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1
Dunbar, Karen, Thomas J. Macartney, and Gopal P. Sapkota. "IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling." Life Science Alliance 4, no. 2 (December 23, 2020): e202000804. http://dx.doi.org/10.26508/lsa.202000804.
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Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling the recruitment of neo-substrates, such as CK1α, and their degradation via the ubiquitinproteasome system. Here, we report FAM83F as such a neo-substrate. The eight FAM83 proteins (A-H) interact with and regulate the subcellular distribution of CK1α. We demonstrate that IMiD-induced FAM83F degradation requires its association with CK1α. However, no other FAM83 protein is degraded by IMiDs. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. Our findings reveal that the efficiency and extent of target protein degradation by IMiDs depends on the nature of inherent multiprotein complex in which the target protein is part of.
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Yang, Seung-Joo, Seungje Jeon, Jeong Won Baek, Kwang Min Lee, and Chul-Seung Park. "Regulation of AMPK Activity by CRBN Is Independent of the Thalidomide-CRL4CRBN Protein Degradation Axis." Pharmaceuticals 14, no. 6 (May 26, 2021): 512. http://dx.doi.org/10.3390/ph14060512.
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Cereblon (CRBN), a primary target of immune-modulatory imide drugs (IMiDs), functions as a substrate receptor in the CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN) E3 ubiquitin ligase complex. Binding of IMiDs to CRBN redirects the CRL4CRBN E3 ubiquitin ligase to recruit or displace its substrates. Interaction between CRBN and the AMPK α subunit leads to CRL4CRBN-dependent degradation of the γ subunit and inhibits AMPK activity. However, the effect of thalidomide on the function of CRBN as a negative regulator of AMPK through interaction with the α subunit remains unclear. Here, we show that thalidomide does not affect AMPK activation or the binding affinity between CRBN and the AMPK α subunit. Thalidomide had no effect on AMPK activity independent of CRBN expression. The N-terminal region and C-terminal tail of CRBN, which is distinct from the IMiD binding site, were critical for interaction with the AMPK α subunit. The present results suggest that CRL4CRBN negatively regulates AMPK through a pathway independent from the CRBN-IMiD binding region.
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Costacurta, Matteo, Jackson He, Philip E. Thompson, and Jake Shortt. "Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy." Journal of Personalized Medicine 11, no. 11 (November 11, 2021): 1185. http://dx.doi.org/10.3390/jpm11111185.
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Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.
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Tochigi, Taro, Toshihiro Miyamoto, Kiwamu Hatakeyama, Teppei Sakoda, Daisuke Ishihara, Hidetoshi Irifune, Takahiro Shima, et al. "Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug–induced thrombocytopenia." Blood 135, no. 24 (June 11, 2020): 2146–58. http://dx.doi.org/10.1182/blood.2019003749.
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Abstract Immunomodulatory drugs (IMiDs) are key agents for the treatment of multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the recruitment of neosubstrates to cereblon, a substrate receptor of the E3 ubiquitin ligase complex; therefore, identification of cell-specific neosubstrates is important to understand the effects of IMiDs. In clinical practice, IMiDs induce thrombocytopenia, which frequently results in the discontinuation of IMiD treatment. In the current study, we sought to identify the molecular mechanism underlying thrombocytopenia induced by IMiD treatment. We found that IMiDs strongly impaired proplatelet formation, a critical step in functional platelet production, through the inhibition of autocrine estradiol signaling in human megakaryocytes. Furthermore, we identified aromatase, an indispensable enzyme for estradiol biosynthesis, as a novel neosubstrate of cereblon. IMiDs promoted the recruitment of aromatase to cereblon, resulting in the degradation of aromatase in a proteasome-dependent manner. Finally, aromatase was significantly degraded in the bone marrow of patients with multiple myeloma who developed thrombocytopenia with IMiD treatment. These data suggest that aromatase is a neosubstrate of cereblon that is responsible for IMiD-induced thrombocytopenia.
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Xu, Yibing, JianWu Li, Greg Ferguson, Frank Mercurio, Gody Khambatta, Lisa Morrison, Antonia Lopez-Girona, et al. "Identification of Novel Activities of Immunomodulatory Drugs: Cytoskeleton Reorganization through Modulation of Rho GTPases." Blood 112, no. 11 (November 16, 2008): 2565. http://dx.doi.org/10.1182/blood.v112.11.2565.2565.
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Abstract Immunomodulatory drugs including the IMiDs®, lenalidomide, and pomalidomide represent a novel class of compounds that have both anti-cancer and anti-inflammatory properties. While many studies have demonstrated that IMiDs have broad in vitro and in vivo biological activities including antiangiogenesis, inhibition of TNFa expression, enhancement of antitumor immunity, and induction of IL-2 in T cells, the molecular mechanism through which these drugs exert their effects is largely undefined. In primary human monocytes, IMID1 selectively activated RhoA and Rac1, but not Cdc42 or Ras. Importantly, the activation of these GTPases occurred immediately following treatment with IMID1 in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that IMID1enhanced F-actin formation, stabilized microtubules, and increased monocyte cell migration, all of which were blocked by selective inhibitors of ROCK1, a downstream effector of RhoA or Rac1. Finally, we demonstrated that IMID1 was able to regulate the activity of Rho GTPases and formation of F-actin in primary human T cells similarly as it did in monocytes, and showed that the activation of RhoA was essential for IMID1-induced IL-2 expression in T cells. In conclusion, these studies demonstrate a novel and acute molecular activity from IMiDs mediated via Rho GTPases. Activation of Rho by IMiDs and the resulting effect on cytoskeletal reorganization may represent a critical mechanism by which IMiDs function as therapeutic immunomodulatory agents.
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Firoozmand, Amin, Naveed Ali, Nausheen Ahmed, Pingfu Fu, Shufen Cao, George Brown, Hannah Schmikla, et al. "A highly effective and practical desensitization regimen: Results in comparable clinical outcomes for multiple myeloma patients with skin rash after immunomodulatory drugs." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 12104. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.12104.
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12104 Background: Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy for patients with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% in some reports impeding maximal benefit of this agent. The optimal management of IMiDs-associated skin is unclear. The concurrent weekly Dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD. Furthermore, we assessed the impact of this desensitization regimen on clinical outcome. Methods: A total of 160 patients were evaluated. The incidence of rash was found to be 13% (n = 21). A cohort of age- and gender-matched without rash (n = 39) was randomly selected. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range, 2-232). Rashes were graded as low (I-II) in 89% (n = 17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to no-rash controls, there was no significant difference in PFS (0.13) or OS (p = 0.12) in multivariate regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in reinstituting IMiDs in our cohort. It may provide a highly effective and practical short term immunosuppression required to enable patients to restart IMiDs and enjoy comparable outcome to pts without skin rash.
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Caracciolo, Daniele, Caterina Riillo, Giada Juli, Francesca Scionti, Katia Todoerti, Nicoletta Polerà, Katia Grillone, et al. "miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma." Cancers 13, no. 17 (August 29, 2021): 4365. http://dx.doi.org/10.3390/cancers13174365.
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Background: MYC is a master regulator of multiple myeloma (MM) by orchestrating several pro-tumoral pathways, including reprograming of the miRNA transcriptome. MYC is also involved in the acquirement of resistance to anti-MM drugs, including immunomodulatory imide drugs (IMiDs). Methods: In silico analysis was performed on MM proprietary and on public MMRF-CoMMpass datasets. Western blot and chromatin immunoprecipitation (ChIP) experiments were performed to validate miR-22 repression induced by MYC. Cell viability and apoptosis assays were used to evaluate lenalidomide sensitization after miR-22 overexpression. Results: We found an inverse correlation between MYC and miR-22 expression, which is associated with poor outcome in IMiD-treated MM patients. Mechanistically, we showed that MYC represses transcription of miR-22, which, in turn, targets MYC, thus establishing a feed-forward loop. Interestingly, we found that IMiD lenalidomide increases miR-22 expression by reducing MYC repression and, most importantly, that the combination of lenalidomide with miR-22 mimics results in a synergistic direct and NK-mediated cytotoxic activity. Conclusions: Taken together, our findings indicate that: (1) low miR-22 expression could represent a potential predictive biomarker of poor lenalidomide response in MM patients; and (2) miR-22 reduces MYC oncogenic activity, thus triggering a novel synthetic lethality loop, which sensitizes MM cells to lenalidomide.
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Gemechu, Yohannes, David Millrine, Shigeru Hashimoto, Jaya Prakash, Ksenia Sanchenkova, Hozaifa Metwally, Parajuli Gyanu, Sujin Kang, and Tadamitsu Kishimoto. "Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs." Proceedings of the National Academy of Sciences 115, no. 46 (October 29, 2018): 11802–7. http://dx.doi.org/10.1073/pnas.1814446115.
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Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup. In our current study, we investigated the degradative effect toward IKZF1 and CK-1α, a target substrate of IMiDs. Unlike WT mice which were resistant to lenalidomide and pomalidomide, T lymphocytes from CRBNI391V mice responded with a higher degree of IKZF1 and CK-1α protein degradation. Furthermore, IMiDs resulted in an increase in IL-2 among CRBNI391V mice but not in the WT group. We have also tested a thalidomide derivative, FPFT-2216, which showed an inhibitory effect toward IKZF1 protein level. As opposed to pomalidomide, FPFT-2216 and lenalidomide degrades CK-1α. Additionally, we assessed the potential therapeutic effects of IMiDs in dextran sodium sulfate (DSS)-induced colitis. In both WT and humanized mice, lenalidomide showed a significant therapeutic effect in the DSS model of colitis, while the effect of pomalidomide was less pronounced. Thus, while IMiDs’ degradative effect on IKZF1 and CK-1α, and up-regulation of IL-2, is dependent on CRBN, the therapeutic benefit of IMiDs in a mouse model of inflammatory bowel disease occurs through a CRBN–IMiD binding region independent pathway.
