (33%) then received a PI-based regimen in 2nd line; 61 pts received an IMiD with 1st-line therapy, of whom 35 (57%) then received an IMiD-based regimen in 2nd line. Among 1st/2nd-line pts, 2%/12% received monoclonal antibody therapy. Conclusions PIs and IMiDs remain the global backbones of MM therapy, with V-based regimens most commonly used in NDMM pts, regardless of intended transplant status. These data from INSIGHT MM are beginning to elucidate regional differences in disease presentation and treatment selection, including higher numbers of pts receiving ASCT in the US/EU vs Taiwan/LA, which are likely reflective of differences in healthcare systems and access to MM treatments in the participating countries. Future studies will evaluate the impact of these regional variations on outcomes. Table. Table. Disclosures Usmani: Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Hungria:Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Leleu:Karyopharm: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Celgene: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; BMS: Honoraria, Other: steering committee membership ; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Davies:Abbvie: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; ASH: Honoraria; MMRF: Honoraria. Costello:Poseida Therapeutics, Inc.: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Rifkin:Takeda: Consultancy; EMD Serono: Consultancy; McKesson: Equity Ownership; Celgene: Consultancy; Amgen: Consultancy; Sandoz: Consultancy; Boehringer Ingelheim: Consultancy. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Chari:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; The Binding Site: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Cook:Bristol-Myers Squibb: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Berdeja:Teva: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Zonder:Takeda: Honoraria; Coelum: Honoraria; BMS: Research Funding; Celgene: Consultancy, Honoraria; Alnylam: Honoraria; Janssen: Honoraria; Pharmacyclics: Other: DSMC. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Hajek:Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Demers:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Romanus:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Ren:Takeda Pharmaceuticals International Co.: Employment. Skacel:Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stull:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Terpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding.

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

Abstract Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Abstract Background: In the absence of an HLA matched related donor, unrelated donor hematopoietic cell transplantation (HCT) is an alternative. Recently, HLA-haploidentical HCT using posttransplant cyclophosphamide (PTCY-haplo) has been increasingly performed. Unrelated donor peripheral blood stem cell transplantation (PBSCT) program was initiated in 2011 in Japan with rather slow increase, therefore, bone marrow is the main stem cell source for HCT from unrelated donors, while PTCY-haplo is mainly PBSCT. We compared outcomes of unrelated donor bone marrow transplant (UBMT) and PTCY-haplo. Methods: This is a retrospective analysis of a registry data of the Japan Society for HCT and the Japanese Data Center for HCT using the Transplant Registry Unified Management Program (TRUMP). Patients with acute leukemia and myelodysplastic syndromes, aged between 16 and 69 years, who undergone their first HCT between 2012 and 2015 were included in the study. HLA-A, -B, -C, and -DRB1 allele-level 8/8 matched (n=1,470), 7/8 matched (n=859), and 6/8 matched (n=186) T-cell replete UBMT recipients, and 140 recipients of PTCY-haplo (PBSCT, n=133; BMT, n=6; PBSCT+BMT, n=1) were identified as subjects for analyses. Adjusted comparison of the groups on overall mortality was performed with the use of the Cox proportional-hazards regression model. For other outcomes with competing risks, Fine and Gray's proportional-hazards model for subdistribution of a competing risk was used. The models were used to estimate adjusted probabilities, with consideration of other significant clinical variables in the final multivariate models. Results: The median age for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 52(16-69), 46.5(17-68), 50(16-69), 50(16-68). According to refined disease risk index (rDRI), patients with high or very high rDRI were 32%, 54%, 34%, 34% for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Myeloablative conditioning was used in 74%, 51%, 73%, 68% of patients for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT. Median follow-up period of survivors for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT were 2.79 (0.03-5.603),1.82 (015-3.89), 3.00 (0.09-5.57), 3.17 (0.27-5.58). In adjusted comparison by multivariate analyses setting 8/8 matched UBMT as the reference, PTCY-haplo showed similar overall mortality (relative risk [RR]=0.97, 95% confidence interval [CI], 0.75-1.26, p=0.823), decreased risk of non-relapse mortality (RR=0.43, 95% CI, 0.25-0.74, p=0.003), increased risk of relapse (RR=1.57, 95% CI, 1.21-2.03, p=0.001), and decreased risk of grade II to IV acute GVHD (RR=0.68, 95% CI, 0.48-0.95, p=0.023). Relative risks for 7/8 matched and 6/8 matched UBMT were 1.08 (p=0.223) and 1.27 (p=0.032) for overall mortality, 1.29 (p=0.004) and 1.73 (p<0.001) for non-relapse mortality, 0.89 (p=0.201) and 0.81 (p=0.215) for relapse, and 1.30 (p<0.01) and 1.84 (p<0.001) for grade II to IV acute GVHD. Other predictive variables identified for overall mortality were patient age older than 50 years old compared to younger at transplant, male sex, refined disease risk index of Intermediate, High, or Very High compared to Low, and HCT-CI total points of 1 or 3 or greater compared to 0. Adjusted probabilities for 8/8 matched UBMT, PTCY-haplo, 7/8 matched, and 6/8 matched UBMT at two years post-transplant were 61%, 58%, 52%, 60% for overall survival, 23%, 27%, 21%, 19% for relapse, and 20%, 6%, 24%, 33% for non-relapse mortality (Figure 1). Conclusions: PTCY-haplo showed notably low non-relapse mortality which contributed to comparable short-term survival outcomes with 8/8 matched UBMT. Disclosures Ishiyama: Alexion Pharmaceuticals, Inc.: Honoraria. Ichinohe:Otsuka Pharmaceutical Co.: Research Funding; Nippon Shinyaku Co.: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; JCR Pharmaceuticals: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Takeda Pharmaceutical Co.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Mundipharma: Honoraria; Novartis.: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; MSD: Research Funding; Chugai Pharmaceutical Co.: Research Funding; CSL Behring: Research Funding; Eisai Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; Ono Pharmaceutical Co.: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding.

Abstract Background A lack of objective data exists on differences in treatment practices and outcomes for MM between countries. The EMMOS study aimed to document and describe current treatment regimens and disease progression patterns of MM pts at different stages of the disease in real-world medical practice. Methods Adult pts initiating any new MM therapy, irrespective of treatment line at study entry or therapy type received, were eligible for inclusion in the EMMOS registry. A multi-staged pt/site recruitment model was applied to minimize selection bias; enrollment was stratified by country, region, and practice type. Pts' medical/disease features, treatment history, and remission status were recorded at baseline. Prospective data on treatment, efficacy, and safety were collected electronically every 3 mos until 2 yrs after the last pt enrolled. Responses were investigator-assessed (no predefined criteria). Here we report data from the final analysis of EMMOS. Pts were grouped according to receipt of high-dose chemotherapy/stem cell transplantation in any treatment line (SCT pts, non-SCT pts). Within a given line, pts may have received induction, SCT, consolidation, and/or maintenance therapy; if multiple drug combinations were used within a line, the line grouping was based on the combination received in cycle 1. Results 2358 pts were enrolled between Oct 2010-Oct 2012 in 22 countries in Europe and Africa; the last pt completed follow-up in Oct 2014. Of these, 775 pts had undergone SCT in any treatment line. Baseline characteristics in the prospective phase by starting line are shown in the Table. As expected, there was a higher proportion of younger pts (≤65 yrs) in the SCT vs non-SCT group across all treatment lines, and in both groups a higher proportion of pts in 4th + vs earlier lines with ISS stage III disease. While cytogenetics were evaluated in a small number of pts overall (670/2358 [28%]), these assessments were performed significantly more frequently in SCT vs non-SCT pts (p<0.0001). In 380 prospective 1st line (L1) SCT pts, 299 (79%) underwent SCT-based treatment in L1; induction was with a bortezomib (btz)-based combination in 83% (47% btz without immunomodulatory drug [IMiD]; 36% btz + IMiD), IMiD in 11%, and other (ie. no btz/IMiD) in 6%. In 81 SCT pts who received non-SCT-based treatment in L1 (21%), 36% received btz without IMiD, 40% other, and 17% IMiD-based combinations. In 345 pts receiving L2, most frequent therapies were btz without IMiD (45% of pts), IMiD without btz (30%), other (13%), and btz + IMiD (12%); non-btz/IMiD combinations were increasingly prevalent in pts receiving L3 or L4 (24% and 40%, respectively). In the non-SCT population, 58% of pts received a btz-based combination in L1, most frequently btz without IMiDs (54%). In pts receiving L2, btz or IMID were equally represented (39%); in L3, non-SCT pts were most likely to receive other therapies (39%) versus 27% btz without IMiD and 32% IMiD without btz. Based on preliminary data, mean EQ5D score at baseline was 0.316 (range -0.594, 0.731) in the overall pt population, which increased slightly to 0.410 (-0.429, 0.731) at 12 mos and was largely comparable between countries. Resource utilization (hospitalization, ICU, ER visit, outpatient visit, full-time care) appeared highest in Germany (67.6 records per pt) and lowest in Croatia (7.5 per pt), with those in Germany spending a mean of 12.1 days in hospital per stay. Efficacy/safety data will be presented at the meeting. Conclusion This large, real-world, observational study provides for the first time a comprehensive picture of the baseline characteristics and therapy of MM pts treated in Europe, the Middle-East, and Africa. These data provide a framework towards the design of future protocols aiming to improve outcomes in MM. Table. Baseline characteristics by starting line Non-SCT pts SCT pts L1 (n=897) L2 (n=319) L3 (n=184) L4+ (n=166) Total* (N=1566) L1 (n=378) L2 (n=161) L3 (n=107) L4+ (n=120) Total* (N=775) Age ≤65 yrs, % 36 34 35 39 36 87 76 72 71 80 ISS Stage II/III, % 36/44 34/47 43/38 22/52 35/44 33/35 44/27 34/26 23/48 34/34 Salmon-Durie Stage 2/3, % 28/64 25/66 24/71 29/62 27/65 22/68 25/67 20/65 11/81 20/69 Bone lesion history, % 64 72 75 70 68 66 74 77 80 71 Cytogenetics assessed, % 24 19 19 14 21 51 35 43 33 44 Del 17p 8 8 9 13 8 10 7 4 13 9 t(4,14) 6 7 9 4 6 7 14 13 8 9 ISS, International staging system; L, line *17 non-SCT and 9 SCT pts were enrolled but did not receive a line of therapy within 75 days of baseline Disclosures Mohty: Celgene: Honoraria; Janssen: Honoraria. Terpos:Amgen: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Mateos:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Array BioPharma: Consultancy; Onyx Pharmaceuticals: Consultancy; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Genmab A/S: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Sanofi Aventis: Consultancy. Lejniece:Amgen: Honoraria; Sandoz: Honoraria. Beksac:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis Pharma: Research Funding. De Stefano:Shire: Speakers Bureau; Roche: Research Funding; Bruno Farmaceutici: Research Funding; Janssen Cilag: Research Funding; Amgen: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Speakers Bureau. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pečeliūnas:Johnson & Johnson: Honoraria, Research Funding. Willenbacher:CTI: Consultancy, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Da Silva:Janssen Pharmaceuticals: Research Funding. Louw:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Nemet:Sanofi: Honoraria; Pliva: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Couturier:Janssen-Cilag: Employment. Olie:Johnson & Johnson: Equity Ownership; Janssen-Cilag: Employment. Feys:Janssen Pharmaceutica N.V.: Employment, Equity Ownership. Thoret-Bauchet:Janssen-Cilag: Employment.