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Coto, Pablo, Sabino Riestra, Paloma Rozas, Ana Señaris, and Rubén Queiro. "Improving the standard of care for patients with spondyloarthritis-related immune inflammatory conditions: results of a Delphi study and proposal for early detection." Therapeutic Advances in Chronic Disease 11 (January 2020): 204062232090429. http://dx.doi.org/10.1177/2040622320904295.
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Background: Our objective was to provide consensus recommendations on the optimal management of the immune-mediated inflammatory diseases (IMIDs) seen in patients with spondyloarthritis (SpA) using a multidisciplinary approach, and to develop a simple tool to help earlier recognition and referral of coexisting IMIDs in patients who already have one type of IMID. Methods: A total of 28 experts in the multidisciplinary management of the SpA-associated IMIDs assessed two questionnaires: one with statements focused on the multidisciplinary management of IMIDs, and a second questionnaire focused on questions useful for early recognition and referral. Panelists assessed the statements with a 9-point ordinal scale (1 = strongly disagree, 9 = strongly agree) using a modified Delphi methodology. Results: Consensus was reached on 72 out of the 82 statements (87.8%). Panelists agreed that the multidisciplinary approach to IMIDs is not sufficiently developed. The creation of multidisciplinary IMID units might be necessary. These units might focus primarily on patients with two or more coexisting IMIDs, or on IMIDs that are especially complex from a diagnostic or therapeutic point of view. Specialists who attend to patients with IMIDs should perform a screening for other coexisting IMIDs. A simple tool to help earlier recognition and referral of coexisting IMIDs is proposed. Conclusions: There is a need to improve care for patients with SpA-associated IMIDs. We provide expert recommendations to guide the adoption of a multidisciplinary approach for these cases, and a simple tool that may be useful for earlier recognition of coexisting IMIDs.
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Olszewski, Adam J., Stacie Dusetzina, Amy J. Davidoff, and Amal N. Trivedi. "Closure of Medicare Part D coverage gap by the Affordable Care Act (ACA) and use of oral anti-myeloma agents." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 6522. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.6522.
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6522 Background: Medicare Part D pays for oral anti-myeloma immunomodulatory drugs (IMiDs, lenalidomide and thalidomide), but has a coverage gap resulting in an out-of-pocket (OOP) expense of > $ 3000 for the 1st prescription (Rx). Patients (pts) eligible for Low Income Subsidies (LIS) are exempt from cost sharing, and LIS is associated with IMiD receipt ( Olszewski, ASH 2016). In 2011, the ACA partly closed the coverage gap with a 50% manufacturer discount on the price of brand-name drugs within the gap. We examined effects of this policy on IMiD use. Methods: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we selected Part D enrollees who started anti-myeloma chemotherapy in 2008-2012. We identified IMiD use in periods pre-ACA (2008-10) and post-ACA (2011-12), among pts with or without LIS. After confirming parallel trends in IMiD use before the ACA, we examined the effect of ACA discount on IMiD use in a difference-in-differences (DiD) model, using LIS recipients as controls whose OOP costs were not influenced by the ACA. Results: Among 3,313 Part D enrollees (of whom 31% received LIS), 41% received IMiDs as part of their anti-myeloma regimen. Compared with the pre-ACA period, in the post-ACA period the median gross IMiD cost of the 1st Rx increased for all pts (Table). OOP costs for the 1st Rx, and for the 1st year of IMiD therapy, decreased for LIS non-recipients. Proportion of pts entering catastrophic coverage with their 1st IMiD Rx decreased from 71% to 49%. However, there was no statistically significant effect of the ACA discount on the proportion of pts treated with IMiDs (DiD estimator, 3% [95%CI, -4 to 10]; P=.40), or on the time from diagnosis to 1st Rx (median 1.5 mo. in all groups). Conclusions: The ACA-mandated partial closure of coverage gap lowered the OOP costs for Part D enrollees treated with IMiDs. As the median OOP cost remains > $2400 for the 1st Rx, and > $4900 for the 1st year of therapy, the policy may be insufficient to overcome the financial barrier for beneficiaries who do not receive the LIS. [Table: see text]
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Charliński, Grzegorz, David H. Vesole, and Artur Jurczyszyn. "Rapid Progress in the Use of Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in the Treatment of Multiple Myeloma." Cancers 13, no. 18 (September 17, 2021): 4666. http://dx.doi.org/10.3390/cancers13184666.
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Over the past two decades, the improvement in our understanding of the biology of MM and the introduction of new drug classes, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), and monoclonal antibodies (MoAb), have significantly improved outcomes. The first IMiD introduced to treat MM was thalidomide. The side effects observed during treatment with thalidomide initiated work on the synthesis of IMiD analogs. Subsequently, lenalidomide and pomalidomide were developed, both with different safety profiles, and they have better tolerability than thalidomide. In 2010, the cereblon (CRBN) protein was discovered as a direct target of IMiDs. By binding to CRBN, IMiDs change the substrate specificity of the CRBN E3 ubiquitin ligase complex, which results in the breakdown of internal Ikaros and Aiolos proteins. Most clinical trials conducted, both in newly diagnosed, post-transplant maintenance and relapsed/refractory MM, report a beneficial effect of IMiDs on the extension of progression-free survival and overall survival in patients with MM. Due to side effects, thalidomide is used less frequently. Currently, lenalidomide is used at every phase of MM treatment. Lenalidomide is used in conjunction with other agents such as PIs and MoAb as induction and relapsed therapy. Pomalidomide is currently used to treat relapsed/refractory MM, also with PIs and monoclonal antibodies. Current clinical trials are evaluating the efficacy of IMiD derivatives, the CRBN E3 ligase modulators (CELMoDs). This review focuses on the impact of IMiDs for the treatment of MM.
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Heider, Michael, Ruth Eichner, Jacob Stroh, Anna Kuisl, Jana Zecha, Jannis Lawatscheck, Martina Rudelius, et al. "The IMiD-Target Cereblon Determines Transmembrane Protein Quality Control Promoting Tumor Metabolism." Blood 134, Supplement_1 (November 13, 2019): 314. http://dx.doi.org/10.1182/blood-2019-129064.
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Introduction: Cereblon (CRBN) is the target for immunomodulatory drugs (IMiDs) such as thalidomide and its derivatives lenalidomide and pomalidomide, which are key therapeutics for hematologic malignancies such as multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). We have previously described a ubiquitin-independent chaperone-like function of CRBN, which stabilizes the transmembrane proteins CD147 and MCT1. IMiDs interfere with this chaperone-like function of CRBN in a competitive manner to mediate both their anti-tumor and their teratotoxic effects (Eichner et al. Nature Medicine 2016). So far, the underlying mechanisms of transmembrane protein maturation, the global impact of CRBN on the cell surface proteome and the precise molecular mechanism of IMiDs, especially their clinically well-established synergy with proteasomal inhibitors remain unclear. Methods: Novel CRBN-clients were identified by cross-validation of the CRBN-interactome with a cell surface proteomic screen. Various molecular and cell biological methods including immunofluorescence, flow cytometry, immunoprecipitations, GST-pulldowns, amino acid transport and proliferation assays were used to decipher underlying mechanisms. In vitro assays and in vivo xenograft experiments were performed using MM cell lines and patient-derived CD138+ MM cells. 18FDG- and 18FET-PET was used for imaging of xenografted tumors. Results: Our unbiased screening approaches imply a global role of CRBN in transmembrane protein maturation. In particular, we identify the amino acid transporter LAT1 and its functional subunit CD98hc as novel CRBN client proteins, which are frequently overexpressed in MM to drive cell proliferation. CD98hc/LAT1 become destabilized and inactivated upon IMiD treatment, which attenuates MM cell proliferation, tumor formation and perturbs the uptake of essential amino acids, thereby further linking IMiD-activity to tumor-metabolism. CD98hc/LAT1 destabilization only occurs in IMiD-sensitive patients and cell lines, thus being a potential biomarker to predict IMiD-response. Moreover, inhibition of LAT1 is cytotoxic in both IMiD-sensitive and -resistant cells, which makes it an attractive therapeutic option for IMiD-resistant and -refractory patients. Mechanistically, we show CRBN to function as a new selective co-chaperone of HSP90, which facilitates transmembrane protein maturation in a ubiquitin-independent way, which is impaired by IMiD-treatment. Conclusion: We establish CRBN as a transmembrane protein-specific co-chaperone for HSP90 and identify modulation of the CRBN-CD98hc/LAT1 axis as crucial means by which IMiDs mediate their anti-tumor activity. Notably, we specify CD98hc/LAT1 as valuable biomarkers for IMiD-response and druggable targets for IMiD-resistant and -refractory MM patients and beyond. Furthermore, this ubiquitin-independent mechanism solves the paradox regarding the well documented synergistic anti-myeloma activity of IMiDs and proteasomal inhibitors. Disclosures Götze: AbbVie: Membership on an entity's Board of Directors or advisory committees. Bassermann:Celgene: Consultancy, Research Funding.
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Dimopoulos, Konstantinos, Peter Gimsing, Gangning Liang, Kirsten Grønbæk, Alexandra Helbo Søgaard, and Ranjani Lakshminarasinham. "Cereblon Is Downregulated By Promoter Nucleosome Occupancy in Acquired IMiD Resistance: The Potential of IMiD Resensitization By Epigenetic Therapy." Blood 128, no. 22 (December 2, 2016): 3258. http://dx.doi.org/10.1182/blood.v128.22.3258.3258.