Background: BCL11A is a key transcription factor that suppresses the production of fetal hemoglobin (HbF) in red blood cells (RBCs), leading to the production of adult Hb (HbA). In diseases with hemoglobin production defects such as b-thalassemia, or in sickle cell disease (SCD), HbF upregulation could ameliorate anemia and reduce transfusion requirements, such as in β-thalassemia, or reduce clinical complications, including vaso-occlusive crises (VOCs), in SCD. To induce potentially curative levels of HbF in erythrocytes, we used the ex vivo CRISPR-Cas9-based gene-editing platform to edit the erythroid enhancer region of BCL11A in hematopoietic stem and progenitor cells (HSPCs), producing CTX001. Aims: CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) are multi-center, first-in-human studies of CTX001 for transfusion-dependent b-thalassemia (TDT) and SCD, respectively. Here, we present available safety and efficacy results from all patients with at least 3 months of follow-up from both studies as of July 2020. Methods: Patients (aged 18 to 35 years) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/year or ≥10 units/year in the previous 2 years, and those with severe SCD, defined as ≥2 VOCs/year requiring medical care in the previous 2 years, were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF (filgrastim) and plerixafor (for TDT) or plerixafor alone (SCD). The erythroid enhancer region of BCL11A was edited in CD34+ cells using a specific CRISPR guide RNA and Cas9 nuclease. Prior to CTX001 infusion on Day +1, patients received myeloablation with 4 days of busulfan. Patients were monitored for stem cell engraftment and hematopoietic recovery, adverse events, total Hb and HbF production, hemolysis, F-cells, pRBC transfusion requirements (TDT), and VOCs (SCD) during follow-up. Results: Data are presented for patients with TDT (N=5; RBC transfusion history range: 23.5 to 61 units/year; CTX001 post-infusion follow-up through Months 15, 6, 4, 4, and 3, respectively) and with SCD (N=2; 7 VOCs/year and 7.5 VOCs/year, respectively, annualized over 2 years prior to consent; CTX001 post-infusion follow-up through Months 12 and 3, respectively). In the patients with TDT, median neutrophil engraftment occurred on Day +32 (range: +27 to +36); median platelet engraftment occurred on Day +37 (range: +34 to +52). In the patients with SCD, neutrophil engraftment occurred on Day +30 and Day +22 and platelet engraftment occurred on Day +30 and Day +33, respectively. All patients demonstrated increases in total Hb and HbF over time (Figure). Patients with TDT ceased receiving pRBC transfusions soon after CTX001 infusion, with the last pRBC transfusion occurring between 0.9 and 1.9 months after CTX001 infusion. The first patient with TDT who received CTX001 has remained transfusion-free for over 15 months. Patients with SCD have had no VOCs since CTX001 infusion. The first SCD patient who received CTX001 has remained free of VOCs for over 1 year. In all 7 patients, the safety profile after CTX001 infusion was generally consistent with busulfan myeloablation. Four serious adverse events (SAEs) related or possibly related to CTX001 were reported in 1 patient with TDT: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. All 4 of these SAEs occurred in the context of HLH and were either resolved or clinically improving at the time of this analysis. No other CTX001-related SAEs were reported in the other patients with TDT or in any patients with SCD. Conclusions: These data demonstrate that CTX001, a first-in-human, CRISPR-Cas9-modified autologous HSPC product, has resulted in increases in HbF and total Hb in the first 7 patients infused. All patients infused with CTX001 demonstrated hematopoietic engraftment with a post-infusion safety profile generally consistent with myeloablation. All 5 patients with TDT have been transfusion-free since ~2 months after CTX001 infusion and the 2 patients with severe SCD have had no VOCs during follow-up after CTX001 infusion. These early data demonstrate that CTX001 is a potential functional cure for the treatment of TDT and SCD. Data will be updated for the presentation. Data from these ongoing studies were submitted on behalf of the CLIMB THAL-111 and CLIMB SCD-121 Investigators. Figure Disclosures Frangoul: Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Bobruff:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cappellini:BMS: Honoraria; CRISPR Therapeutics, Novartis, Vifor Pharma: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fernandez:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Grupp:Juno/BMS: Other; Cellectis: Other; TCR2: Other: SAB; Servier: Research Funding; Janssen/JnJ: Consultancy; CBMG: Consultancy; Humanigen: Consultancy; GlaxoSmithKline: Consultancy; Roche: Consultancy; CRISPR Therapeutics/Vertex Pharmaceuticals: Other; Allogene: Other; Kite/Gilead: Research Funding; Novartis: Consultancy, Other: SSC, Research Funding; Adaptimmune: Other: SAB; Jazz: Other: SSC. Handgretinger:Amgen: Honoraria. Ho:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Imren:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Kattamis:Agios: Consultancy; Vertex: Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; Genesis Pharma SA: Membership on an entity's Board of Directors or advisory committees; Vifor: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apopharma/Chiesi: Honoraria, Speakers Bureau. Lekstrom-Himes:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Lu:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. de Montalembert:Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulcahey:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Shanbhag:Vertex Pharmaceuticals Incorporated: Current Employment, Current equity holder in publicly-traded company. Sheth:Agios: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; La Jolla: Research Funding; Acceleron: Consultancy; Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding; DisperSol Technologies: Research Funding; Terumo: Research Funding; Vertex Pharmaceuticals/CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soni:CRISPR Therapeutics: Current Employment, Current equity holder in private company. Steinberg:Vertex Pharmaceuticals/CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Fulcrum Therapeutics: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Imara: Membership on an entity's Board of Directors or advisory committees. Weinstein:CRISPR Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wu:Bayer: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Daratumumab is a human monoclonal antibody targeting CD38 that demonstrated superior efficacy in combination with lenalidomide and dexamethasone (DRd) versus lenalidomide and dexamethasone alone (Rd) in a pre-specified interim analysis of a randomized phase 3 study of relapsed or refractory multiple myeloma (RRMM; Dimopoulos MA, et al. N Engl J Med 2016; in press). We report subgroup analyses from this study in patients (pts) who received 1 to 3 prior lines of therapy (1-3 PL), including outcomes based on high-risk cytogenetics within these subgroups. Methods: Patients (pts) who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was progression-free survival (PFS). The site investigator determined the number of prior lines of therapy according to IMWG consensus guidelines. Treatment-free interval (TFI) was defined as the duration between the end/start date of last line of prior therapy and the date of randomization. Pts with high-risk cytogenetic status had at least one of the following abnormalities as assessed via fluorescence in-situ hybridization or karyotyping by local laboratory assessment: t(4;14), t(14;16), or del17p. Results: In the 1-3 PL subgroup (DRd, n=272; Rd, n=264), PFS was significantly improved with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.50; P<0.0001), with estimated 12-month PFS rates of 83.2% vs 60.4%, respectively. Time to progression was also significantly longer with DRd vs Rd (median: NR vs 18.4 months; HR, 0.32; 95% CI, 0.22-0.46; P<0.0001). ORR (94% vs 77%), rates of very good partial response (VGPR) or better (76% vs 45%) and complete response (CR) or better (44% vs 20%) were significantly higher with DRd vs Rd, respectively (P<0.0001 for all). Among responders, median time to VGPR or better was 2.8 months in DRd vs 2.9 months in Rd; median time to CR or better was 6.7 months vs 7.5 months, respectively. For pts in the 1-3 PL subgroup with high-risk cytogenetics (n=33 in each treatment group), significantly longer PFS was observed in DRd vs Rd (median: NR vs 8.3 months; HR, 0.30; 95% CI, 0.14-0.67; P=0.0019). Significantly higher ORR (91% vs 69%; P=0.0267), rate of VGPR or better (73% vs 28%; P=0.0004), and rate of CR or better (36% vs 9%; P=0.0104) were achieved in pts with high-risk cytogenetic status treated with DRd vs Rd, respectively. For 1-3 PL pts who had a TFI of >12 months (DRd, n=138; Rd, n=145), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.42; 95% CI, 0.24-0.74; P=0.0019; Figure A); the estimated 12-month PFS rate was 88.0% vs 74.5%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 86%, P=0.0084), along with rate of VGPR or better (77% vs 56%; P=0.0008) and rate of CR or better (43% vs 27%; P=0.0083). Among pts with a TFI of ≤12 months (DRd, n=134; Rd, n=119), median PFS was NR in DRd vs 10.3 months in Rd (HR, 0.32; 95% CI, 0.21-0.51; P<0.0001; Figure B); the estimated 12-month PFS rate was 78.1% vs 43.1%, respectively. ORR (92% vs 67%), rate of VGPR or better (76% vs 32%), and rate of CR or better (44% vs 10%) were all significantly higher with DRd vs Rd (P<0.0001 for all). Among pts with 1-3 PL who were refractory to their last line of therapy (DRd, n=73; Rd, n=67), PFS was significantly prolonged with DRd vs Rd (median: NR vs 10.3 mo; HR, 0.42; 95% CI, 0.25-0.72; P=0.0010). ORR (92% vs 66%; P=0.0002), rate of VGPR or better (72% vs 34%; P<0.0001), and rate of CR or better (47% vs 14%; P<0.0001) were significantly higher with DRd vs Rd. Data for all subgroup analyses will be updated for the meeting. Conclusions: Responses with DRd were deep and durable which translated into significantly improved clinical outcomes vs Rd in 1-3 PL pts with RRMM. The results of these subgroup analyses suggest that the treatment benefit of DRd vs Rd was maintained across these subgroups, including pts with TFI of ≤12 months and those who were refractory to their last line of therapy. Figure Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization Figure. Progression-free survival in patients with 1 to 3 prior lines of therapy and treatment-free interval of (A) >12 months (B) ≤12 months prior to randomization Disclosures Usmani: Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Belch:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria. White:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria. Benboubker:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy. Ho:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Khokhar:Janssen: Employment. Guckert:Janssen: Employment; Johnson & Johnson: Equity Ownership. Wu:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Janssen: Employment; Johnson & Johnson: Equity Ownership. San-Miguel:Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

AbstractA motif that runs throughout the reunion scene of Genesis 32–33 is the intersection of the human and the divine. The present article highlights this literary theme, exploring structural, linguistic, and narrative resonances that, both implicitly and explicitly, direct the reader’s attention to this motif and its significance in these chapters.

Intimal hyperplasia (IH) remains the major culprit in revascularization failures. We aimed to unravel relationships between acute changes in circumferential arterial wall strain and genesis of IH. Methods To induce IH, we employed a validated model using a 9-0 nylon suture tie around the distal mouse common carotid artery (n=10) and an external 35-gauge needle mandrel (OD=0.14mm), with subsequent removal of the mandrel to create a distal common carotid focal stenosis (~78% lumen diameter/~85% flow reduction). Wall strains were measured in three, 1 mm wide regions along the vessel proximal to the focal stenosis at pre-op day 1 and at post-op day 4 (before detectable IH) using Vevo 2100 ultrasonography with VevoVasc software. At post-op day 28, arteries were perfusion fixed and IH was assessed in the same regions as those where strain was analyzed. Strain and morphology were also assessed in the contralateral control artery. Results Decreased wall strain was noted in all regions proximal to the focal stenosis from 0.26 ± 0.01 to 0.11 ± 0.02 (p<0.001) with no change in the control artery from pre-op to post-op day 4 (p=0.45). Based on a strain level histogram, vessels were divided into groups with strain ≤0.1 and >0.1. All segments (n = 13) with wall strain ≤0.1 at post-op day 4 had significant IH at day 28. In regions with strains >0.1 at day 4, only 30% had IH at day 28. The average pre-op strains were identical in >0.1 and ≤0.1 strain groups (0.27 ± 0.09 and 0.27 ± 0.08). Mean intimal thickness in vessels with strain ≤0.1 was 32 ± 20 μm, significantly greater than 8.0 ± 16 μm in the group with strain >0.1 (p<0.01). To further understand the mechanisms underlying changes in strain, systolic and diastolic lumen areas were assessed. Although systolic lumen areas in both >0.1 and ≤0.1 groups remained unchanged from pre-op to post-op day 4 (p=0.46), diastolic area was significantly increased in regions with post-op day 4 strain ≤0.1 (p=0.04) but remained unchanged in mice with post-op day 4 strain >0.1 (p=0.67). Conclusions Acute reduction in wall strain precedes the formation of IH in this murine model and this change is primarily caused by an increase in diastolic lumen area. Manipulations of wall strain offer a strategy to prevent and attenuate occlusive IH lesions after revascularizations.

'He did what the cipher could not, he rescued himself.' -- Alfred Bester, The Stars My Destination (23) On many levels, the new Nine Inch Nails album The Fragile is a gritty meditation about different types of End: the eternal relationship cycle of 'fragility, tension, ordeal, fragmentation' (adapted, with apologies to Wilhelm Reich); fin-de-siècle anxiety; post-millennium foreboding; a spectre of the alien discontinuity that heralds an on-rushing future vastly different from the one envisaged by Enlightenment Project architects. In retrospect, it's easy for this perspective to be dismissed as jargon-filled cyber-crit hyperbole. Cyber-crit has always been at its best too when it invents pre-histories and finds hidden connections between different phenomena (like the work of Greil Marcus and early Mark Dery), and not when it is closer to Chinese Water Torture, name-checking the canon's icons (the 'Deleuze/Guattari' tag-team), texts and key terms. "The organization of sound is interpreted historically, politically, socially ... . It subdues music's ambition, reins it in, restores it to its proper place, reconciles it to its naturally belated fate", comments imagineer Kodwo Eshun (4) on how cyber-crit destroys albums and the innocence of the listening experience. This is how official histories are constructed a priori and freeze-dried according to personal tastes and prior memes: sometimes the most interesting experiments are Darwinian dead-ends that fail to make the canon, or don't register on the radar. Anyone approaching The Fragile must also contend with the music industry's harsh realities. For every 10 000 Goth fans who moshed to the primal 'kill-fuck-dance' rhythms of the hit single "Closer" (heeding its siren-call to fulfil basic physiological needs and build niche-space), maybe 20 noted that the same riff returned with a darker edge in the title track to The Downward Spiral, undermining the glorification of Indulgent hedonism. "The problem with such alternative audiences," notes Disinformation Creative Director Richard Metzger, "is that they are trying to be different -- just like everyone else." According to author Don Webb, "some mature Chaos and Black Magicians reject their earlier Nine Inch Nails-inspired Goth beginnings and are extremely critical towards new adopters because they are uncomfortable with the subculture's growing popularity, which threatens to taint their meticulously constructed 'mysterious' worlds. But by doing so, they are also rejecting their symbolic imprinting and some powerful Keys to unlocking their personal history." It is also difficult to separate Nine Inch Nails from the commercialisation and colossal money-making machine that inevitably ensued on the MTV tour circuit: do we blame Michael Trent Reznor because most of his audience are unlikely to be familiar with 'first-wave' industrial bands including Cabaret Voltaire and the experiments of Genesis P. Orridge in Throbbing Gristle? Do we accuse Reznor of being a plagiarist just because he wears some of his influences -- Dr. Dre, Daft Punk, Atari Teenage Riot, Pink Floyd's The Wall (1979), Tom Waits's Bone Machine (1992), David Bowie's Low (1977) -- on his sleeve? And do we accept no-brain rock critic album reviews who quote lines like 'All the pieces didn't fit/Though I really didn't give a shit' ("Where Is Everybody?") or 'And when I suck you off/Not a drop will go to waste' ("Starfuckers Inc") as representative of his true personality? Reznor evidently has his own thoughts on this subject, but we should let the music speak for itself. The album's epic production and technical complexity turned into a post-modern studio Vision Quest, assisted by producer Alan Moulder, eleventh-hour saviour Bob Ezrin (brought in by Reznor to 'block-out' conceptual and sonic continuity), and a group of assault-technicians. The fruit of these collaborations is an album where Reznor is playing with our organism's time-binding sense, modulating strange emotions through deeply embedded tonal angularities. During his five-year absence, Trent Reznor fought diverse forms of repetitious trauma, from endogenous depression caused by endless touring to the death of his beloved grandmother (who raised him throughout childhood). An end signals a new beginning, a spiral is an open-ended and ever-shifting structure, and so Reznor sought to re-discover the Elder Gods within, a shamanic approach to renewal and secular salvation utilised most effectively by music PR luminary and scientist Howard Bloom. Concerned with healing the human animal through Ordeals that hard-wire the physiological baselines of Love, Hate and Fear, Reznor also focusses on what happens when 'meaning-making' collapses and hope for the future cannot easily be found. He accurately captures the confusion that such dissolution of meaning and decline of social institutions brings to the world -- Francis Fukuyama calls this bifurcation 'The Great Disruption'. For a generation who experienced their late childhood and early adolescence in Reagan's America, Reznor and his influences (Marilyn Manson and Filter) capture the Dark Side of recent history, unleashed at Altamont and mutating into the Apocalyptic style of American politics (evident in the 'Star Wars'/SDI fascination). The personal 'psychotic core' that was crystallised by the collapse of the nuclear family unit and supportive social institutions has returned to haunt us with dystopian fantasies that are played out across Internet streaming media and visceral MTV film-clips. That such cathartic releases are useful -- and even necessary (to those whose lives have been formed by socio-economic 'life conditions') is a point that escapes critics like Roger Scruton, some Christian Evangelists and the New Right. The 'escapist' quality of early 1980s 'Rapture' and 'Cosmocide' (Hal Lindsey) prophecies has yielded strange fruit for the Children of Ezekiel, whom Reznor and Marilyn Manson are unofficial spokes-persons for. From a macro perspective, Reznor's post-human evolutionary nexus lies, like J.G. Ballard's tales, in a mythical near-future built upon past memory-shards. It is the kind of worldview that fuses organic and morphogenetic structures with industrial machines run amok, thus The Fragile is an artefact that captures the subjective contents of the different mind produced by different times. Sonic events are in-synch but out of phase. Samples subtly trigger and then scramble kinaesthetic-visceral and kinaesthetic-tactile memories, suggestive of dissociated affective states or body memories that are incapable of being retrieved (van der Kolk 294). Perhaps this is why after a Century of Identity Confusion some fans find it impossible to listen to a 102-minute album in one sitting. No wonder then that the double album is divided into 'left' and 'right' discs (a reference to split-brain research?). The real-time track-by-track interpretation below is necessarily subjective, and is intended to serve as a provisional listener's guide to the aural ur-text of 1999. The Fragile is full of encrypted tones and garbled frequencies that capture a world where the future is always bleeding into a non-recoverable past. Turbulent wave-forms fight for the listener's attention with prolonged static lulls. This does not make for comfortable or even 'nice' listening. The music's mind is a snapshot, a critical indicator, of the deep structures brewing within the Weltanschauung that could erupt at any moment. "Somewhat Damaged" opens the album's 'Left' disc with an oscillating acoustic strum that anchor's the listener's attention. Offset by pulsing beats and mallet percussion, Reznor builds up sound layers that contrast with lyrical epitaphs like 'Everything that swore it wouldn't change is different now'. Icarus iconography is invoked, but perhaps a more fitting mythopoeic symbol of the journey that lies ahead would be Nietzsche's pursuit of his Ariadne through the labyrinth of life, during which the hero is steadily consumed by his numbing psychosis. Reznor fittingly comments: 'Didn't quite/Fell Apart/Where were you?' If we consider that Reznor has been repeating the same cycle with different variations throughout all of his music to date, retro-fitting each new album into a seamless tapestry, then this track signals that he has begun to finally climb out of self-imposed exile in the Underworld. "The Day the World Went Away" has a tremendously eerie opening, with plucked mandolin effects entering at 0:40. The main slashing guitar riff was interpreted by some critics as Reznor's attempt to parody himself. For some reason, the eerie backdrop and fragmented acoustic guitar strums recalls to my mind civil defence nuclear war films. Reznor, like William S. Burroughs, has some powerful obsessions. The track builds up in intensity, with a 'Chorus of the Damned' singing 'na na nah' over apocalyptic end-times imagery. At 4:22 the track ends with an echo that loops and repeats. "The Frail" signals a shift to mournful introspectiveness with piano: a soundtrack to faded 8 mm films and dying memories. The piano builds up slowly with background echo, holds and segues into ... "The Wretched", beginning with a savage downbeat that recalls earlier material from Pretty Hate Machine. 'The Far Aways/Forget It' intones Reznor -- it's becoming clear that despite some claims to the contrary, there is redemption in this album, but it is one borne out of a relentless move forward, a strive-drive. 'You're finally free/You could be' suggest Reznor studied Existentialism during his psychotherapy visits. This song contains perhaps the ultimate post-relationship line: 'It didn't turn out the way you wanted it to, did it?' It's over, just not the way you wanted; you can always leave the partner you're with, but the ones you have already left will always stain your memories. The lines 'Back at the beginning/Sinking/Spinning' recall the claustrophobic trapped world and 'eternal Now' dislocation of Post-Traumatic Stress Disorder victims. At 3:44 a plucked cello riff, filtered, segues into a sludge buzz-saw guitar solo. At 5:18 the cello riff loops and repeats. "We're in This Together Now" uses static as percussion, highlighting the influence of electricity flows instead of traditional rock instrument configurations. At 0:34 vocals enter, at 1:15 Reznor wails 'I'm impossible', showing he is the heir to Roger Waters's self-reflective rock-star angst. 'Until the very end of me, until the very end of you' reverts the traditional marriage vow, whilst 'You're the Queen and I'm the King' quotes David Bowie's "Heroes". Unlike earlier tracks like "Reptile", this track is far more positive about relationships, which have previously resembled toxic-dyads. Reznor signals a delta surge (breaking through barriers at any cost), despite a time-line morphing between present-past-future. At 5:30 synths and piano signal a shift, at 5:49 the outgoing piano riff begins. The film-clip is filled with redemptive water imagery. The soundtrack gradually gets more murky and at 7:05 a subterranean note signals closure. "The Fragile" is even more hopeful and life-affirming (some may even interpret it as devotional), but this love -- representative of the End-Times, alludes to the 'Glamour of Evil' (Nico) in the line 'Fragile/She doesn't see her beauty'. The fusion of synths and atonal guitars beginning at 2:13 summons forth film-clip imagery -- mazes, pageants, bald eagles, found sounds, cloaked figures, ruined statues, enveloping darkness. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Pilgrimage" utilises a persistent ostinato and beat, with a driving guitar overlay at 0:18. This is perhaps the most familiar track, using Reznor motifs like the doubling of the riff with acoustic guitars between 1:12-1:20, march cries, and pitch-shift effects on a 3:18 drumbeat/cymbal. Or at least I could claim it was familiar, if it were not that legendary hip-hop producer and 'edge-of-panic' tactilist Dr. Dre helped assemble the final track mix. "No, You Don't" has been interpreted as an attack on Marilyn Manson and Hole's Courntey Love, particularly the 0:47 line 'Got to keep it all on the outside/Because everything is dead on the inside' and the 2:33 final verse 'Just so you know, I did not believe you could sink so low'. The song's structure is familiar: a basic beat at 0:16, guitars building from 0:31 to sneering vocals, a 2:03 counter-riff that merges at 2:19 with vocals and ascending to the final verse and 3:26 final distortion... "La Mer" is the first major surprise, a beautiful and sweeping fusion of piano, keyboard and cello, reminiscent of Symbolist composer Debussy. At 1:07 Denise Milfort whispers, setting the stage for sometime Ministry drummer Bill Reiflin's jazz drumming at 1:22, and a funky 1:32 guitar/bass line. The pulsing synth guitar at 2:04 serves as anchoring percussion for a cinematic electronica mindscape, filtered through new layers of sonic chiaroscuro at 2:51. 3:06 phase shifting, 3:22 layer doubling, 3:37 outgoing solo, 3:50-3:54 more swirling vocal fragments, seguing into a fading cello quartet as shadows creep. David Carson's moody film-clip captures the end more ominously, depicting the beauty of drowning. This track contains the line 'Nothing can stop me now', which appears to be Reznor's personal mantra. This track rivals 'Hurt' and 'A Warm Place' from The Downward Spiral and 'Something I Can Never Have' from Pretty Hate Machine as perhaps the most emotionally revealing and delicate material that Reznor has written. "The Great Below" ends the first disc with more multi-layered textures fusing nostalgia and reverie: a twelve-second cello riff is counter-pointed by a plucked overlay, which builds to a 0:43 washed pulse effect, transformed by six second pulses between 1:04-1:19 and a further effects layer at 1:24. E-bow effects underscore lyrics like 'Currents have their say' (2:33) and 'Washes me away' (2:44), which a 3:33 sitar riff answers. These complexities are further transmuted by seemingly random events -- a 4:06 doubling of the sitar riff which 'glitches' and a 4:32 backbeat echo that drifts for four bars. While Reznor's lyrics suggest that he is unable to control subjective time-states (like The Joker in the Batman: Dark Knight series of Kali-yuga comic-books), the track constructions show that the Key to his hold over the listener is very carefully constructed songs whose spaces resemble Pythagorean mathematical formulas. Misdirecting the audience is the secret of many magicians. "The Way Out Is Through" opens the 'Right' disc with an industrial riff that builds at 0:19 to click-track and rhythm, the equivalent of a weaving spiral. Whispering 'All I've undergone/I will keep on' at 1:24, Reznor is backed at 1:38 by synths and drums coalescing into guitars, which take shape at 1:46 and turn into a torrential electrical current. The models are clearly natural morphogenetic structures. The track twists through inner storms and torments from 2:42 to 2:48, mirrored by vocal shards at 2:59 and soundscapes at 3:45, before piano fades in and out at 4:12. The title references peri-natal theories of development (particularly those of Stanislav Grof), which is the source of much of the album's imagery. "Into the Void" is not the Black Sabbath song of the same name, but a catchy track that uses the same unfolding formula (opening static, cello at 0:18, guitars at 0:31, drums and backbeat at 1:02, trademark industrial vocals and synth at 1:02, verse at 1:23), and would not appear out of place in a Survival Research Laboratories exhibition. At 3:42 Reznor plays with the edge of synth soundscapes, merging vocals at 4:02 and ending the track nicely at 4:44 alone. "Where Is Everybody?" emulates earlier structures, but relies from 2:01 on whirring effects and organic rhythms, including a flurry of eight beat pulses between 2:40-2:46 and