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Abstract The immunomodulatory drugs (also known as IMiDs) thalidomide, lenalidomide and pomalidomide, play a pivotal role in the treatment of multiple myeloma (MM). Recent studies have deciphered the mechanism of action of these drugs and shown that they directly interact with cereblon (CRBN), which is part of an E3-ubiquitin ligase complex. The IMiD-CRBN interaction selectively alters the affinity of CRBN to two important transcriptional factors, Ikaros (IKZF1) and Aiolos (IKZF3), leading to their ubiquitination and subsequent proteasomal degradation, representing a novel mechanism of therapy through ubiquitin-mediated alteration of gene expression. Several studies have underlined the importance of CRBN for the biologic activity of IMiDs, as both human cell lines and patient samples with acquired IMiD-resistance, exhibit a significant reduction of CRBN expression. However, it still remains unknown how CRBN expression is regulated, and subsequently, whether the acquired resistance to IMiDs is potentially druggable and reversible. In this study, we have used the IMiD-sensitive human myeloma cell lines OPM2 and NCI-H929, which were cultured with subtoxic doses of Lenalidomide and Pomalidomide for 4-6 months for acquisition of stable resistance. The lenalidomide- and pomalidomide-resistant cell lines (OPM2-LR, NCI-H929-LR and OPM2-PR, NCI-H929-PR subsequently) were then used as a model of acquired IMiD-resistance. In line with previous studies, we confirmed a significant reduction of CRBN expression, but not it downstream targets, IKZF1 and IKZF3, in the resistant cell lines, both at mRNA and protein level. Using methylation-specific melting curve analysis, we next showed that the downregulation of CRBN is not due to promoter DNA methylation. We therefore proceeded with the assessment of chromatin accessibility through nucleosome positioning using AcceSsIble. Our data show that acquired IMiD-resistance is accompanied by increased nucleosome occupancy (and thus decreased chromatin accessibility - figure 1A) rather than DNA methylation, an event that is also more prominent in promoters and enhancers (figure 1B). Among the top 100 genes whose promoters are nucleosome-occupied was CRBN, an event that could explain the reduced expression observed upon acquired IMiD-resistance. Since both DNA methylation and nucleosome positioning are two potentially reversible epigenetic modifications, we next treated the resistant cell lines with a combination of decitabine (a DNA-methyl-transferase inhibitor) and GSK-126 (an EZH2-inhibitor) for 3 days and then exposed them again to IMiDs. Even though the combination treatment by itself was mildly toxic for the cells, cell viability was even more reduced upon treatment with IMiDs three days after exposure to this combination of epidrugs, suggesting that epigenetic reprogramming and resensitization of IMiD-resistant cells could be feasible (figure 1C). Taken together, our data could potentially explain the mechanism behind CRBN downregulation observed upon IMiD-resistance and provide evidence for possible epigenetic resensitising myeloma cells to IMiDs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Olszewski, Adam J., Stacie B. Dusetzina, Charles B. Eaton, Amy J. Davidoff, and Amal N. Trivedi. "Subsidies for Oral Chemotherapy and Use of Immunomodulatory Drugs Among Medicare Beneficiaries With Myeloma." Journal of Clinical Oncology 35, no. 29 (October 10, 2017): 3306–14. http://dx.doi.org/10.1200/jco.2017.72.2447.
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Purpose The low-income subsidy (LIS) substantially lowers out-of-pocket costs for qualifying Medicare Part D beneficiaries who receive orally administered chemotherapy. We examined the association of LIS with the use of novel oral immunomodulatory drugs (IMiDs; lenalidomide and thalidomide) among beneficiaries with myeloma, who can receive either orally administered or parenteral (bortezomib-based) therapy. Methods Using SEER-Medicare data, we identified Part D beneficiaries diagnosed with myeloma in 2007 to 2011. In multivariable models adjusted for sociodemographic and clinical characteristics, we analyzed associations between the LIS and use of IMiD-based therapy, delays between IMiD refills, and select health outcomes during the first year of therapy. Results Among 3,038 beneficiaries, 41% received first-line IMiDs. Median out-of-pocket cost for the first IMiD prescription was $3,178 for LIS nonrecipients and $3 for LIS recipients, whereas the respective median costs for the first year of therapy were $5,623 and $6, respectively. Receipt of the LIS was associated with a 32% higher (95% CI, 16% to 47%) probability of receiving IMiDs among beneficiaries age 75 to 84 years and a significantly lower risk of delays between refills in all age groups (adjusted relative risk, 0.54; 95% CI, 0.32 to 0.92). Duration of therapy did not significantly differ between LIS recipients and nonrecipients (median, 7.6 months). Patients treated with IMiDs had significantly fewer emergency department visits and hospitalizations compared with patients receiving bortezomib (without IMiDs), but 1-year overall survival and cumulative Medicare costs were similar. Conclusion Medicare beneficiaries with myeloma who do not receive LISs face a substantial financial barrier to accessing orally administered anticancer therapy, warranting urgent attention from policymakers. Limiting out-of-pocket costs for expensive anticancer drugs like the IMiDs may improve access to oral therapy for patients with myeloma.
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Gavriatopoulou, Maria, Ioannis Ntanasis-Stathopoulos, Panagiotis Malandrakis, Despina Fotiou, Magdalini Migkou, Nikolaos Kanellias, Evangelos Eleutherakis-Papaiakovou, et al. "IMiD Retreatment in Patients Refractory to Both an IMiD and an Anti-CD38 Antibody Induces Significant Response Rates Post Anti-CD38 Exposure." Blood 136, Supplement 1 (November 5, 2020): 12. http://dx.doi.org/10.1182/blood-2020-136248.
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INTRODUCTION The survival of myeloma patients has doubled the past decade, however, patients refractory to both proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) still have poor prognosis. Immunotherapy with monoclonal antibodies targeting cell-surface antigens is a promising treatment strategy with different mechanisms of action and has been integrated both in the newly diagnosed and relapsed/refractory setting. The combination of daratumumab, pomalidomide and dexamethasone (DaraPomDex) has demonstrated significant activity even in patients refractory to both drugs and a potential mechanism may be re-sensitization to pomalidomide. Another report showed that daratumumab-refractory patients who previously failed IMiD, responded when the IMiD was added to daratumumab. This provided a proof of principle that anti-CD38 antibodies can alter the underlying pathophysiology, and can potentially overcome refractoriness to IMIDs. Increased CD38 expression after IMiD exposure could be a mechanism of IMiD resistance, and anti-CD38 agents may act by eliminating this effect. Daratumumab induces clonal CD8+ T-cell expansion that may contribute to clinical responses, which is augmented by IMiDs, resulting in synergy.Potential loss of this response in progressing patients may be recaptured after the reintroduction of IMiDs. Another potential mechanism could involve the reemergence of IMiD-sensitive clones after an IMiD-free period. There is data that daratumumab alters the tumor immune microenvironment, and this effect may be long lasting , even after daratumumab discontinuation . The aim of the study was to evaluate the efficacy of re-treatment with IMiD-based therapy in patients refractory both to IMiDs and anti-CD38 antibodies. PATIENTS AND METHODS The study included 38 patients who were refractory to antiCD-38-based therapy and to at least one IMiD. Overall, 26 (68%) patients had received lenalidomide, 11 (29%) pomalidomide and 1 (3%) thalidomide before anti-CD38 treatment. RESULTS Median number of prior lines before IMiD retreatment was 4 (range 2 to 13). The patient distribution per R-ISS was: R-ISS 1: 8, R-ISS 2: 9, R-ISS 3: 4. Overall, 4 (11%) patients received lenalidomide-, 33 (86.5%) pomalidomide-, and 1 (2.5%) thalidomide-based regimens post anti-CD38. The majority of patients were treated with pomalidomide-cyclophosphamide-dexamethasone (PCD) (n=13) and pomalidomide-dexamethasone (PomD) (n=11). The remaining 14 patients were treated with other IMiD-based triplets. Importantly, 10 (26%) patients received the same IMiD as prior to anti-CD38 exposure (lenalidomide n=2, pomalidomide n=8). Median time from diagnosis to IMiD re-treatment was 61.5 months. Overall, 20 patients (53%) achieved a response during IMiD retreatment, including CR=1, VGPR=5, PR=10 and MR=4; 11 patients achieved SD, whereas 7 patients progressed. The disease control rate (DCR=SD+PR+VGPR+CR) was 82%. Among the patients re-exposed to the same IMiD, 5 responded, 3 progressed and 2 remained stable. Among the responders, 1 achieved VGPR with PCD, 2 PR with PCD and DaraPomDex, whereas 2 showed MR with PCD and PCD with Bortezomib. 79% (22/28) of the patients received pomalidomide following previous exposure to lenalidomide; among them, 15/22 (68%) patients responded (1 CR, 4 VGPR, 8 PR, 2 MR), 3 remained stable and 4 progressed. Interestingly, 10 out of 13 (77%) patients who received PCD responded. Median PFS for all patients was 4 months (range 2.9-4.8). Median time to next treatment (TtNT) for the whole study cohort as well as for those who received the same IMiD pre- and post-exposure to anti-CD38 was 4.2 months as well. Median duration of response (DoR) for the responders was 7 months. Median TtNT for those who received pomalidomide after previous exposure to lenalidomide (n=22) was 3.9 months; median DoR among the responders was 6.6 months. Median OS 5.3 range 0.5-35.5. CONCLUSION IMiD retreatment in patients refractory to both an IMiD and an anti-CD38 antibody can induce significant response rates, even among patients re-exposed to the same IMiD. This indicates that after anti-CD38 therapy a long lasting, probably immunomodulatory effect may be associated with some degree of re-sensitization to IMiDs. The subgroup of patients receiving PCD derived the most benefit. In this context, a prospective study evaluating the role of PCD in this population is currently ongoing. Disclosures Gavriatopoulou: Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Kastritis:Takeda: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Pfizer: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel/accommodations/expenses, Research Funding; Genesis Pharma: Consultancy, Honoraria, Other: Travel/accommodations/expenses; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria.