a 3:33 spiralling guitar solo. The 4:26 guitar solo is pure Adrian Belew, and is suddenly ended by spluttering static and white noise at 5:13. "The Mark Has Been Made" signals another downshift into introspectiveness with 0:32 ghostly synth shimmers, echoed by cello at 1:04 which is the doubled at 1:55 by guitar. At 2:08 industrial riffs suddenly build up, weaving between 3:28 distorted guitars and the return of the repressed original layer at 4:16. The surprise is a mystery 32 second soundscape at the end with Reznor crooning 'I'm getting closer, all the time' like a zombie devil Elvis. "Please" highlights spacious noise at 0:48, and signals a central album motif at 1:04 with the line 'Time starts slowing down/Sink until I drown'. The psychic mood of the album shifts with the discovery of Imagination as a liberating force against oppression. The synth sound again is remarkably organic for an industrial album. "Starfuckers Inc" is the now infamous sneering attack on rock-stardom, perhaps at Marilyn Manson (at 3:08 Reznor quotes Carly Simon's 'You're So Vain'). Jungle beats and pulsing synths open the track, which features the sound-sculpting talent of Pop Will Eat Itself member Clint Mansell. Beginning at 0:26, Reznor's vocals appear to have been sampled, looped and cut up (apologies to Brion Gysin and William S. Burroughs). The lines 'I have arrived and this time you should believe the hype/I listened to everyone now I know everyone was right' is a very savage and funny exposure of Manson's constant references to Friedrich Nietzsche's Herd-mentality: the Herd needs a bogey-man to whip it into submission, and Manson comes dangerous close to fulfilling this potential, thus becoming trapped by a 'Stacked Deck' paradox. The 4:08 lyric line 'Now I belong I'm one of the Chosen Ones/Now I belong I'm one of the Beautiful Ones' highlights the problem of being Elect and becoming intertwined with institutionalised group-think. The album version ditches the closing sample of Gene Simmons screaming "Thankyou and goodnight!" to an enraptured audience on the single from KISS Alive (1975), which was appropriately over-the-top (the alternate quiet version is worth hearing also). "The danger Marilyn Manson faces", notes Don Webb (current High Priest of the Temple of Set), "is that he may end up in twenty years time on the 'Tonight Show' safely singing our favourite songs like a Goth Frank Sinatra, and will have gradually lost his antinomian power. It's much harder to maintain the enigmatic aura of an Evil villain than it is to play the clown with society". Reznor's superior musicianship and sense of irony should keep him from falling into the same trap. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "The Big Come Down" begins with a four-second synth/static intro that is smashed apart by a hard beat at 0:05 and kaleidoscope guitars at 0:16. Critics refer to the song's lyrics in an attempt to project a narcissistic Reznor personality, but don't comment on stylistic tweaks like the AM radio influenced backing vocals at 1:02 and 1:19, or the use of guitars as a percussion layer at 1:51. A further intriguing element is the return of the fly samples at 2:38, an effect heard on previous releases and a possible post-human sub-text. The alien mythos will eventually reign over the banal and empty human. At 3:07 the synths return with static, a further overlay adds more synths at 3:45 as the track spirals to its peak, before dissipating at 3:1 in a mesh of percussion and guitars. "Underneath It All" opens with a riff that signals we have reached the album's climatic turning point, with the recurring theme of fragmenting body-memories returning at 0:23 with the line 'All I can do/I can still feel you', and being echoed by pulsing static at 0:42 as electric percussion. A 'Messiah Complex' appears at 1:34 with the line 'Crucify/After all I've died/After all I've tried/You are still inside', or at least it appears to be that on the surface. This is the kind of line that typical rock critics will quote, but a careful re-reading suggests that Reznor is pointing to the painful nature of remanifesting. Our past shapes us more than we would like to admit particularly our first relationships. "Ripe (With Decay)" is the album's final statement, a complex weaving of passages over a repetitive mesh of guitars, pulsing echoes, back-beats, soundscapes, and a powerful Mike Garson piano solo (2:26). Earlier motifs including fly samples (3:00), mournful funeral violas (3:36) and slowing time effects (4:28) recur throughout the track. Having finally reached the psychotic core, Reznor is not content to let us rest, mixing funk bass riffs (4:46), vocal snatches (5:23) and oscillating guitars (5:39) that drag the listener forever onwards towards the edge of the abyss (5:58). The final sequence begins at 6:22, loses fidelity at 6:28, and ends abruptly at 6:35. At millennium's end there is a common-held perception that the world is in an irreversible state of decay, and that Culture is just a wafer-thin veneer over anarchy. Music like The Fragile suggests that we are still trying to assimilate into popular culture the 'war-on-Self' worldviews unleashed by the nineteenth-century 'Masters of Suspicion' (Charles Darwin, Sigmund Freud, Friedrich Nietzsche). This 'assimilation gap' is evident in industrial music, which in the late 1970s was struggling to capture the mood of the Industrial Revolution and Charles Dickens, so the genre is ripe for further exploration of the scarred psyche. What the self-appointed moral guardians of the Herd fail to appreciate is that as the imprint baseline rises (reflective of socio-political realities), the kind of imagery prevalent throughout The Fragile and in films like Strange Days (1995), The Matrix (1999) and eXistenZ (1999) is going to get even darker. The solution is not censorship or repression in the name of pleasing an all-saving surrogate god-figure. No, these things have to be faced and embraced somehow. Such a process can only occur if there is space within for the Sadeian aesthetic that Nine Inch Nails embodies, and not a denial of Dark Eros. "We need a second Renaissance", notes Don Webb, "a rejuvenation of Culture on a significant scale". In other words, a global culture-shift of quantum (aeon or epoch-changing) proportions. The tools required will probably not come just from the over-wordy criticism of Cyber-culture and Cultural Studies or the logical-negative feeding frenzy of most Music Journalism. They will come from a dynamic synthesis of disciplines striving toward a unity of knowledge -- what socio-biologist Edward O. Wilson has described as 'Consilience'. Liberating tools and ideas will be conveyed to a wider public audience unfamiliar with such principles through predominantly science fiction visual imagery and industrial/electronica music. The Fragile serves as an invaluable model for how such artefacts could transmit their dreams and propagate their messages. For the hyper-alert listener, it will be the first step on a new journey. But sadly for the majority, it will be just another hysterical industrial album promoted as selection of the month. References Bester, Alfred. The Stars My Destination. London: Millennium Books, 1999. Eshun, Kodwo. More Brilliant than the Sun: Adventures in Sonic Fiction. London: Quartet Books, 1998. Van der Kolk, Bessel A. "Trauma and Memory." Traumatic Stress: The Effects of Overwhelming Experience on Mind, Body, and Society. Eds. Bessel A. van der Kolk et al. New York: Guilford Press, 1996. Nine Inch Nails. Downward Spiral. Nothing/Interscope, 1994. ---. The Fragile. Nothing, 1999. ---. Pretty Hate Machine. TVT, 1989. Citation reference for this article MLA style: Alex Burns. "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile." M/C: A Journal of Media and Culture 2.8 (1999). [your date of access] <http://www.uq.edu.au/mc/9912/nine.php>. Chicago style: Alex Burns, "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile," M/C: A Journal of Media and Culture 2, no. 8 (1999), <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]). APA style: Alex Burns. (1999) 'This machine is obsolete': a listeners' guide to Nine Inch Nails' The fragile. M/C: A Journal of Media and Culture 2(8). <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]).

Over time, many groups have sought to offer alternatives to the dominant culture of the day; for example, the civil-rights movements, antiwar protests, and environmental activism of the 1960s and 1970s. Not all groupings however can be considered countercultural. Roberts makes a distinction between group culture where cultural patterns only influence part of one’s life, or for a limited period of time; and countercultures that are more wholistic, affecting all of life. An essential element in defining a counterculture is that it has a value-conflict with the dominant society (Yinger), and that it demonstrates viability over time: long enough to pass on the values to the next generation (Roberts). Each society has images of what it means to be a good citizen. These images are driven by ideology and communicated through media channels, educational values and government legislation. Ideologies are not neutral and compete for the “common sense” of citizens; seeking to shape desires and allegiance to a particular way of life. A way of life is expressed in the everyday practices, or routines and choices that make up an ordinary day, the sum of which express the values of individuals and communities. A number of groups or movements have sought to counter the values and practices of dominant cultures only to find themselves absorbed into it. For example, the surfing magazine Tracks was an Australian countercultural text that chronicled the authentic surfing lifestyle of the 1970s. As surfing became big business, the same magazine was transformed into a glossy lifestyle publication. The surfing lifestyle had become part of the expanding field of consumption and Tracks had become one more tool to promote it (Henderson). As the “counter” is absorbed into the dominant consumer culture, new ways to engage the hegemonic culture emerge that offer fresh possibilities of living and engaging in contemporary society. Positioning I hold to a critical postmodern perspective of consumption. That is, while I acknowledge some of the pleasures of consumption, I see a dominant posture of detachment as a result of consumer cultures increased distance from production, producers and the products we buy (Cavanaugh; Sandlin, Kahn, Darts and Tavin). The market is a powerful educator of individuals (Kincheloe; Steinberg), but it is not the only educator. Families, schools, churches and other interest groups also seek to educate, or shape, individuals. These competing influences do not however hold equal power. In many instances the families, schools, churches and interest groups have uncritically adopted the dominant ideology of the market and so reinforce the values of consumerism; such is its hegemonic power. I hold that individuals, and more importantly communities, have some agency to consume in alternative ways that give rise to the formation of different identities. I see critical practices as important in the awareness raising, or awakeness, and shaping of an individual and a community (Freire; Rautins and Ibrahim). Contemporary Cultures Consumption has become the organizing principle of many contemporary cultures (Hoechsmann). The message that to be a good citizen is to be a good consumer is pervasive and promoted as key to economic growth and the remedy to lift countries out of recession. This message of consumption falls on fertile ground with the development of consumerism, or consumer culture. Smart (5) sees this expressed as a way of life that is “perpetually preoccupied with the pursuit, possession, rapid displacement, and replacement of a seemingly inexhaustible supply of things.” These “things” have increasingly become luxury goods and services as opposed to the satisfaction of basic needs and wants (de Geus). Contemporary Alternatives There are examples of contemporary alternatives that open spaces for people to imagine that “another world is possible.” Sandlin, Kahn, Darts and Tavin (102, 103) call upon educators to “critically analyze what it might mean to resist a consumer society predicated on the normalization of overconsumption” and to “celebrate the creative and critical agency of all those who resist and interrogate the hegemony of multinational companies/industries.” A number of examples are worth celebrating and critically analysing to offer input in the engagement with the dominant culture of consumption. The examples of the Adbusters Media Foundation, Bill Talen’s work as a political-theatre activist, and the voluntary simplicity movement will be briefly examined before exploring the contribution of monasticism. The Adbusters Media Foundation produces a glossy bimonthly publication and website that seeks to unmask the destructive power of global corporations. Through the use of cultural resistance techniques such as “culture jamming,” Adbusters remix advertisements to catch the reader by surprise, to make the taken for granted problematic, and to open them to the possibility of an alternative view of reality. These “subvertisements” offer the opportunity for detournement; a turning around or a change in perspective (Darts; Sandlin and Callahan). As people get involved in “culture jamming” they become producers of artifacts and not just consumers of them. The work of Adbusters uses the tools of the media saturated consumer culture to critique that very culture (Rumbo). Advertising performs an ideological function within a consumer culture that addresses people as individual private consumers rather than citizens concerned for the public good (Scatamburlo-D’Annibale). Given the ubiquity of advertising, individuals become ambivalent to its messages but still soak in the dominant narrative. The very form of resistance reinforces the culture of the individualistic citizen as consumer. While it might be seen that the “culture jamming” artifacts of the Adbusters type might not have substantial effect on the broader public, it does provide an accessible means of resistive action for the individual (Haiven). Bill Talen is a political-theatre activist who plays the Southern evangelical preacher Reverend Billy as leader of the Church of Stop Shopping. The Reverend stages “retail interventions” or performances in public spaces and retail stores as an act of “culture jamming”. Reverend Billy uses humour, music, art and theatre in his “services” to create strangeness, discomfort or ambiguity in the lives of the public. In doing so he calls people into transitional spaces where what was normal is disrupted and they are free to imagine differently. This disruption that causes a movement into the unknown is a central pedagogical strategy that seeks to encourage people to question their taken for granted understandings of life (Littler; Sandlin, Learning). Reverend Billy and the Church of Stop Shopping offer a fuller bodied experience of “culture jamming” that engages both the body and the emotions. The act of creating culture together is what fosters a sense of community amongst culture jammers (Sandlin, Popular culture). And yet Reverend Billy and the Church of Stop Shopping appear not to be focused for their own good in that they have formed a number of coalitions with other organisations to work on campaigns that oppose global corporations and the influence of consumerism’s ideology on everyday life. Reverend Billy not only creates disruption in people’s relationship with consumption, he also provides an alternative place to belong. The voluntary simplicity movement involves a growing number of people who choose to limit their incomes and consumption because of new priorities