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Romero-Jimenez, Rosa, Vicente Escudero-Vilaplana, Esther Chamorro-De-Vega, Arantza Ais-Larisgoitia, Maria Elena Lobato Matilla, Ana Herranz-Alonso, and Maria Sanjurjo. "The Characteristics and Functionalities of Mobile Apps Aimed at Patients Diagnosed With Immune-Mediated Inflammatory Diseases: Systematic App Search." Journal of Medical Internet Research 24, no. 3 (March 4, 2022): e31016. http://dx.doi.org/10.2196/31016.
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Background Immune-mediated inflammatory diseases (IMIDs) are systemic conditions associated with a high social and health impact. New treatments have changed the prognosis of IMIDs and have increased patient autonomy in disease management. Mobile apps have enormous potential to improve health outcomes in patients with IMIDs. Although a large number of IMID apps are available, the app market is not regulated, and functionality and reliability remain uncertain. Objective Our aims are to review available apps for patients with IMIDs or caregivers and to describe the main characteristics and functionalities of these apps. Methods We performed an observational, cross-sectional, descriptive study of all apps for patients with IMIDs. Between April 5 and 14, 2021, we conducted a search of the App Store (iOS) and Play Store (Android) platforms. We used the names of the different IMIDs as search terms. The inclusion criteria were as follows: content related to IMIDs, English or Spanish language, and user population consisting of patients and health care consumers, including family and caregivers. The variables analyzed were as follows: app name, type of IMID, platform (Android or iOS), country of origin, language, category of the app, cost, date of the last update, size, downloads, author affiliation, and functionalities. Results We identified 713 apps in the initial search, and 243 apps met the criteria and were analyzed. Of these, 37% (n=90) were on Android, 27.2% (n=66) on iOS, and 35.8% (n=87) on both platforms. The most frequent categories were health and well-being/fitness apps (n=188, 48.5%) and medicine (n=82, 37.9%). A total of 211 (82.3%) apps were free. The mean time between the date of the analysis and the date of the most recent update was 18.5 (SD 19.3) months. Health care professionals were involved in the development of 100 (41.1%) apps. We found differences between Android and iOS in the mean time since the last update (16.2, SD 14.7 months vs 30.3, SD 25.7 months) and free apps (85.6% vs 75.8%; respectively). The functionalities were as follows: general information about lifestyles, nutrition, or exercises (n=135, 55.6%); specific information about the disease or treatment (n=102, 42%); recording of symptoms or adverse events (n=51, 21%); agenda/calendar (n=44, 18.1%); reminder medication (n=41, 16.9%); and recording of patient-reported outcomes (n=41, 16.9%). A total of 147 (60.5%) apps had more than one functionality. Conclusions IMID-related apps are heterogeneous in terms of functionality and reliability. Apps may be a useful complement to IMID care, especially inpatient education (their most frequent functionality). However, more than half of the IMID apps had not been developed by health care professionals or updated in the last year.
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Lai, Edward Chia-Cheng, Ya-Chun Huang, Tzu-Chi Liao, and Meng-Yu Weng. "Premature coronary artery disease in patients with immune-mediated inflammatory disease: a population-based study." RMD Open 8, no. 1 (January 2022): e001993. http://dx.doi.org/10.1136/rmdopen-2021-001993.
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BackgroundThe associations between premature atherosclerosis and immune-mediated inflammatory diseases (IMIDs) are not fully investigated. To determine whether IMIDs are associated with premature atherosclerosis, we examined the risk of incident coronary artery disease (CAD) in men less than 45 years old and women less than 50 years old with various forms of IMIDs compared with general population.MethodsA population-based cohort was established and included patients with IMID, who were followed until the development of CAD, withdrawal from the insurance system, death, or 31 December 2016, whichever point came first. Patients with IMID included rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren’s syndrome (SjS), idiopathic inflammatory myositis, systemic sclerosis (SSc), Behcet’s disease (BD), and systemic vasculitis (SV). The comparison group was 1 000 000 beneficiaries sampled at random from the whole population as matched control participants. The Kaplan-Meier method was used to compare the cumulative incidences of CAD in patients with and without IMID.ResultsAmong 58 862 patients with IMID, 2139 (3.6%) developed CAD and 346 (1.3%) developed premature CAD. Relative to the comparison cohorts, the adjusted HRs for premature CAD were 1.43 (95% CI 1.09 to 1.86) for primary SjS, 2.85 (95% CI 2.63 to 3.43) for SLE, 3.18 (95% CI 1.99 to 5.09) for SSc and 2.27 (95% CI 1.01 to 5.07) for SV.ConclusionsPrimary Sjogren’s syndrome, SLE, SSc and SV are associated with an increased risk of premature CAD. Our findings will support essential efforts to improve awareness of IMID impacting young adults.
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Nadeau Nguyen, Michelle, Afrouz Nayernama, Steven Christopher Jones, Yvette L. Kasamon, and Peter E. Waldron. "Solid Organ Transplant Rejection Associated with the Use of the Immunomodulatory Drugs (IMIDs)." Blood 134, Supplement_1 (November 13, 2019): 2189. http://dx.doi.org/10.1182/blood-2019-123146.
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Introduction: IMIDs are a cornerstone of multiple myeloma treatment and have a recently expanded role in the treatment of selected lymphomas. However, the safety of chemotherapeutic regimens containing IMIDs in patients with a history of solid organ transplantation (SOT) is uncertain. Recently, several published case reports have described SOT rejection (SOTr) among patients taking IMIDs. Methods: To investigate a potential association between IMID exposure and SOTr, we evaluated postmarketing adverse event reports submitted to the FDA Adverse Event Reporting System (FAERS) and published in the literature. We descriptively characterized the clinical outcomes and severity of SOTr and utilized the World Health Organization-Uppsala Monitoring (WHO-UMC) scale to assess drug causality. Results: We identified 22 cases of SOTr associated with the use of lenalidomide (n=16), pomalidomide (n=3), or thalidomide (n=3) from FAERS and the literature. After IMID initiation, the median time to onset of SOTr was 39 days (range 3-70 days) with 89% of cases occurring by 60 days. Notably, SOTr occurred within 2 weeks of lenalidomide and pomalidomide administration in 5 cases, including 2 patients with a distant history of SOT (lenalidomide, n=1; pomalidomide, n=1). The most commonly affected organs were the kidney (n=13) and heart (n=10), with 3 of these cases involving rejection of both organs. In 12 cases, rejection was confirmed with biopsy findings of acute T-cell mediated rejection. Notably, 6 of these 12 cases provided baseline biopsy findings prior to IMID initiation that indicated stable organ function and showed no signs of rejection. All cases were complicated by serious outcomes including 7 deaths described as related to graft rejection. Other serious clinical manifestations included surgical excision of the original transplanted organ (n=2), requirement of a second transplant (n=3), and dialysis (n=4), including 2 cases that required long-term renal replacement therapy. We determined the causality as probable (no confounding factor identified) in 6 cases and possible (confounding factor identified) in the remaining 16 cases. The most frequently reported confounding factor was concomitant change of the baseline immunosuppressive regimen with the initiation of the IMID (n=7). Notably, 5 of the 7 cases with fatal outcome had immunosuppression reduced at IMID therapy initiation, including 2 cases with a distant history of SOT and stable graft function. Conclusion: To our knowledge, this is the largest case series describing SOTr with the IMIDs. These cases are characterized by serious events including death and reduced long-term survival of the graft. Although this analysis is limited by the quality of spontaneous adverse event reporting, the strong temporal relationship and the histologic findings of T-cell mediated rejection provide reasonable evidence of a contributory role of IMIDs to SOTr. This risk is plausible because IMIDs induce T-cell proliferation, enhance interleukin-2 and interferon-gamma production, and inhibit regulatory T-cell function. Increased surveillance for early signs of acute rejection is warranted for SOT recipients receiving IMID therapy. The US prescribing information is currently being revised to reflect the risk of SOTr across all IMIDs. Disclosures No relevant conflicts of interest to declare.
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Millrine, David, Mami Tei, Yohannes Gemechu, and Tadamitsu Kishimoto. "Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production." Proceedings of the National Academy of Sciences 113, no. 38 (September 6, 2016): 10625–30. http://dx.doi.org/10.1073/pnas.1611751113.
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Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon–Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.
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Liu, Jiye, Teru Hideshima, Lijie Xing, Su Wang, Wenrong Zhou, Mehmet K. Samur, Tomasz Sewastianik, et al. "ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment." Science Advances 7, no. 23 (June 2021): eabg2697. http://dx.doi.org/10.1126/sciadv.abg2697.
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Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor κB (NF-κB) and extracellular signal–regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-α induces proteasomal degradation of TRAF2, noncanonical NF-κB, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.
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Haberman, Rebecca H., Ramin Herati, David Simon, Marie Samanovic, Rebecca B. Blank, Michael Tuen, Sergei B. Koralov, et al. "Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease." Annals of the Rheumatic Diseases 80, no. 10 (May 25, 2021): 1339–44. http://dx.doi.org/10.1136/annrheumdis-2021-220597.
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ObjectiveTo investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.ResultsAlthough healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.ConclusionsIn two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.
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Vij, Ravi, Mehdi M. Moezi, Robin Foà, Gordon Cook, Antonio Palumbo, Hakan Kaya, Brian Durie, et al. "A New Multinational Observational Study In Multiple Myeloma: Initial Report Of The PREAMBLE Study." Blood 122, no. 21 (November 15, 2013): 1964. http://dx.doi.org/10.1182/blood.v122.21.1964.1964.
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Abstract Introduction The advent of novel immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have improved clinical outcomes of multiple myeloma (MM) in the past decade. Clinical trial data have shown combination novel therapies (IMiD+PI) can provide even further improvement. The PREAMBLE (Prospective Research Assessment in Multiple Myeloma: an Observational Evaluation) is a global study designed to evaluate clinical effectiveness, healthcare resource utilization, and patient-reported outcomes associated with novel therapies for treatment of relapsed or refractory MM (R/R MM) in the real-world daily practices in the US and Europe. We describe the study design and baseline characteristics of the first 111 patients enrolled. Methods This is a prospective, observational, longitudinal cohort study of adult patients with R/R MM who received at least 1 prior therapy and initiated treatment with IMiDs, PIs, or IMiDs+PIs within 90 days prior to or 30 days after enrollment. Follow-up is up to 3 yrs after consent. Patients receive standard of care treatment as determined by the treating physician. Planned enrollment is 1000 patients in North America (NA) and Europe (EU; France, Germany, Italy, and UK). Results As of June 28, 2013, 111 patients from 63 sites in NA (n=64) and EU (n=47) have been enrolled. Baseline characteristics are summarized in Table 1. Cytogenetics (by FISH) was determined in 51% (n=57) of patients; of these, 16% (n=9) were high risk with del 17p (78%) as the predominant abnormality. Baseline treatment varied by region: of the patients in NA, IMiDs were used in 44% (n=28), PIs in 36% (n=23), and IMiD+PI in 20% (n=13) versus 60% (n=28), 34% (n=16), and 6% (n=3), respectively, in EU. Of the 16% high risk patients and the 25% of patients initially diagnosed at ISS stage III, none received IMiD+PI. The percentage of patients who received only 1 prior regimen at enrollment was 46% (n=26) in the IMiD group, 41% (n=16) in the PI group, and 63% (n=10) in the IMiD+PI group while the percentage of patients who received 3 or more prior regimens was 16% (n=9) in the IMiD group, 36% (n=14) in the PI group, and 6% (n=1) in the IMiD+PI group. Median time from diagnosis to enrollment for patients receiving IMiDs was 43 months, PIs was 42 months, and IMiDs+PIs was 33 months. Conclusion PREAMBLE provides a rich data source for evaluation of clinical, economic, and humanistic outcomes in patients treated for R/R MM. Initial data suggest different treatment patterns between patients in the US and in EU. Continued follow-up and larger sample size may help identify factors associated with different treatment choices and impact on clinical effectiveness, tolerability, resource utilization, and humanistic outcomes in patients treated for R/R MM. Disclosures: Vij: Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Speakers Bureau; BMS: Honoraria; Lilly: Honoraria. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Kaya:Millennium: Honoraria, Speakers Bureau. Durie:Millennium: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Cella:BMS: Consultancy. Annemans:BMS: Consultancy. Su:BMS: Employment, Equity Ownership. Mukhopadhyay:BMS: Employment, Equity Ownership. Le:BMS: Employment. Petrucci:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria.
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Tascilar, K., D. Simon, G. Krönke, A. Kleyer, A. Ramming, R. Atreya, M. Tenbusch, et al. "POS1426 PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW- FREQUENCY VIRAL SYMPTOM CLUSTERS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 996.2–997. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1598.
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Background:Viral respiratory infections are common in the general population and result in a spectrum of outcomes ranging from effective viral clearance with no symptoms, to a maladaptive immune response that can result in severe symptomatic disease and death. Although patients with immune-mediated inflammatory diseases (IMID) are considered susceptible to poor outcomes from infectious syndromes, it is not known whether IMID patients are overall more prone to manifest common viral infection symptoms.Objectives:To explore frequency patterns of common viral infection symptoms in IMID patients.Methods:We previously recruited patients with IMIDs and individuals with no IMIDs for a seroprevalence study between February 1st and April 30th 2020 (1). Participants were questioned for the presence of eleven common viral disease symptoms. We clustered these data using an unsupervised binary data clustering algorithm (2) into 6 symptom clusters based on symptom frequency. Three major clusters (broadly symptomatic, intermediately symptomatic and oligo-/asymptomatic) and 2 sub-clusters (higher and lower frequency) for each major cluster. In addition, qualitative symptom clustering was done. We estimated standardized residuals to quantify the over/underrepresentation of IMID diagnosis frequencies in each subject cluster. We used Poisson regression to compare symptom counts by diagnosis.Results:We analyzed 1909 participants (757 with IMIDs; 1152 non-IMID controls; Table 1). Within each major subject cluster (Figure 1A), IMID patients showed the highest positive deviation from the expected frequencies in lower frequency sub-clusters while non IMID controls showed the highest positive deviations in the higher frequency sub-clusters (Figure 1B). Inflammatory bowel disease and psoriasis were remarkably overrepresented in the lower frequency sub-cluster of the broadly-symptomatic cluster while RA was overrepresented in the lower frequency sub-clusters of intermediate and oligo-/asymptomatic clusters. X axis of Figure 1A presents qualitative symptom clusters. Regression analysis shows that RA patients among other IMIDs reported overall less symptoms (RR= 0.69, 95%CI, 0.58 - 0.80) compared to non-IMID controls.Figure 1.A) distribution of common viral respiratory disease symptoms across patient and symptom clusters. B) Standardized residuals indicating deviation from expected frequencies of IMID diagnoses across patient clusters. sob: shortness of breath, mskpain: musculoskeletal painConclusion:This analysis shows that symptoms of common respiratory viral infections are less frequent in RA patients and to a lesser extent in other IMID patient. As major clusters in this analysis can also be considered to represent exposure categories, these data suggest that IMIDs or their treatments may mitigate common respiratory viral infection symptoms.References:[1]Simon D. et al. Nat Commun (2020) 11, 3774[2]Bhatia P. et al. J. Stat. Softw (2017) 76(9)Table 1.Participant characteristics and distribution of IMID diagnoses across subject clusters.ClustersBroad SymptomaticIntermediate SymptomaticOligo-AsymptomaticOverallHigherLowerHigherLowerHigherLowerN190910185412259283769Age, years, mean (SD)45.4(15.2)42.4(13.3)47.3 (15.2)42.4(12.9)50.4(15.5)41.8(14.9)46.8(15.9)Male1080 (56.6)42 (41.6)38 (44.7)196 (47.6)137 (52.9)178 (62.9)489 (63.6)Diagnosis, n(%)No-IMID1152 (60.3)72 (71.3)44 (51.8)280 (68.0)112 (43.2)207 (73.1)437 (56.8)RA226 (11.8)7 (6.9)5 (5.9)29 (7.0)56 (21.6)17 (6.0)112 (14.6)IBD178 (9.3)5 (5.0)15 (17.6)46 (11.2)29 (11.2)19 (6.7)64 (8.3)SpA142 (7.4)7 (6.9)5 (5.9)23 (5.6)25 (9.7)14 (4.9)68 (8.8)Psoriasis89 (4.7)4 (4.0)9 (10.6)14 (3.4)8 (3.1)13 (4.6)41 (5.3)Other122 (6.4)6 (5.9)7 (8.2)20 (4.9)29 (11.2)13 (4.6)47 (6.1)Symptom count/patient, mean (SD)1.2 (1.7)6.0 (1.3)3.9 (1.1)2.2 (1.0)1.5 (0.6)0.5 (0.5)0.0 (0.0)IBD, inflammatory bowel disease.Acknowledgements:This study was supported by the Deutsche Forschungsgemeinschaft (DFG- FOR2886 PANDORA and the CRC1181), the Bundesministerium für Bildung und Forschung (BMBF; project MASCARA), the H2020 GA 810316 - 4D-Nanoscope ERC Synergy Project, the IMI funded project RTCure, the Emerging Fields Initiative MIRACLE of the Friedrich-Alexander-Universität Erlangen-Nürnberg as well as the Schreiber Stiftung gemeinnützige Gesellschaft mbH.Disclosure of Interests:None declared
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Park, Isaac, Tra Mi Phan, and Jing Fang. "Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q." Cancers 13, no. 20 (October 11, 2021): 5084. http://dx.doi.org/10.3390/cancers13205084.
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Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.
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Huang, Xiangao, David Jayabalan, Maurizio Di Liberto, Zhengming Chen, Anna C. Schinzel, Scott Ely, Adriana C. Rossi, et al. "Inhibition of CDK4/CDK6 Sensitizes Myeloma to IMiD By Reducing the MEIS2 to Cereblon Ratio That Accelerates IKZF1 and IKZF3 Degradation." Blood 126, no. 23 (December 3, 2015): 500. http://dx.doi.org/10.1182/blood.v126.23.500.500.