in life. Those involved call into question the dominant cultures view of the “good life” in favour of a less materialistic lifestyle that is more “personally fulfilling, spiritually enlightening, socially beneficial, and environmentally sustainable” (Johnson 527). Grigsby’s research (qtd. in Johnson) found that participants were involved in forming their own identities through their lifestyle choices. The voluntary simplicity movement, it appears, is a niche for those who understand consumption from a postmodern perspective and participate in alternative lifestyle practices. Sandlin (Complicated) sees the formation of collective identity as crucial to a movement’s ability to effectively engage in external education. A shared vision, or telos, is central to that forming of collective identity. However, the voluntary simplicity movement is focused primarily on individual lifestyle changes, thus making it ineffectual as a collective to challenge dominant ideologies or to engage in external education to that end. Each of the examples above provides some insight into a considered engagement with the dominant culture: the creation of Adbuster like “culture jamming” artifacts provides an accessible means of engagement for the individual; Bill Talen’s interventions show an appreciation of the importance of community in supporting countercultural choices; and the voluntary simplicity movement promotes a “whole of life” approach to countercultural engagement. However, when comparing the above examples with Roberts’s definition of a counterculture they appear to be lacking. Roberts (121) holds that “the term counter-culture might best be reserved for groups which are not just a reaction formation to the dominant society, but which have a supporting ideology that allows them to have a relatively self-sufficient system of action.” The remainder of this article examines monasticism as an example of a counter-culture that offers an alternative model of “the good-life” based on a clear ideology and a fifteen hundred year history. Considering Monasticism As seen above, the work of countering the dominant ideology is not without its difficulties. bell hooks found that offering an education that enhances students’ journey to wholeness went against the anti-intellectualism of the current education system. What enabled her to stand within and resist the oppressive dominant culture, and offer alternatives, was the sustaining power of spirituality in her life, the basis of her hope. Tolliver and Tisdell appreciate that spirituality can be an elusive term, but that amongst the definitions offered there are commonalities. These are that: spirituality is about a connection to what is referred to by various names, such as the Life Force, God, a higher power or purpose, Great Spirit, or Buddha Nature. It is about meaning making and a sense of wholeness, healing and the interconnectedness of all things. […] As many have noted, those who value spirituality generally believe that it is possible for learners to come to a greater understanding of their core essence through transformative learning experiences that help them reclaim their authenticity. (Tolliver and Tisdell 38) There is a growing interest in the age-old traditions of Christian monasticism as a means of addressing the challenges of contemporary life (Adams; Jamison). When the BBC broadcast the television series The Monastery in 2005, millions of viewers tuned in to follow the way five ordinary men were affected by the experience of living in a monastery for forty days and nights. Similarly in Australia in 2007, the ABC broadcast the television series The Abbey that followed the experiences of five ordinary women enclosed for 33 days and nights in the space and routines of the Benedictine nuns at Jamberoo Abbey. It was when watching these television series that I was led to consider monasticism as an example of cultural resistance, and to ponder the contribution it might make to the conversation around counter-cultures. As an observer, I find something compelling about monasticism, however I am aware of the possibility of romanticising it as a way of life. The tensions, difficulties and struggles represented in the television series help to temper that. Benedictine spirituality is the foundation for life at the Worth Abbey (The Monastery) and the Jamberoo Abbey (The Abbey). The essential dynamic that underlies this spirituality is a shaping of life according to the Bible and the guidelines set out in the sixth century Rule of Benedict. Monastic life in a Benedictine abbey is marked by certain routines, or rhythms, that are designed to help the community better love God, self and one another (Benedict, chapter 4). “Listen” is the first word in the Rule of Benedict and is closely linked to silence (Benedict, chapter 6). As a key part of monastic life, silence gives the monastics the freedom and space to listen to God, themselves, one another, and the world around them. As Adams (18) points out, “the journey to knowing God must include the discipline of coming to know yourself, and that risky journey invariably starts in silence.” The rhythm of monastic life therefore includes times in the day for silence and solitude to facilitate listening and self-reflection. For Benedict, distractions in the head are actually noises inside the heart: the result of human desires and preoccupations. Silence, and the reflection that occurs within it, allows the monastic to listen for, and see their own relationship to, competing ideologies. This everyday practice of listening might be explained as paying attention to what is noticed, reflecting on it and the internal response to it. In this way listening is an active engagement with the words read (Irvine), the stories heard, the conversations had, and the objects used. Hoffman (200) observes that this practice of attentive listening is evident in decision making within the monastery. Seen in this way, silence acts as a critical practice counter to the educative agenda of consumerism. Physical work is a basic part of monastic life. All members of the community are expected to share the load so that there is no elitism, no avoiding work. This work is not to be seen as a burden but an outlet for creativity (Benedict, chapter 57). By being involved in the production of goods or the growing of crops for the community and others, monastics embody practices that resist the individual consumer identity that consumerism seeks to create. Monastics also come to appreciate the work involved in the products they create and so become more appreciative of, and place greater value on them. Material things are not privately owned but are to be seen as on loan so that they are treated with a level of gratitude and care (Benedict, chapter 32). This attitude of not taking things for granted actually increases the enjoyment and appreciation of them (De Waal). De Waal likens this attitude to the respect shown towards people and things at the Japanese tea ceremony. She says that “here in the most simple and yet profound ceremony there is time to gaze at things, to enjoy them, and to allow them to reveal themselves as they truly are” (87). Such a listening to what products truly are in the dominant consumer culture might reveal chairs made from the denuded forests that destroy habitats, or shoes made with child labour in unsafe conditions. The monastic involvement in work and their resulting handling of material things is a critical practice counter to the ideology of consumerism and the attitude towards products flooding markets today. Community is central to monastic life (Veilleux). Through vows, the monastic commits to life in a particular place with particular people. The commitment to stability means that when conflict arises or disagreements occur they need to be worked out because there is no running away. Because a commitment to working things out requires attention to what is real, monastic community acts as a counter of all that is not real. The creation of false need, the promise of fulfilment, and the creation of identity around consumption can be viewed through the same commitment to reality. This external stability is a reflection of inner stability marked by a unity and coherence of purpose and life (De Waal). A monastic community is formed around a shared telos that gives it a collective identity. While people are welcomed as guests into the community with Benedictine hospitality, the journey to becoming a member is intentionally difficult (Benedict, chapter 58). The importance of committing to community and the sharing of the collective telos is not a rushed decision. The stability and permanence of monastic commitment to community is a counter to the perpetual chasing and replacing of other goods and experiences that is a part of consumerism. The deliberate attention to practices that form a rhythm of life involving the whole person shows that monastic communities are intentional in their own formation. Prayer and spiritual reading are key parts of monastic life that demonstrate that spirituality is central in the formation of individuals and communities (Benedict, prologue). The formation is aligned to a particular ideology that values humanity as being made in the image of God and therefore the need to focus on the connection with God. A holistic humanity addresses issues and development of the mind, body and spirit. Examining Ideology The television series The Monastery and The Abbey demonstrate that when guests enter a monastic community they are able to experience an alternative model of “the good life”. If, as Roberts suggests, a counter-culture looks to reform society by providing an alternative model, then change is based upon seeing the alternative. The guests in the monastic community are involved in discussions that make explicit the monastic ideology and how it shapes the countercultural values and practices. In doing so, the guests are invited to listen to, or examine the consumerist ideology that permeates their society and shapes their everyday experiences. In evaluating the conflicting ideologies, the guests are free to choose an alternative view, which, as the television series showed are not necessarily that of the monastic community, and may in fact remain that of consumerism. Conclusion While ideologies are not neutral, they are often invisible. The dominant ideology of consumerism reduces citizens to individualistic consumers and naturalises the need for never ending consumption. A number of groups or movements attempt to expose the logic of consumerism and offer alternative ways of consuming. Each has their own strengths and weaknesses; some are absorbed into the very culture they seek to counter while others remain apart. Christian monasticism, based on the Bible and the Rule of Benedict, engages in the social practices of listening, physical work, and commitment to community. The formation of individuals, and the community, is based explicitly on an ideology that values humanity as made in God’s image. This model has stood the test of time and shown itself to be a legitimate counterculture that is in value-conflict with the current dominant culture of consumption. References Adams, Ian. Cave, Refectory, Road. Norwich: Canterbury Press, 2010. Benedict and Patrick Barry. Saint Benedict’s Rule. Mahweh, New Jersey: Hidden Spring, 2004. Cavanaugh, William. Being Consumed: Economics and Christian Desire. Grand Rapids, Michigan: Eerdmans, 2008. Darts, David. “Visual Culture Jam: Art, Pedagogy, and Creative Resistance.” Studies in Art Education 45 (2004):313–327. De Geus, Marius. “Sustainable Hedonism: The Pleasures of Living within Environmental Limits.” The Politics and Pleasures of Consuming Differently. Eds. Kate Soper, Martin Ryle, and Lyn Thomas. London: Palgrave MacMillian. 2009. 113–129 De Waal, Esther. Seeking God: The Way of St Benedict. London: Fount, 1996. Freire, Paulo. Pedagogy of the Oppressed. London: Penguin, 1970. Grigsby, Mary. Buying Time and Getting By: The Voluntary Simplicity Movement. Albany, NY: State University of New York Press, 2004. Haiven, Max. “Privatized Resistance: AdBusters and the Culture of Neoliberalism.” The Review of Education, Pedagogy, and Cultural Studies 29 (2007): 85–110. Henderson, Margaret. “The Big Business of Surfing’s Oceanic Feeling: Thirty Years of Tracks Magazine.” Growing Up Postmodern: Neoliberalism and the War on the Young. Ed. Ronald Strickland. London: Rowman & Littlefield, 2002. 141–167 hooks, Bell. Teaching Community. New York: Routledge, 2003. Hoechsmann, Michael. “Rootlessness, Reenchantment, and Educating Desire: A Brief History of the Pedagogy of Consumption.” Critical Pedagogies of Consumption. Eds. Jennifer Sandlin & Peter McLaren. New York: Routledge, 2010. 23–35. Hoffman, Mary. “Ora et Labora (Prayer and Work): Spirituality, Communication and Organizing in Religious Communities”. JCR 30 (2007): 187–212. Irvine, R. D.G. “How to Read: Lectio Divina in an English Benedictine Monastery”. Culture and Religion 11.4 (2010):395–411. Jamison, Christopher. Finding Sanctuary. London: Weidenfeld & Nicolson, 2006. Johnson, Brett. “Simply Identity Work? The Voluntary Simplicity Movement.” Qualitative Sociology 24.4 (2004): 527–530. Kincheloe, Joe. “Consuming the All-American Corporate Burger: McDonald’s “Does It All for You”. Critical Pedagogies of Consumption. Eds. Jennifer Sandlin & Peter McLaren. New York: Routledge, 2010. 137–147. Littler, Jo. “Beyond the Boycott: Anti-Consumerism, Cultural Change and the Limits of Reflexivity”. Cultural Studies 19.2 (2005): 227–252. Rautins, Cara, and Awad Ibrahim. “Wide-Awakeness: Toward a Critical Pedagogy of Imagination, Humanism, Agency, and Becoming.” International Journal of Critical Pedagogy 3.3 (2011): 24–36.Reverend Billy and the Stop Shopping Choir. 2014. 26 Nov. 2014 ‹http://www.revbilly.com›. Roberts, Keith. “Toward a Generic Concept of Counter-Culture.” Sociological Focus 11.2 (1978): 111–126. Rumbo, Joseph. “Consumer Resistance in a World of Advertising Clutter: The Case of Adbusters”. Psychology & Marketing 19.2 (2002): 127–148. Sandlin, Jennifer. “Popular Culture, Cultural Resistance, and Anticonsumption Activism: An Exploration of Culture Jamming as Critical Adult Education.” New Directions for Adult and Continuing Education 115 (2007): 73–82. Sandlin, Jennifer. “Complicated Simplicity: Moral Identity Formation and Social Movement Learning in the Voluntary Simplicity Movement.” Adult Education Quarterly 59.4 (2009): 298–317. Sandlin, Jennifer. “Learning to Survive the ‘Shopocalypse’: Reverend Billy’s Anti-Consumption ‘Pedagogy of the Unknown’.” Critical Studies in Education 51.3 (2010): 295–311. Sandlin, Jennifer, and Jamie Callahan. “Deviance, Dissonance, and Detournement.” Journal of Consumer Culture 9.1 (2009): 79–115. Sandlin, Jennifer, Richard Kahn, David Darts, and Kevin Tavin. “To Find the Cost of Freedom: Theorizing and Practicing a Critical Pedagogy of Consumption.” Journal for Critical Education Policy Studies 7.2 (2009): 98–123. Scatamburlo-D’Annibale, V. “Beyond the Culture Jam.” Critical Pedagogies of Consumption. Eds. Jennifer Sandlin & Peter McLaren. New York: Routledge, 2010. 224–236. Smart, Barry. Consumer Society: Critical Issues and Environmental Consequences. London: Sage, 2010. Steinberg, Shirley. “Barbie: The Bitch Can Buy Anything.” Critical Pedagogies of Consumption. Eds. Jennifer Sandlin & Peter McLaren. New York: Routledge, 2010. 148–156. Tolliver, Derise, and Elizabeth Tisdell. “Engaging Spirituality in the Transformative Higher Education Classroom.” New Directions for Adult and Continuing Education 109 (2006): 37–47. Veilleux, Armand. “Identity with Christ: Modeling our Lives on RB 72.” Cistercian Studies Quarterly 45.1 (2010):13–33. Yinger, Milton. “Contraculture and Subculture.” American Sociological Review 25 (1960): 625–635.