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Abstract Lenalidomide (Len) and pomalidomide (Pom) are immunomodulatory drugs (IMiDs) effective in hematologic malignancies, in combination therapies for multiple myeloma (MM) in particular. Cereblon (CRBN), a component of the CRL4CRBN E3 ligase, is required for IMiD's anti-myeloma activity. Emerging evidence suggests that IMiDs bind CRBN and block an endogenous substrate MEIS2 from binding to CRBN, thereby facilitating the recruitment of transcription factors IKZF1 and IKZF3 to CRL4CRBN and their degradation. This then leads to loss of IRF4 necessary for myeloma survival. The clinical relevance of these novel findings, however, has not been defined. To address this question, we've investigated the mechanism of IMiD action and the functional consequences in freshly isolated primary bone marrow myeloma cells (BMMCs) (n=31) in stromal co-culture ex vivo in the context of the clinical response to Len or Pom in vivo before or after biopsy. We showed by whole transcriptome sequencing, protein analysis and functional assays that 1) BMMCs are addicted to IKZF3-IRF4 for survival; 2) Len-mediated IRF4 loss leads to de-repression of IRF7, induction of interferon (IFN) response genes and TRAIL-mediated apoptosis; and 3) the magnitude of IFN induction is tightly associated with killing of BMMCs by Len. Importantly, the IMiD sensitivity in BMMCs ex vivo correlated with the prior or subsequent clinical response to IMiD-based therapies in individual myeloma patients, suggesting that the clinical response to IMiDs in myeloma is largely intrinsic to myeloma cells. IMiDs have been reported to cause cell cycle arrest. We found that before evidence of killing, Len and Pom induced late G1 arrest by both repressing CCNA2 (encoding cyclin A) mRNA synthesis and elevating p21 and p27 proteins independent of Rb and p53. This result suggests that IMiDs preferentially kill cells in G1 arrest, and that induction of p rolonged early G1 arrest (pG1) beyond the normal G1 transit time by selective inhibition of CDK4/CDK6 with palbociclib (PD 0332991, Ibrance) may sensitize MM cells to IMiD killing, as it does to killing by other agents. Indeed, induction of pG1 by palbociclib overrides cell cycle regulation by Len, and sensitizes BMMCs to Len-mediated apoptosis by augmenting the loss of IRF4 protein and the induction of IRF7, IFNb and TRAIL. Further investigation revealed that induction of pG1 by CDK4/CDK6 inhibition sensitizes primary myeloma cells to IMiD killing by rapid acceleration of Len-mediated loss of IKZF1 and IKZF3 proteins, within one hour of IMiD addition. Loss and gain of function studies demonstrates that MEIS2 opposes pG1 sensitization to Len killing; however, MEIS2 itself is regulated by the cell cycle. Induction of pG1 reduces the ratio of MEIS2 to CRBN by both reducing the MEIS2 protein rapidly and increasing the CRBN protein at a later time in cooperation with Len. In summary, our data provide the first evidence that induction of prolonged early G1 arrest by selective inhibition of CDK4/CDK6 amplifies IMiD killing of primary myeloma cells by both repressing MEIS2 and increasing CRBN protein in cooperation with Len. This leads to a profound reduction in the ratio of MEIS2 to CRBN that accelerates the loss of IKZF1, IKZF3 and IRF4, and enhances IFN and TRAIL induction. Reducing the MEIS2/CRBN ratio thus represents a novel mechanism by which CDK4/CDK6 inhibition sensitizes myeloma to IMiDs, and a means for developing mechanism-based IMiD therapy through cell cycle control. Disclosures Huang: Celgene: Research Funding. Off Label Use: Palbociclib (PD 0332991) is a specific CDK4/CDK6 inhibitor used to stop the cell cycle.. Rossi:Calgene: Speakers Bureau. Pearse:Celegen: Consultancy. Mark:Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Niesvizky:Celgene: Consultancy, Speakers Bureau. Chen-Kiang:Celgene: Consultancy.
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Welsh, Seth, Daniel Riggs, Erin Meermeier, Chang-Xin Shi, Victoria Garbitt, Meaghen E. Sharik, Megan Du, et al. "Disrupting Ectopic Super-Enhancers to Treat Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 1593. http://dx.doi.org/10.1182/blood-2021-147551.
Full textAbstract:
Abstract Multiple myeloma (MM) is an incurable form of plasma cell cancer in which primary and secondary chromosomal translocations routinely juxtapose oncogenes to plasma cell-specific super-enhancers. Coincidentally, drugs which target super-enhancers have had success clinically. For example, immunomodulatory imide drugs (IMiDs) degrade super-enhancer-binding pioneer factors IKAROS and AIOLOS, while glucocorticoids (Dexamethasone) and proteasome inhibitors (Bortezomib) have the ability to transrepress or block the processing of super-enhancer-forming NF-κB proteins, respectively. Currently, alternative enhancer-targeting drugs are also in clinical development, like p300 inhibitors which target the acetyl-binding bromodomains and/or histone acetyl transferase activity of the chromatin-regulating coactivator homologs CBP and EP300. Despite showing therapeutic promise, our understanding of how these drugs function, alone or together, remains incomplete. Case in point, we find that IMiD-induced degradation of its target proteins IKAROS and AIOLOS does not guarantee a therapeutic response in vitro, and patients successfully treated with IMiDs eventually relapse; meanwhile, coactivator-targeting therapies like p300 inhibitors are often too toxic in vivo, and lack a therapeutic window. To improve the outcomes of MM patients we need to understand the heterogeneous genetics and transcription-factor milieus of the myeloma enhancer landscape, as well as how to increase the precision of enhancer-disrupting drugs. To accomplish this, our lab utilizes more than 60 human myeloma cell lines that have been extensively characterized at the genetic, proteomic, and drug-therapeutic-response levels. Additionally, we have generated a highly-predictive immunocompetent mouse model (Vk*MYC hCRBN+) that develops human-like MM and is sensitive to both IMiDs and a new class of therapeutics termed "degronimids" (normal mice do not respond to IMiDs or degronimids). Our central hypothesis is that combining a broad coactivator-targeting drug (e.g., the p300 inhibitor GNE-781), with a MM-specific transcription factor-targeting drug (e.g., IMiDs) restricts toxicities to myeloma cells and thus improves the therapeutic window. Currently, we are testing a variety of coactivator-targeting compounds alongside traditional IMiD therapies and other preclinical transcription factor-targeting drugs both in vivo and in vitro. We show that Vk*MYC hCRBN+ mice are exquisitely sensitive to GNE-781, requiring one fourth of the dose needed to treat other cancers and therefore avoiding the neutropenia and thrombocytopenia seen at higher doses. Second, we show that although IMiDs and GNE-781 induce an effective but transient response in vivo as single agents, the combination of the two drugs proved curative, with a progressive deepening of the anti-tumor response occurring even after therapy is discontinued. Ongoing experiments aim to determine how this drug combination, and other coactivator + transcription factor-targeting combinations, permanently disrupt myeloma-specific super-enhancers. Disclosures Neri: BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Bahlis: Sanofi: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genentech: Consultancy. Boise: AstraZeneca: Honoraria, Research Funding; AbbVie/Genentech: Membership on an entity's Board of Directors or advisory committees. Chesi: Abcuro: Patents & Royalties: Genetically engineered mouse model of myeloma; Pi Therapeutics: Patents & Royalties: Genetically engineered mouse model of myeloma; Pfizer: Consultancy; Novartis: Consultancy, Patents & Royalties: human CRBN transgenic mouse; Palleon Pharmaceuticals: Patents & Royalties: Genetically engineered mouse model of myeloma.
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Patil, Ajinkya, Mark Manzano, and Eva Gottwein. "CK1α and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma." Blood 132, no. 6 (August 9, 2018): 577–86. http://dx.doi.org/10.1182/blood-2018-01-828418.
Full textAbstract:
Key Points CK1α is essential for the survival of PEL cell lines, and its degradation mediates toxicity of IMiDs. Loss of IRF4 expression is a CK1α-, IKZF1-, and IKZF3-independent arm of IMiD toxicity in PEL cell lines.
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Suska, Anna, Maciej Rafał Czerniuk, and Artur Jurczyszyn. "Next-generation immunomodulatory drugs in multiple myeloma." Postępy Higieny i Medycyny Doświadczalnej 73 (December 31, 2019): 791–802. http://dx.doi.org/10.5604/01.3001.0013.6907.
Full textAbstract:
Multiple myeloma (MM) is a hematological malignancy that mainly affects elderly patients, with the median age of 69 years at the time of diagnosis. Despite the recent increase in the number of drugs used in the antimyeloma therapy, the disease remains incurable, with remissions and subsequent relapses. Immunomodulatory drugs (IMIDs), known to have multiple mechanisms of actions, including direct anti-MM activity and immune-stimulatory properties, are currently the backbone in multidrug regimens. New generation IMIDs are recommended nowoby ESMO – lenalidomide is included in frontline therapy, while pomalidomide is accepted from the third line. Clinical trials proved lack of apparent cross-resistance between immunomodulatory agents, confirmed their high efficacy and acceptable safety profile in individuals with relapsed multiple myeloma (RRMM) refractory to proteasome inhibitors and lenalidomide, even with adverse cytogenetic abnormalities. Also, triplet pomalidomide-based combinations with bortezomib, carfilzomib, cyclophosphamide, daratumumab or elotuzumab were proved to be effective and safe in this group of patients. The most common adverse events of the new generation IMIDs are the following: hematological toxicity (neutropenia, thrombocytopenia, anemia), fatigue and, while administered with dexamethasone, infections. However, peripheral neuropathy, significantly limiting the use of first generation IMID - thalidomide, is much less frequently observed. Due to the increased risk of venous thromboembolism, thromboprophylaxis should be implemented in the whole course of IMID therapy. Data from real-life settings demonstrate that new generation IMIDs are a cost-effective treatment option in relapsed/ refractory myeloma. Currently, one drug program with the new IMIDs is available in Poland.
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Simon, David, Koray Tascilar, Filippo Fagni, Gerhard Krönke, Arnd Kleyer, Christine Meder, Raja Atreya, et al. "SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases." Annals of the Rheumatic Diseases 80, no. 10 (May 6, 2021): 1312–16. http://dx.doi.org/10.1136/annrheumdis-2021-220461.
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ObjectivesTo better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs).MethodsPatients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded.ResultsVaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12–8.85) for controls and 6.90 (6.45–7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID.ConclusionsImmune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
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Davis, Lorraine, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, and Daniel W. Sherbenou. "309 MYC Inhibition Overcomes IMiD Resistance in Heterogeneous Multiple Myeloma Populations." Journal of Clinical and Translational Science 6, s1 (April 2022): 54. http://dx.doi.org/10.1017/cts.2022.169.
Full textAbstract:
OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.
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Madan, Sumit, Martha Q. Lacy, Angela Dispenzieri, Morie A. Gertz, Francis Buadi, Suzanne R. Hayman, Kristen Detweiler-Short, et al. "Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma." Blood 118, no. 7 (August 18, 2011): 1763–65. http://dx.doi.org/10.1182/blood-2011-04-350009.
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Abstract The efficacy of retreatment with immunomodulatory drugs (IMiDs) among patients with multiple myeloma who received this class of drugs for initial therapy is unknown. We studied 140 patients who received either thalidomide-dexamethasone (81; 58%) or lenalidomide-dexamethasone (59; 42%) as first-line therapy of multiple myeloma followed by repeat IMiD (thalidomide [34; 24%] or lenalidomide [106; 76%]) as one of the salvage regimens. A median of 2 treatments (range, 1-6), including a stem cell transplant in 105 patients (75%), were administered before IMiD-based salvage therapy. The median time from diagnosis to repeat exposure to IMiD was 28 months. Among the 113 evaluable patients, 50 (44%) achieved at least a partial response, and 63 (56%) achieved less than a partial response to repeat IMiD. Response rates with lenalidomide retreatment were higher than with repeat administration of thalidomide.