Photo by Patrick Tomasso on Unsplash ABSTRACT In cases where the law conflicts with bioethics, the status of rights must be determined to resolve some of the tensions. This paper considers the origins of both legal and philosophical rights, arguing that rights per se do not exist naturally. Even natural rights that are constitutional or statutory came from relationships rather than existing in nature. Once agreed upon, rights develop moral influence. INTRODUCTION l. The Question of Rights The language of rights is omnipresent in current discourse in law, bioethics, and many other disciplines. Rights dialogue is frequently contentious – some thinkers take issue with various uses of rights in the modern dialogue. For example, some criticize “rights talk,” which heightens social conflict when used as a “trump” against disfavored arguments.[1] Others are displeased by what is termed “rights inflation,” where too many novel rights are developed, such that the rights these scholars view as “more important” become devalued.[2] Some solutions have been proposed: one recommendation is that rights should be restricted to extremely important or essential ones. Some Supreme Court justices make arguments for applying original meanings in legal cases.[3] Conflict over the quantity and status of rights has long been a subject of debate in law and philosophy. Even Jefferson had to balance his own strict reading of the Constitution with tendencies to exceed the plain text of the document.[4] This thread of discourse has grown in political prominence over the years, with more Supreme Court cases that suggest newly developed (or, perhaps, newly recognized) rights. The theoretical conflict between textualists and those looking to intent or context could lead to repealing rights to abortion, sterilization, or marital privacy and deeply impacts our daily lives. Bioethics is ubiquitous, and rights discourse is fundamental. This paper analyzes the assumptions that underlie the existence of rights. The law is steeped in philosophy, though philosophical theories have an often-unacknowledged role. This is especially true in cases that navigate difficult bioethical issues. As a result of this interleaving, the ontological status of rights is necessary to resolve some of the theoretical tensions. Many philosophers have either argued for or implicitly included human rights in their theories of morality and legality. However, there is no universally accepted definition of rights; various philosophers have their own approaches. For example: Louden comments, “Rights are permissions rather than requirements. Rights tell us what the bearer is at liberty to do”; Martin thinks that a right is “an established way of acting”; Hohfeld concludes that all rights are claims.[5] Similarly, there is dissent about the qualities of rights: The Declaration of Independence characterizes rights as unalienable, but not all thinkers agree. Nickel comments, “Inalienability does not mean that rights are absolute or can never be overridden by other considerations. . . Perhaps it is sufficient to say that [human] rights are very hard to lose.”[6] This discord necessitates additional analysis. “Many people tend to take the validity of. . . rights for granted. . . However, moral philosophers do not enjoy such license for epistemological complacency.”[7] Because of the fundamental impact that political and moral philosophy enacted as the law have, this paper considers the origins of both legal and philosophical rights, arguing that rights per se do not exist naturally. Even natural rights that are constitutional or statutory came from relationships rather than existing in nature. Once agreed upon, rights take on moral force. ll. Legal Rights: From Case to Constitution Bioethics and law sometimes address rights differently. Three Supreme Court cases marked the development of privacy rights in the United States: Griswold v. Connecticut (1965), Roe v. Wade (1973) and Cruzan v. Director, Missouri Department of Health (1990). These cases shape the normative dialogue and consider complex moral quandaries. Griswold v. Connecticut concerned providing contraception to married couples in contravention of state law. Justice Douglas writes for the majority that, based in “a right of privacy older than the Bill of Rights,” legally protected zones of privacy extend from the text of the Constitution. “Specific guarantees in the Bill of Rights have penumbras, formed by emanations from those guarantees that help give them life and substance.”[8] Writing in dissent, Justice Black argues that there is not a broad right to privacy included in the provisions of the Constitution, and expresses concern over “dilut[ion] or expans[ion]” of enumerated rights by terms such as privacy, which he characterizes as abstract and ambiguous – and subject to liberal reinterpretation.[9] He concludes that the government does have the right to invade privacy “unless prohibited by some specific constitutional provision.”[10] Also dissenting, Justice Stewart finetunes the argument: rather than look to community values beyond the Constitution, the Court ought to rely solely on text of the document, in which he “can find no such general right of privacy in the Bill of Rights, in any other part of the Constitution, or in any case ever decided by this court.”[11] Thus, Griswold v. Connecticut is an example of the tensions within the Supreme Court over strict textualism or broader interpretations of the Constitution that look to intent and purpose. Roe v. Wade held that there is a right to privacy found through the Due Process Clause of the Fourteenth Amendment that includes the right to make medical decisions including abortion. While the conclusion – that there is a Constitutionally protected right to abortion, with certain limits seems to expand the Griswold doctrine of privacy rights, dissent to the ruling stems from much the same concern as before. Justice Rehnquist writes: A transaction resulting in an operation such as this is not "private" in the ordinary usage of that word. Nor is the "privacy" that the Court finds here even a distant relative of the freedom from searches and seizures protected by the Fourth Amendment to the Constitution, which the Court has referred to as embodying a right to privacy.[12] However, he then departs from the stricter approach of Justices Black and Stewart: I agree… that the "liberty," against deprivation of which without due process the Fourteenth Amendment protects, embraces more than the rights found in the Bill of Rights. But that liberty is not guaranteed absolutely against deprivation, only against deprivation without due process of law.[13] This is a tempering of the stricter constructionism found earlier, where more latitude is allowed for the interpretation of the text of the Constitution, even though there are clearly limits on how far the words may be stretched, with the genesis of a new right. Later, in Planned Parenthood of Southwestern Pennsylvania v. Casey, the Court further refined Roe v. Wade implementing an “undue burden” test.[14] In Cruzan v. Director, Missouri Department of Health, the Court held that there is a general liberty interest in the refusal of medical treatment. The case continues the tradition of Griswold and Roe v. Wade ensuring a liberty that is beyond the text, but also allows states to impose a strict evidentiary burden to shape how the right is exercised. The Court affirmed the lower court’s decision that “because there was no clear and convincing evidence of Nancy [Cruzan’s] desire to have life-sustaining treatment withdrawn. . . her parents lacked authority to effectuate such a request.”[15] The Supreme Court found that the clear and convincing evidentiary burden applied by the Missouri Supreme Court was consistent with the Due Process clause. Justice Scalia notes that even though he agrees with the Court’s decision, he finds this judgment unnecessary or, perhaps counterproductive, because the philosophical underpinnings of the case “are neither set forth in the Constitution nor known to the nine Justices of this Court any better than they are known to nine people picked at random from the Kansas City telephone directory” and should be left to the states to legislate as they see fit.[16] He goes on to further argue that the Due Process clause “does not protect individuals against deprivations of liberty simpliciter”; rather, it protects them from infringements of liberty that are not accompanied by due process.[17] Justice Scalia’s textualist position likely influenced his remarks.[18] Comparing these cases, I argue there is a distinct effort to make the Constitution amenable to contemporary mores and able to address present issues that is moderated by justices who adhere to the text. The legal evolution of rights that are beyond the text of the Constitution may reflect social norms as well as the framers’ intent. Rights are protected by the Constitution, but the Constitution is mutable, through both case law and legislation. Prior to the adoption of the Constitution, the Declaration of Independence declared: We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness.--That to secure these rights, Governments are instituted among Men, deriving their just powers from the consent of the governed.[19] The Declaration of Independence gives insight into rights prior to the Constitution by referring to a priori rights extended by a creator, sheltered and supported by the state.[20] For earlier evidence of rights, Supreme Court cases often reference English common law doctrines. The common law was informed by preexisting principles and drew on a historical body of thought: philosophy. Exploring philosophy can give insight about the evolution of law. lll. Philosophical Rights: Issues of Ontology A moral right, the precursor to many legal rights, in some ways is a claim that bears moral weight. One relevant distinction is between positive and negative rights: a positive right is a claim on another to do something for the right holder; a negative right is a claim on others to leave the rights holder alone. Some rights are per se (that is, rights that have a de novo ontological origin) and some are constructed (rights that are secondary to some other theoretical apparatus). We must appeal to the state of nature to understand the origin of rights. If rights exist in the state of nature, they are de novo; if not, they are constructed. The state of nature is the theoretical realm where there are no social conventions or no normative rules. The theoretical state of nature is stateless. Hobbes writes about the state of nature. He constructs the person within as incorporating two normative qualities: the law of nature, “whereby individuals are forbidden to do anything destructive of their lives or to omit the means of self-preservation,” and the right of nature, where the person has the “right to all things” – those things required for self-preservation.[21] Similarly, more contemporary philosophers have also inferred that the right to freedom is a natural right.[22] I argue that nature allows every person the freedom to all things, or a natural right against limitation on freedom. Every person has the capacity to do whatever they want, in accordance with their reason; liberty, rather than being a normative claim, is a component of the essence of beings. Yet both nature and other people pose some limitations. Early modern contractarians’ status theories maintain that human attributes engender rights. [23] A specific formulation of human status ethics can be found in Kantian deontology. From the autonomous and rational will, Kant evolves his Categorical Imperative: “Act only according to that maxim whereby you can at the same time will that it should become a universal law.”[24] Without (or before) law, philosophers suggested behaviors should reflect moral rights. Like Rawls, I maintain that the state of nature includes both a scarcity of resources and individuals with whom we may develop conflicts of interest.[25] Individually, we are vulnerable to others, and because of that natural vulnerability, we have an inclination toward self-interest.[26] Therefore, we eventually find the state of nature unsatisfactory and move to create a civil society. Then the subsequent pathway to creating “rights” is well known. People agree on them and act accordingly. Then, they are enshrined in the law.[27] I attribute the impetus to move from the state of nature toward government to interpersonal interaction that creates a form of the social contract. Rawls qualitatively describes this when he notes the “identity of interests” that powers interpersonal cooperation.[28] To me, the development of positive social relations has three components. The first is the human capacity for empathy. Empathy is commonly accepted by psychologists as universal.[29] Kittay deepens the concept of human empathy, arguing that there is a “register of inevitable human dependency” – a natural sense of care found in the human experience of suffering and decay and death to which we all eventually succumb, necessitating a recognition of interdependence and cooperation.[30] The second is the importance of identity in generating social cooperation.[31] There is a sense of familial resemblance that resonates when we see others in our lives, forming the base of the identification that allows us to create bonds of mutual assent. A microsociety develops when people are exposed to each other and acts as a miniaturized state, governed by what is at first an implicit social contract. An internal order is generated and can be codified. The third component of social relations is the extension of the otherness-yet-sameness beyond human adults. Mirroring connects the fully abled adult man and the woman, as well as the child, the physically and mentally disabled, and could extend to animals as well.[32] Therefore, to me, it seems that rights do not exist per se in the state of nature, but because of our human capacities, relationships yield a social contract. This contract governs interpersonal relations with normative power: rights are constructed. Once constructed based on people in micro-society and then larger groups, rights were codified. Negative rights like those found in the U.S. Constitution allow people in liberal society to codify nearly universal ground rules in certain arenas while respecting minority views and differing priorities. However, the social contract is not absolute: it may be broken by any party with the power to enforce their will upon the other and it will evolve to reflect changing standards. So, there is a subtle distinction to be made: in unequal contractual social relations, there are not constructed rights but rather privileges. In a social relationship that aims at equal status among members, these privileges are normative claims – rights that are not inherent or a priori but mandated to be equally applied by society’s governing body. In this way, I differ from Rawls. To me, justice is a fundamental moral principle only for societies that aim at cooperation, where advancing the interests of all is valued.