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Garcillán, Beatriz, Miguel Salavert, José R. Regueiro, and Sabela Díaz-Castroverde. "Response to Vaccines in Patients with Immune-Mediated Inflammatory Diseases: A Narrative Review." Vaccines 10, no. 2 (February 15, 2022): 297. http://dx.doi.org/10.3390/vaccines10020297.
Full textAbstract:
Patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and inflammatory bowel disease, are at increased risk of infection. International guidelines recommend vaccination to limit this risk of infection, although live attenuated vaccines are contraindicated once immunosuppressive therapy has begun. Biologic therapies used to treat IMIDs target the immune system to stop chronic pathogenic process but may also attenuate the protective immune response to vaccines. Here, we review the current knowledge regarding vaccine responses in IMID patients receiving treatment with biologic therapies, with a focus on the interleukin (IL)-12/23 inhibitors. B cell-depleting therapies, such as rituximab, strongly impair vaccines immunogenicity, and tumor necrosis factor (TNF) inhibitors and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) fusion protein abatacept are also associated with attenuated antibody responses, which are further diminished in patients taking concomitant immunosuppressants. On the other hand, integrin, IL-6, IL-12/23, IL-17, and B-cell activating factor (BAFF) inhibitors do not appear to affect the immune response to several vaccines evaluated. Importantly, treatment with biologic therapies in IMID patients is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or developing severe disease. However, the efficacy of SARS-CoV-2 vaccines on IMID patients may be reduced compared with healthy individuals. The impact of biologic therapies on the response to SARS-CoV-2 vaccines seems to replicate what has been described for other vaccines. SARS-CoV-2 vaccination appears to be safe and well tolerated in IMID patients. Attenuated but, in general, still protective responses to SARS-CoV-2 vaccination in the context of certain therapies warrant current recommendations for a third primary dose in IMID patients treated with immunosuppressive drugs.
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Barankiewicz, Joanna, Anna Szumera-Ciećkiewicz, Aleksander Salomon-Perzyński, Paulina Wieszczy, Agata Malenda, Filip Garbicz, Monika Prochorec-Sobieszek, Irena Misiewicz-Krzemińska, Przemysław Juszczyński, and Ewa Lech-Marańda. "The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients." Journal of Clinical Medicine 10, no. 12 (June 18, 2021): 2683. http://dx.doi.org/10.3390/jcm10122683.
Full textAbstract:
Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins’ expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy.
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Rundgren, Ida Marie, Anita Ryningen, Tor Henrik Anderson Tvedt, Øystein Bruserud, and Elisabeth Ersvær. "Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes." Molecules 25, no. 2 (January 16, 2020): 367. http://dx.doi.org/10.3390/molecules25020367.
Full textAbstract:
Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell–cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.
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LeBlanc, Richard, Teru Hideshima, Laurence P. Catley, Reshma Shringarpure, Renate Burger, Nicholas Mitsiades, Constantine Mitsiades, et al. "Immunomodulatory drug costimulates T cells via the B7-CD28 pathway." Blood 103, no. 5 (March 1, 2004): 1787–90. http://dx.doi.org/10.1182/blood-2003-02-0361.
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Abstract Although thalidomide (Thal) does not directly induce T-cell activation, it increases proliferation of T cells following CD3 activation. In this study, we examined the immunomodulatory effects of a more potent analog of Thal, immunomodulatory drug (IMiD), on T cells. Although IMiD3 does not directly stimulate proliferation of normal donor CD3+ T cells, it significantly costimulates proliferation of CD3+ T cells induced by CD3 ligation (stimulation index [SI], 2.4), immature dendritic cells (DCs; SI, 2.1), and mature DCs (SI, 2.6). T-cell proliferation triggered by DCs was abrogated by cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA-4–Ig), and IMiD3 partially overcomes this inhibitory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4–Ig on Epstein-Barr virus (EBV) and influenza (Flu)–specific CD4 and CD8 T-cell responses, as measured by cytokine capture and enzyme-linked immunosorbent spot (ELISPOT) assay. IMiD3 did not induce up-regulation of CD28 expression on T cells, or of CD80-CD86 expression on dendritic cells. Importantly, IMiD3 triggers tyrosine phosphorylation of CD28 on T cells, followed by activation of nuclear factor κB (NF-κB), a known downstream target of CD28 signaling. These results therefore define the costimulatory mechanism whereby IMiD3 induces T-cell activation and provide the cellular and molecular basis for use of IMiD3 as an adjuvant in immunotherapeutic treatment strategies for multiple myeloma.
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Ott, Christopher J., Gang Lu, Jaime Reyes, Charles Y. Lin, William G. Kaelin, and James E. Bradner. "Disruption of the Ikaros-Mediated Gene Expression Program in Multiple Myeloma with Immunomodulatory Agents." Blood 124, no. 21 (December 6, 2014): 420. http://dx.doi.org/10.1182/blood.v124.21.420.420.
Full textAbstract:
Abstract The close chemical analogues lenalidomide and pomalidomide are immunomodulating drugs (IMiDs) that possess antineoplastic activity in multiple myeloma (MM) and other hematologic malignancies. IMiDs exert intrinsic antiproliferative effects on MM cells at least in part through direct interaction with intracellular cereblon. Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex that also includes CUL4, RBX1, and DDB1 – together referred to as CRL4CRBN. Direct binding of IMiDs to a small hydrophobic pocket of the CRBN carboxy-terminal domain induces altered ubiquitinylation activity, including disrupted autoubiquitinylation of CRL4CRBN (Ito et al. Science, 2010; Fischer et al. Nature, 2014). Recently, we and others described the zinc finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) as endogenous targets of CRL4CRBN ubiquitinylation in MM cells (Lu et al. Science, 2014; Kronke et al. Science, 2014). We found that treatment of MM cells with lenalidomide (LEN) causes increased ubiquitinylation of IKZF1 and IKZF3 by CRL4CRBN, and targets them for degradation by the proteasome. This loss of IKZF1/3 was both necessary and sufficient to observe the cellular antiproliferative effects of LEN, suggesting that this a primary mechanism of IMiD activity in MM. However, it remains unclear how depletion of these transcription factors ultimately leads to reduced proliferation of myeloma cells. Several gene products are known to be perturbed in MM cells upon IMiD treatment, including transcriptional downregulation of the master regulator transcription factor IRF4 (Zhu et al. Blood, 2011; Lu et al. Science, 2014). Yet rescue experiments with exogenous expression of IRF4 cannot fully rescue effects of IMiD treatment in MM cells, suggesting that other IKZF1/3 target genes play a role in the antiproliferative effects of IMiDs. Here we use complementary gene expression and genomic approaches to discern the global effects of IMiD treatment on MM cells. Using chromatin-immunoprecipitation followed by high-throughput sequencing (ChIP-seq), we have determined the genome-wide binding profile of both IKZF1 and IKZF3 in MM cells. We find both IKZF1 and IKZF3 occupy genomic regions including promoters, gene bodies, and distal enhancer elements. In MM cells, IKZF1 and IKZF3 enrichment almost always co-occurs, corresponding to reports of IKZF1/3 heterodimers facilitating transcriptional programs in lymphoid cells (Morgan et al. EMBO, 1997). Treatment of MM cells with LEN results in a dramatic decrease of both IKZF1 and IKZF3 binding to the genome at promoters and enhancers. Additionally, we performed ChIP-seq on RNA polymerase II (RNAPII) after LEN treatment in order to determine how IMiD-mediated IKZF1/3 depletion affects cellular transcriptional activity. Loss of IKZF1/3 binding to target genes most often correlates with increased density of RNAPII in gene bodies, suggesting transcriptional derepression of IKZF1/3 target genes. This observation was confirmed with genome-wide expression analysis by microarray. Among the derepressed target genes were genes with known tumor suppressor activity including CDKN1A, KLF6, and TXNIP. The IRF4 locus was also found to be a direct target of IKZF1/3, including binding to a large distal enhancer region upstream of the IRF4 coding region. Yet unlike most other IKZF1/3 target genes, RNAPII density within the IRF4 gene body is significantly decreased upon LEN treatment, suggesting that unique transcriptional regulatory mechanisms function at this locus that are distinct from other IKZF1/3 targets. Knockdown of IKZF1 and IKZF3 expression by shRNAs results in increased TXNIP and decreased IRF4 mRNA and protein expression, further suggesting that IMiD-mediated degradation of IKZF1/3 leads to opposite effects on these genes. TXNIP encodes the thioredoxin binding protein, which increases cellular reactive oxygen species and promotes G0/G1 cell cycle arrest. Forced exogenous overexpression of TXNIP inhibits MM cell growth, indicating a potential additional mechanism of IMiD activity. These studies define the IKZF1/3-mediated transcription program in MM cells and detail its perturbation by IMiDs. Ultimately these data will be informative for understanding the downstream effectors of intrinsic IMiD activity in hematologic malignancies, and to further understand mechanisms for acquired or innate resistance to these therapies. Disclosures No relevant conflicts of interest to declare.
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Pal, Rekha, Sara A. Monaghan, Andrea Cortese Hassett, Markus Y. Mapara, Peter Schafer, G. David Roodman, Margaret V. Ragni, Lynn Moscinski, Alan List, and Suzanne Lentzsch. "Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia." Blood 115, no. 3 (January 21, 2010): 605–14. http://dx.doi.org/10.1182/blood-2009-05-221077.
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AbstractThe immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.