[33] CONCLUSION From Liberty to Law Social contractualism purports to provide moral rules for its followers even when other ethical systems flounder in the state of nature. Relationships consider the needs and wants of others. Rights exist, with the stipulation that they are constructed under social contracts that aim for equality of application. I also suggest that contractualist approaches may even expand the parties who may be allowed rights, something that has significant bearing on the law and practical bioethics. The strict/loose constructionism debate that has played out in the Supreme Court’s decisions focuses on whether rights are enumerated or implied. Theoretical or implicit contracts may be change quickly, based on the power dynamics in a social relationship. Theoretical bounds of the social contract (possibly including animals, nonhumans, etc.) may be constricted by an official contract, so these concerns would need to be adjudicated in the context of the Constitution. In certain cases, strict interpretation reflects the rights determined by the social compact and limits new positive rights; in others, a broad interpretation keeps government out of certain decisions, expanding negative rights to reflect changing social norms. The negative rights afforded in the Constitution provide a framework meant to allow expansive individual choices and freedom. The underlying social compact has more to do with the norms behind societal structure than forcing a set of agreed upon social norms at the level of individual behavior. The Constitution’s text can be unclear, arbitrary, or open to multiple meanings. The literary theorist may be willing to accept contradiction or multiple meanings, but the legal scholar may not. The issue of whether the social compact is set or evolving affects constitutional interpretation. The law is itself may be stuck in a state of indeterminacy: the law, in the eyes of the framers, was centered on a discourse steeped in natural, human rights, attributed to a creator. Today, there is an impulse toward inherent human dignity to support rights. The strict/loose constructionism debate concerns interpretation.[34] In conclusion, rights have no ontological status per se, but are derived from a complex framework that springs from our relationships and dictates the appropriateness of our actions. While the Constitution establishes the negative rights reflecting a social compact, interpretations recognize the limitations on rights that are also rooted in societal relationships. The author would like to thank Stephen G. Post, PhD, and Caitlyn Tabor, JD, for providing feedback on early drafts of this paper. [1] Mary Ann Glendon, A World Made New: Eleanor Roosevelt and the Universal Declaration of Human Rights (New York: Random House, 2001), 14. [2] James Griffin, On Human Rights (Oxford: Oxford University, 2008). [3] Maurice Cranston, What Are Human Rights? (London: Bodley Head, 1973). [4] Barry Balleck, “When The Ends Justify the Means: Thomas Jefferson and the Louisiana Purchase,” Presidential Studies Quarterly 22, no. 4 (1992): 679-680. [5] Robert Louden, “Rights Infatuation and the Impoverishment of Moral Theory,” Journal of Value Inquiry 17 (1983): 95; Rex Martin, A System of Rights (Oxford: Oxford University, 1993), 1; Wesley Hohfeld, Fundamental Legal Conceptions (New Haven: Yale University, 1919), 36. [6] James Nickel, "Human Rights", The Stanford Encyclopedia of Philosophy (Summer 2019 Edition), ed. Edward N. Zalta, accessed 27 April 2021, https://plato.stanford.edu/archives/sum2019/entries/rights-human/. [7] Andrew Fagan, “Human Rights,” Internet Encyclopedia of Philosophy, ed. James Fieser and Bradley Dowden, accessed 27 April 2021, https://iep.utm.edu/hum-rts/. [8] Griswold v. Connecticut 381 U.S. 479 (1965), para. 18, https://www.law.cornell.edu/supremecourt/text/381/479. [9] Griswold v. Connecticut 381 U.S. 479 (1965), para. 69 https://www.law.cornell.edu/supremecourt/text/381/479. [10] Griswold v. Connecticut 381 U.S. 479 (1965), para. 69 https://www.law.cornell.edu/supremecourt/text/381/479. [11] Griswold v. Connecticut 381 U.S. 479 (1965), para. 92 https://www.law.cornell.edu/supremecourt/text/381/479. [12] Roe v. Wade 410 U.S. 113 (1973), 172, https://www.law.cornell.edu/supremecourt/text/410/113%26amp. [13] Roe v. Wade 410 U.S. 113 (1973), 172-173, https://www.law.cornell.edu/supremecourt/text/410/113%26amp. [14] Planned Parenthood of Southeastern Pa. v. Casey, 505 U.S. 833 (1992), https://supreme.justia.com/cases/federal/us/505/833/#:~:text=Casey%2C%20505%20U.S.%20833%20(1992)&text=A%20person%20retains%20the%20right,the%20mother%20is%20at%20risk. [15] Cruzan v. Director, Missouri Department of Health 497 U.S. 261 (1990), https://www.law.cornell.edu/supct/html/88-1503.ZO.html. [16] Cruzan v. Director, Missouri Department of Health 497 U.S. 261 (1990), https://www.law.cornell.edu/supct/html/88-1503.ZO.html. [17] Cruzan v. Director, Missouri Department of Health 497 U.S. 261 (1990), https://www.law.cornell.edu/supct/html/88-1503.ZO.html. [18] It is worth noting that some of the Supreme Court’s conservatives – like Scalia, Thomas, Roberts – have expressed explicit disdain for the right to privacy introduced in Griswold. Jamal Greene, “The So-Called Right to Privacy,” UC Davis Law Review 43 (2010): 715-747, https://scholarship.law.columbia.edu/faculty_scholarship/622. [19] National Archives. “Declaration of Independence: A Transcription.” July 4, 1776; reviewed July 24, 2020, https://www.archives.gov/founding-docs/declaration-transcript. [20] However, the reference to a creator has come to mean a natural right and a priori best describes it rather than a religious underpinning. To borrow from Husserl, this approach will be bracketed out. [21] DJC Carmichael, “Hobbes on Natural Right in Society: The ‘Leviathan’ Account,” Canadian Journal of Political Science 23, no. 1 (1990): 4-5. [22] HLA Hart, “Are There Any Natural Rights?” The Philosophical Review 64, no. 2 (1955): 175. [23] Warren Quinn, Morality and Action (Cambridge: Cambridge UP, 1993), 170. [24] Immanuel Kant, Groundwork of the Metaphysic of Morals, trans. James Ellington, 3rd ed. (Indianapolis: Hackett, 1993), 30. [25] John Rawls, A Theory of Justice: Revised Edition (Cambridge: Belknap, 1999), 109. [26] JS Mill, Remarks on Bentham’s Philosophy, in Collected Works of John Stuart Mill, Vol. X, ed. JM Robson (Toronto: U of Toronto Press, 1985), 13-14. [27] Rex Martin, A System of Rights (Oxford: Oxford University, 1993), 1; Kenneth Baynes, “Kant on Property Rights and the Social Contract,” The Monist 72, no. 3 (1989): 433-453. [28] John Rawls, A Theory of Justice: Revised Edition (Cambridge: Belknap, 1999), 109. [29] Frederik von Harbou, “A Remedy Called Empathy: The Neglected Element of Human Rights Theory,” Archives for Philosophy of Law and Social Philosophy 99, no. 2 (2013): 141. [30] Eva Feder Kittay. Learning from My Daughter: The Value and Care of Disabled Minds (Oxford: Oxford UP, 2019), 145-146. [31] Jane Gallop, “Lacan’s ‘Mirror Stage’: Where to Begin,” SubStance 11, no. 4 (1983): 121; Lacan, Jacques. The Seminar of Jacques Lacan: Book X: Anxiety: 1962-1963, trans. Cormac Gallagher, 26-27, https://www.valas.fr/IMG/pdf/THE-SEMINAR-OF-JACQUES-LACAN-X_l_angoisse.pdf. (In Lacanian psychoanalytic theory, human development necessitates both recognition of the Self and the separation of the Self from the Other.) [32] Lacan, Jacques. The Seminar of Jacques Lacan: Book X: Anxiety: 1962-1963, trans. Cormac Gallagher, 27-28, https://www.valas.fr/IMG/pdf/THE-SEMINAR-OF-JACQUES-LACAN-X_l_angoisse.pdf. [33] There is an interesting discussion to be had about whether social contract theory allows for this gradation in quality of contracts, or whether the two are fundamentally different phenomena. I cannot answer this question here; John Rawls, A Theory of Justice: Revised Edition (Cambridge: Belknap, 1999), 102-103. [34] Ruthellen Josselson, “The Hermeneutics of Faith and the Hermeneutics of Suspicion,” Narrative Inquiry 14, no. 1 (2004): 2-4.

Introduction Sharing food is central to culture. Indeed, according to Montanari, “food is culture” (xii). Ways of sharing knowledge about food, such as the exchange of recipes, give longevity to food sharing. Recipes, an important cultural technology, expand the practice of sharing food beyond specific times and places. The means through which recipes, and information about food, is shared has historically been communicated through whatever medium is available at the time. Cookbooks were among the first printed books, with the first known cookbook published in 1485 at Nuremberg, which set a trend in which cookbooks were published in most of the languages across Western Europe by the mid 16th century (Mennell). Since then, recipe collections have found a comfortable home in new and emerging media, from radio, to television, and now, online. The proliferation of cookbooks and other forms of food-related media “can be interpreted as a reflection of culinary inexperience, if not also incompetence—otherwise why so much reliance on outside advice?” (Belasco 46). Food-related media has also been argued to reflect both what people eat and what they might wish they could eat (Neuhaus, in Belasco). As such, cookbooks, television cooking shows, and food websites help shape our identity and, as Gallegos notes, play “a role in inscribing the self with a sense of place, belonging and achievement” (99). Food writing has expanded beyond the instructional form common to cookbooks and television cooking shows and, according to Hughes, “has insinuated itself into every aspect of the literary imagination” (online) from academic writing through to memoir, fiction, and travel writing. Hughes argues that concerns that people are actually now cooking less that ever, despite this influx of food-related media, miss the point that “food writing is a literary activity […] the best of it does what good writing always does, which is to create an alternative world to the one you currently inhabit” (online). While pragmatic, this argument also reinforces the common perception that food writing is a professional pursuit. It is important to note that while cookbooks and other forms of food-related media are well established as a means for recipes to be communicated, recipes have a longer history of being shared between individuals, that is, within families and communities. In helping to expand recipe-sharing practices, food-related media has also both professionalised and depersonalised this activity. As perhaps a reaction to this, or through a desire to re-establish communal recipe-sharing traditions, blogging, and specifically food blogging, has emerged as a new and viable way for people to share information about food in a non-professional capacity. Blogging has long been celebrated for its capacity to give “ordinary” people a voice (Nilsson). Due to their social nature (Walker Rettberg) and the ability for bloggers to create “networks for sharing ideas, trends and information” (Walker Rettberg 60), blogs are a natural fit for sharing recipes and information about food. Additionally, blogs, like food-related media forms such as cookbooks, are also used as tools for identity building. Blogger’s identities may be closely tied to their offline identity (Baumer, Sueyoshi and Tomlinson), forged through discussions about their everyday lives (Lövheim) or used in a professional capacity (Kedrowicz and Sullivan). Food blogs, broadly defined as blogs primarily focused on food, are one of the most prominent means through which so-called “ordinary” people can share recipes online, and can be seen to challenge perceptions that food writing is a professional activity. They may focus specifically on recipes, restaurant reviews, travel, food ethics, or aesthetic concerns such as food styling and photography. Since food blogs began to appear in the early 2000s, their number has steadily increased, and the community has become more established and structured. In my interview with the writer of the popular blog Chocolate & Zucchini, she noted that when she started blogging about food in 2003 there were perhaps a dozen other food bloggers. Since then, this blogger has become a professional food writer, published author, and recipe developer, while the number of food bloggers has grown dramatically. It is difficult to know the precise number of food blogs—as at July 2012, Technorati ranked more than 16,000 food blogs, including both recipe and restaurant review blogs (online)—but it is clear that they are both increasing in number and have become a common and popular blog genre. For the purposes of this article, food blogs are understood as those blogs that mostly feature recipes. The term “recipe blog” could be used, but food bloggers make little distinction between different topic categories—whether someone writes recipes or reviews, they are referred to as a food blogger. As such, I have used the term “food blog” in keeping with the community’s own terminology and practices. Recipes published on blogs reach a wider audience than those shared between individuals within a family or in a community, but are not as exclusive or professional, in most instances, as traditional food-related media. Blogging allows for the compression of time and space, as people can connect with others from around the world, and respond and reinvigorate posts sometimes several years after they have been written. In this sense, food blogs are more dynamic than cookbooks, with multiple entry points and means for people to discover them—through search engines as well as through traditional word of mouth referrals. This dynamism allows food bloggers to form an active community through which “ordinary” people can share their passion for food and the pleasures of cooking, seek advice, give feedback, and discuss such issues as seasonality, locality, and diet. This article is based on research I conducted on food blogs between 2010 and 2012, which used an ethnographic, cultural studies approach to online community studies to provide a rich description of the food blogging community. It examines how food blogging provides insight into the eating habits of “ordinary” people in a more broad-based manner than traditional food-related media such as cookbooks. It looks at how food blogging has evolved from a subcultural activity to an established and recognised element of the wider food-related media ecology, and in this way has been transformed from a hobbyist activity to a cottage industry. It discusses how food blogs have influenced food-related media and the potential they have to drive food trends. In doing so, this research does not consider the Internet, or online communities, as separate or distinct from offline culture. Instead, it follows Richard Rogers’s argument for a new approach to Internet studies, in which “one is not so much researching the Internet, and its users, as studying culture and society with the Internet” (29). A cultural studies approach is useful for understanding food blogs in a broader historical and cultural context, since it considers the Internet as “a rich arena for thinking about how contemporary culture is constituted” (Hine et al. 2). Food Blogging: From Hobbyist Activity to Cottage Industry Benkler argues that “people have always created their own culture” (296); however, as folk culture has gradually been replaced by mass-produced popular culture, we have come to expect certain production values in culture, and lost confidence in creating or sharing it ourselves, for fear of it not meeting these high standards. Such mass-produced popular culture includes food-related media and recipes, as developing and sharing recipes has become the domain of celebrity chefs. Food blogs are created by “ordinary” people, and in this way continue the tradition of community cookbooks and reflect an increased interest in both the do-it-yourself phenomena, and a resurgence of a desire to share and contribute to folk culture. Jenkins argues that “a thriving culture needs spaces where people can do bad art, get feedback, and get better” (140-1). He notes that the Internet has drastically expanded the availability of these spaces, and argues that: "some of what amateurs create will be surprisingly good, and some artists will be recruited into commercial entertainment or the art world. Much of it will be good enough to engage the interest of some modest public, to inspire someone else to create, to provide new content which, when polished through many hands, may turn into something more valuable down the line" (140-1). Food blogs provide such a space for amateurs to share their creations and get feedback. Additionally, some food bloggers, like the artists to whom Jenkins refers, do create recipes, writing, and images that are “surprisingly good”, and are recruited, not into commercial entertainment or the art world, but into food-related media. Some food bloggers publish cookbooks (for example, Clotilde Dusoulier of Chocolate & Zucchini), or food-related memoirs (for example, Molly Wizenberg of Orangette), and some become food celebrities in their own right, as guests on high profile television shows such as Martha Stewart (Matt Armendariz of mattbites) or with their own cooking shows (Ree Drummond of The Pioneer Woman Cooks). Others, while not reaching these levels of success, do manage to inspire others to create, or recreate their, recipes. Mainstream media has a tendency to suggest that all food bloggers have professional aspirations (see, for example, Phipps). Yet, it is important to note that, many food bloggers are content to remain hobbyists. These food bloggers form the majority of the community, and blog about food because they are interested in food, and enjoy sharing recipes and discussing their interest with like-minded people. In this way, they are contributing to, and engaging with, folk culture within the blogging community. However, this does not mean that they do not have a broader impact on mainstream food-related media. Food-Related Media Response As the food blogging community has grown, food-related media and other industries have responded with attempts to understand, engage with, and manage food bloggers. Food blogs are increasingly recognised as an aspect of the broader food-related media and, as such, provide both competition and opportunities for media and other industries. Just as food blogs offer individuals opportunities for entry into food-related media professions, they also offer media and other industries opportunities to promote products, reach broader audiences, and source new talent. While food bloggers do not necessarily challenge existing food-related media, they increasingly see themselves as a part of it, and expect to be viewed as a legitimate part of the media landscape and as an alternative source of food-related information. As such, they respond positively to the inclusion of bloggers in food-related media and in other food-related environments. Engaging with the food blogging community allows the wider food-related media to subtly regulate blogger behaviour. It can also provide opportunities for some bloggers to be recruited in a professional capacity into food-related media. In a sense, food-related media attempt to “tame” food bloggers by suggesting that if bloggers behave in a way that they deem is acceptable, they may be able to transition into the professional world of food writing. The most notable example of this response to food blogs by food-related media is the decision to publish blogger’s work. While not all food bloggers have professional aspirations, being published is generally viewed within the community as a positive outcome. Food bloggers are sometimes profiled in food-related media, such as in the Good Weekend magazine in The Sydney Morning Herald (Karnikowski), and in MasterChef Magazine, which profiles a different food blogger each month (T. Jenkins). Food bloggers are also occasionally commissioned to write features for food-related media, as Katie Quinn Davies, of the blog What Katie Ate, who is a regular contributor to delicious magazine. Other food bloggers have been published in their own right. These food bloggers have transitioned from hobbyists to professionals, moving beyond blogging spaces into professional food-related media, and they could be, in Abercrombie and Longhurst’s terms, described as “petty producers” (140). As professionals, they have become a sort of “brand”, which their blog supports and promotes. This is not to say they are no longer interested in food or blogging on a personal level, but their relationship to these activities has shifted. For example, Dusoulier has published numerous books, and was one of the first food bloggers to transition into professional food-related media. However, her career in food-related media—as a food writer, recipe developer and author—goes beyond the work of a petty producer. Dusoulier edited the first English-language edition of I Know How To Cook (Mathiot), which, first published in 1932 (in French), has been described as the “bible” of traditional French cookery. Her work revising this classic book reveals that, beyond being a high-profile member of the food blogging community, she is a key figure in wider food culture. Such professional food bloggers achieve a certain level of celebrity both within the food blogging community and in food-related media. This is reflective of broader media trends in which “ordinary” people are “plucked from obscurity to enjoy a highly circumscribed celebrity” (Turner 12), and, in this way, food bloggers challenge the idea that you need to be an “expert” to talk publicly about food. Food Blogging as an Established Genre Food blogs are often included alongside traditional food-related media as another source of food-related information. For example, the site Eat your books, which indexes cookbooks, providing users with an online tool for searching the recipes in the books they own, has begun to index food blogs as well. Likewise, in 2010, the James Beard Foundation announced that their prestigious journalism awards had “mostly abolished separate categories based on publishing platforms”, although they still have an award for best food blog (Fox online). This inclusion reflects how established food blogging has become. Over time, food blogs have co-evolved and converged with food-related media, offering greater diversity of opinion. Ganda Suthivarakom, a food blogger and now director of the SAVEUR website, says that “in 2004, to be a food blogger was to be an outsider in the world of food media. Today, it couldn’t be more different” (online). She argues that “food blogs leveled the playing field […] Instead of a rarefied and inaccessible group of print reviewers having a say, suddenly thousands of voices of varying skill levels and interests chimed in, and the conversation became livelier” (Suthivarakom online). It is worthwhile noting that while there are more voices and more diversity in traditional food-related media, food blogging has also become somewhat of a cliché: it has even been satirised in an episode of The Simpsons (Bailey and Anderson). As food blogging has evolved it has developed into an established and recognised genre, which may be nuanced to the bloggers themselves, but often appears generic to outsiders. Food blogging has, as it were, gone mainstream. As such, the thousands of voices are also somewhat of an echo chamber. In becoming established as a genre, food blogs reflect the gradual convergence of different types of food-related media. Food blogs are part of a wider trend towards user-generated, food-related online content. It could also be argued that reality shows take cues from food blogs in terms of their active audiences and use of social media. MasterChef in particular is supported by a website, a magazine, and active social media channels, reflecting an increasing expectation of audience participation and interactivity in the delivery of food-related information. Food bloggers have also arguably contributed to the increasingly image-driven nature of food-related media. They have also played a key role in the popularity of sharing photos of food through platforms such as Instagram and Pinterest. Food Blogs and Food Trends Food blogs, like cookbooks, can be seen to both reflect and shape culture (Gallegos). In addition to providing an archive of what “ordinary” people are cooking on a scale not previously available, they have potential to influence food trends. Food bloggers are essentially food enthusiasts or “foodies”. According to De Solier, “most foodies see themselves as culturalists rather than materialists, people whose self-making is bound up in the acquisition of cultural experiences and knowledge, rather than the accumulation of material things” (16). As foodies, food bloggers are deeply engaged with food, keen to share their knowledge and, due to the essential and convivial nature of food, are afforded many opportunities to do so. As such, food blogs have influence beyond the food blogging community. For example, food bloggers could be seen to be responsible, in part at least, for the current popularity of macarons. These sweet, meringue-based biscuits were featured on the blog A la cuisine! in 2004—one of the earliest examples of the recipe in the food blogging community. Its popularity then steadily grew throughout the community, and has since been featured on high-profile and popular blogs such as David Lebovitz (2005), The Traveller’s Lunchbox (2005), and La Tartine Gourmand (2006). Creating and posting a recipe for macarons became almost a rite of passage for food bloggers. At a food blogging conference I attended in 2011, one blogger confided to me that she did not feel like a proper blogger because she had not yet made macarons. The popularity of macarons then extended beyond the food blogging community. They were the subject of a book, I Love Macarons (Ogita), first published in Japanese in 2006 and then in English in 2009, and featured in a cooking challenge on MasterChef (Byrnes), which propelled their popularity into mainstream food culture. Macarons, which could have once been seen as exclusive, delicate, and expensive (Jargon and Passariello) are now readily available, and can even be purchased at MacDonalds. Beyond the popularity of specific foods, the influence of food bloggers can be seen in the growing interest in where, and how, food is produced, coupled with concerns around food wastage (see, for example, Tristram). Concerns about food production are sometimes countered by the trend of making foods “from scratch,” a popular topic on food blogs, and such trends can also be seen in wider food culture, such as with classes on topics ranging from cheese making to butchering (Severson). These concerns are also evident in the growing interest in organic and ethical produce (Paish). Conclusion Food blogs have demonstrably revitalised an interest in recipe sharing among “ordinary” people. The evolution of food blogs, however, is just one part of the ongoing evolution of food-related media and recipe sharing technologies. Food blogs are also an important part of food culture, and indeed, culture more broadly. They reflect a renewed interest in folk culture and the trend towards “do-it-yourself”, seen in online and offline communities. Beyond this, food blogs provide a useful case study for understanding how our online and offline lives have become intertwined, and showcase the Internet as a part of everyday life. They remind us that new means of sharing food and culture will continue to emerge, and that our relationships to food and technology, and our interactions with food-related media, must be continually examined if we are to understand the ways they both shape and reflect culture. References Abercrombie, Nicholas, and Brian Longhurst. Audiences: A Sociological Theory of Performance and Imagination. London: Sage, 1998. Armendariz, Matt. Mattbites. 21 Apr. 2013 ‹http://mattbites.com/›. Bailey, Timothy, and Mike B. Anderson. “The Food Wife.” The Simpsons. 2011. 13 Nov. Baumer, Eric, Mark Sueyoshi, and Bill Tomlinson. "Exploring the Role of the Reader in the Activity of Blogging." ACM Conference on Human Factors in Computing Systems. 2008. Belasco, Warren. Food: The Key Concepts. Oxford: Berg, 2008. Benkler, Yochai. The Wealth of Networks: How Social Production Transforms Markets and Freedom. New Haven: Yale U P, 2006. Byrnes, Holly. "Masterchef's Macaron Madness." The Daily Telegraph (2010). 6 Jul. ‹http://www.dailytelegraph.com.au/entertainment/masterchefs-macaroon-madness/story-e6frewyr-1225888378794%3E. Clement. “Macarons (IMBB 10).” A La Cuisine!. 21 Nov. 2004. 21 Apr. 2013 ‹http://www.alacuisine.org/alacuisine/2004/11/macarons_imbb_1.html›. DeSolier, Isabelle. "Making the Self in a Material World: Food and Moralities of Consumption." Cultural Studies Review 19.1 (2013): 9–27. Drummond, Ree. The Pioneer Woman Cooks!. 21 Apr. 2013 ‹http://thepioneerwoman.com/cooking/›. Dusoulier, Clotilde. Chocolate and Zucchini. 21 Apr. 2013. ‹http://chocolateandzucchini.com/›. Fox, Nick. "Beard Awards Will Not Distinguish between Online and Print Journalism." New York Times (2010). 14 Oct. ‹http://dinersjournal.blogs.nytimes.com/2010/10/14/beard-awards-will-not-distinguish-between-online-and-print-journalism/%3E›.. Gallegos, Danielle. "Cookbooks as Manuals of Taste." Ordinary Lifestyles: Popular Media, Consumption and Taste. Eds. Bell, David and Joanne Hollows. Maidenhead: Open University Press, 2005. 99–110. Hine, Christine, Lori Kendall, and Danah Boyd. "Question One: How Can Qualitative Internet Researchers Define the Boundaries of Their Projects?" Internet Inquiry: Conversations About Method. Eds. Baym, Nancy K. and Annette N. Markham. Los Angeles: Sage, 2009. 1-32. Hughes, Kathryn. "Food Writing Moves from Kitchen to Bookshelf." guardian.co.uk (2010). 19 June ‹http://www.guardian.co.uk/books/2010/jun/19/anthony-bourdain-food-writing. Jargon, Julie, and Christina Passariello. "Mon Dieu! Will Newfound Popularity Spoil the Dainty Macaron?" Wall Street Journal. 2 March (2010). 21 April 2013 ‹http://online.wsj.com/article/SB10001424052748704269004575073843836895952.html›. Jenkins, Henry. Convergence Culture: Where Old and New Media Collide. New York: New York U P, 2008. Jenkins, Trudi. "Blog File." MasterChef Magazine 2010: 20. Karnikowski, Nina. "Eat, Cook, Blog." Good Weekend 18 Feb. 2012: 29–33. Kedrowicz, April Ann, and Katie Rose Sullivan. "Professional Identity on the Web: Engineering Blogs and Public Engagement." Engineering Studies 4.1 (2012). Lebovitz, David. David Lebovitz. 21 Apr. 2013. ‹http://www.davidlebovitz.com›. Lebovitz, David. “French Chocolate Macaron Recipe.” David Lebovitz. 26 Oct. 2005. 21 Apr. 2013. ‹http://www.davidlebovitz.com/2005/10/french-chocolat/›. Lövheim, Mia. "Young Women's Blogs as Ethical Spaces." Information, Communication & Society 14.3 (2011): 338–54. Mathiot, Ginette. I Know How to Cook. Trans. Forster, Imogen. UK ed. London: Phaidon Press Limited, 2009. Melissa. “The Mighty Macaron.” The Traveller’s Lunchbox. 27 Sep. 2005. 21 April 2013. ‹http://www.travelerslunchbox.com/journal/2005/9/27/the-mighty-macaron.html Mennell, Stephen. All Manners of Food. 2nd ed. U of Illinois P, 1996. Montanari, Massimo. Food Is Culture. Trans. Albert Sonnenfeld. New York: Columbia U P, 2006. Nilsson, Bo. "Politicians’ Blogs: Strategic Self-Presentations and Identities." Identity: An International Journal of Theory and Research 12.3 (2012): 247–65. Ogita, Hisako. I Love Macarons. San Francisco: Chronicle Books LLC, 2009. Paish, Matt. "Ethical Food Choices Influencing Product Development, Research Finds." Australian Food News 21 Dec. 2011. ‹http://www.ausfoodnews.com.au/2011/12/21/ethical-food-choices-influencing-product-development-research-finds.html›. Peltre, Béatrice. “Macarons or Victim of a Food fashion—Les macarons ou victime d’une mode culinaire.” La Tartine Gourmande. 10 Dec. 2006. 21 Apr. 2013. ‹http://www.latartinegourmande.com/2006/12/10/macarons-or-victim-of-a-food-fashion-les-macarons-ou-victime-dune-mode-culinaire/›. Phipps, Catherine. "From Blogs to Books." The Guardian (2011). 6 June ‹http://www.guardian.co.uk/lifeandstyle/wordofmouth/2011/jun/06/from-blogs-to-books›. Quinn Davies, Katie. "Brunch Time." delicious. 2012: 98–106. Rogers, Richard. The End of the Virtual: Digital Methods. Inaugural Lecture: Delivered on the Appointment to the Chair of New Media & Digital Culture. 8 May 2009. Vossiuspers UvA. Severson, Kim. "Don't Tell the Kids." The New York Times. 2 Mar. 2010. sec. Dining & Wine. Suthivarakom, Ganda. "How Food Blogging Changed My Life " Saveur. 9 May 2011. Technorati. "Blog Directory / Living". 2012. 22 Jul. 2012. ‹http://technorati.com/blogs/directory/living/food/%3E. Tristram, Stuart. Waste: Uncovering the Global Food Scandal. London: Penguin, 2009. Turner, Graeme. Ordinary People and the Media: The Demotic Turn. Theory, Culture & Society. Ed. Featherstone, Mike. London: Sage, 2010. Walker Rettberg, Jill. Blogging. Digital Media and Society Series. Cambridge: Polity, 2008. Wizenberg, Molly. Orangette. 21 Apr. 2013. ‹http://orangette.blogspot.com.au/›.