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Manic, Marina S., and Vesna Najdanovic-Visak. "Solubility of Mixtures Containing Soybean Oil, Ionic Liquid and Methanol." Open Chemical Engineering Journal 10, no. 1 (April 8, 2016): 41–49. http://dx.doi.org/10.2174/1874123101610010041.
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This paper presents data on mutual solubility of the binary (soybean oil + ionic liquid) and ternary (soybean oil + methanol + ionic liquid) systems, where ionic liquid stands for 1-butyl-3-methylimidazolium thiocyanate [C4MIM][SCN] or 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide [C4MIM][NTf2] or 1-butyl-3-methylimidazolium dicyanamide [C4MIM][DCA] or 1-butyl-3-methylimidazolium hexafluorophosphate [C4MIM][PF6] or 1-butyl-3-methyl imida zolium hydrogensulfate [C4MIM] [HSO4] or 1-decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C10MIM][NTf2] or methyltrioctylammonium bis(trifluoromethylsulfonyl)imide [ALIQUAT][NTf2] or methyltrioctylammonium chloride [ALIQUAT][Cl]. Solubilities were determined by the cloud point titration method in the temperature range of 298 K to 343 K. Obtained results suggest that imidazolium based ionic liquids exhibit lower solubility in soybean oil than ionic liquids with the aliquat cation. Thus, aliquat based ionic liquids are good candidate to be used as co-solvents for biphasic (methanol + soybean oil) mixture.
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Lindner, Stefanie, Christian Steinebach, Namrata Udeshi, Deepak Mani, Hannes Kehm, Simon Köpff, Steven A. Carr, Michael Gütschow, and Jan Krönke. "Pomalidomide-Based Homo-Protacs for the Chemical Knockdown of Cereblon." Blood 132, Supplement 1 (November 29, 2018): 260. http://dx.doi.org/10.1182/blood-2018-99-116376.
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Abstract The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide are all approved for the treatment of multiple myeloma. IMiDs bind cereblon (CRBN), a substrate adaptor for the CRL4 E3 ubiquitin ligase (CRL4CRBN). In multiple myeloma, IMiDs enhance the binding of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) to CRL4CRBN, leading to their ubiquitination and degradation. Depletion of IKZF1 and IKZF3 results in growth inhibition in multiple myeloma cells. In addition, IMiDs can block the physiologic function of CRBN what has been shown to contribute to the anti-proliferative effects as well as other properties of the drug. Recently, IMiDs were exploited for the generation of Proteolysis Targeting Chimeras (PROTACs). These molecules link the IMiD structure to another small molecule that binds a protein of interest (POI). Such IMiD-based PROTACs are capable to guide the CRBN-CRL4 E3 ligase to the POI, resulting in its ubiquitination and degradation. Here, we designed pomalidomide-based homobifunctional PROTACs and investigated their ability to induce self-directed CRBN ubiquitination and degradation (Figure 1A). We evaluated different attachment strategies, modifications and linker lengths and tested the effect of a series of homo-dimeric compounds on their potency to deplete CRBN protein levels. The homodimeric compound 15a with a linker length of 8 atoms was identified as the most potent CRBN degrader with a minimal remaining effect on IKZF1 (Figure 1B). Homodimeric PROTACs with longer linkers exhibited a weaker capability for CRBN degradation and had a more potent effect on IKZF1 protein levels. The effect of compound 15a on CRBN was blocked after pre-treatment with a proteasome inhibitor or MLN4924, a neddylation activating enzyem inhibitor that blocks Cullin E3 ligases. Co-immunoprecipitation revealed that 15a induces interaction of two CRBN molecules. The homo-PROTAC 15a was active at low concentrations below 100 nM and had long-lasting effects on the intracellular CRBN level (Figure 1B). Applying global proteome analyses in the multiple myeloma cell line MM1.S demonstrated that PROTAC 15a specifically induced degradation of CRBN and had only weak effects on IKZF1 and IKZF3 and no effect on the other members of the CRL4 ligase family, including DDB1 and CUL4A which are in close proximity to CRBN in the CRL4CRBN complex. CRBN inactivation by our compounds had no effect on proliferation of different multiple myeloma cell lines. Pre-treatment with Homo-PROTAC 15a prevented pomalidomide-induced degradation of IKZF1 and IKZF3, and antagonized the effects of pomalidomide and lenalidomide on multiple myeloma cell growth. This was consistent with genetic inactivation of CRBN by CRISPR/Cas9. In conclusion, we generated the first chemical inhibitors of CRBN that can serve as a useful tool for future biomedical investigations on CRBN-related signaling. These compounds will also help to discriminate whether an IMiD effect depends on CRBN-mediated targeted degradation of neo-substrates or from blocking the physiologic function of CRBN. Furthermore, our data confirm the essential role of CRBN in IMiD activity in multiple myeloma. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Kimpton, Miriam, Ryan Buyting, Daniel J. Corsi, Natasha Rupani, Marc Carrier, and Arleigh McCurdy. "Incidence and Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Receiving Immunomodulatory Agents." Blood 128, no. 22 (December 2, 2016): 2624. http://dx.doi.org/10.1182/blood.v128.22.2624.2624.
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Abstract Multiple myeloma (MM) is an incurable plasma cell disorder representing 10% of all hematologic malignancies. Cancer is a known risk factor for venous thromboembolism (VTE). Patients with MM are at a particularly high risk of developing VTE owing to patient characteristics (e.g. previous history of VTE), disease characteristics, and treatment characteristics including use of the immunomodulatory agents (IMIDs). Unfortunately, standard criteria to identify the patients most at risk for developing VTE in MM while receiving IMIDs are unknown. We sought to assess the incidence of VTE and its associated risk factors in MM patients receiving IMID therapy. A retrospective cohort study including 1680 consecutive patients with multiple myeloma treated at our centre between January 01, 1995 and January 26, 2016 was conducted. The annual incidence of VTE on immunomodulatory agents including thalidomide, lenalidomide, and pomalidomide was derived. Univariate incidence ratio analyses of VTE for different risk factors was performed including: previous history of VTE, concomitant use of dexamethasone, and ≥/< 6 months after IMID initiation. A total of 309 MM patients treated with an immunomodulatory agent were identified. Nineteen patients were excluded (incomplete data, lost to follow). Of the remaining 290 patients, the mean age was 67.9 and 42.4% were female. Twenty-seven VTE events were recorded. The overall risk ratio was 6.1 for the development of VTE. Patients with a personal history of VTE had an increased risk of suffering a VTE while on IMID therapy (IRR 5.4; CI, 1.9-13.6). The time from the initiation of the IMID therapy (less than 6 months) also increased the risk of developing a VTE (IRR 51.7; CI,19.4-160.1). The concomitant use of dexamethasone was not associated with a statistically significant increased risk (IRR 1.7; CI, 0.3-69.5). Incidence risk ratios for these risk factors are depicted in Table 1. Our results suggest that a personal history of VTE and the time from the initiation of the IMID (less than 6 months) are associated with an increased risk of VTE in MM patients receiving IMID therapy. This may be helpful in determining which multiple myeloma patients treated with an IMID agent warrant more aggressive thromboprophylaxis. Further prospective studies are needed to determine the optimal agent, intensity, and duration of thromboprophylaxis in patients with MM on IMID therapy. Disclosures McCurdy: Celgene: Honoraria.
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Man, Louise, Amy L. Morris, Jacqueline Brown, Surabhi Palkimas, and Kelly Mercer Davidson. "Use of Direct Oral Anticoagulants in Patients on Immunomodulatory Agents." Blood 128, no. 22 (December 2, 2016): 1449. http://dx.doi.org/10.1182/blood.v128.22.1449.1449.
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Abstract The risk of venous thromboembolism (VTE) is increased in individuals with cancer, particularly in those with multiple myeloma. The immunomodulatory agents (IMiDs) thalidomide, lenalidomide and pomalidomide are commonly used to treat multiple myeloma and other hematologic malignancies and are associated with increased risk of VTE. Current National Comprehensive Cancer Network (NCCN) guidelines (v.1.2016) on cancer-associated VTE utilize a risk assessment model based on a few small studies to guide VTE prophylaxis for multiple myeloma patients being treated with an IMiD (Palumbo, et al. Leukemia, 2008). Aspirin is recommended for lower risk patients while prophylactic-dose low molecular weight heparin or therapeutic warfarin are recommended for higher risk patients. The use of direct oral anticoagulants (DOACs) for cancer-associated VTE is currently under investigation (Raskob, et al. Lancet Haematol, 2016). Little is known about their role in VTE prophylaxis in patients on IMiDs. The purpose of this study was to explore the use of DOACs in patients receiving IMiDs. We performed a retrospective chart review of all patients at the University of Virginia Health System who received an IMiD and who were taking either a DOAC or warfarin between January 1, 2010 and December 31, 2015. DOACs included dabigatran, rivaroxaban, and apixaban. IMiDs included lenalidomide, thalidomide, and pomalidomide. The primary endpoint was to assess the safety of DOACs as compared to warfarin, and the secondary endpoint was to assess their efficacy. We collected baseline patient information, as well as diagnosis, IMiD, anticoagulant, antiplatelet agent and dose, duration of treatment, concurrent antineoplastic therapies, and thrombotic risk factors. We utilized the NCCN definitions of individual and myeloma-related thrombotic risk factors. Many patients had changes in their IMiD or anticoagulation. Thus, separate encounters were collected, where an encounter was the combination of an IMiD agent and dose, the anticoagulant, the antiplatelet agent (if any), and the thrombotic risk profile for that time period. Descriptive analyses were performed on all encounters in both groups. Rates of bleeding and thrombotic events were calculated. There were 21 discrete patients in the DOAC group and 16 in the warfarin group. Characteristics and outcomes are described in Table 1. There were four non-major bleeding events in the DOAC group; two of the four bleeding events occurred while on concomitant aspirin therapy. The patient with hematuria stopped anticoagulation and cystoscopy revealed bladder cancer. The other patients did not change or stop therapy. There were six bleeding events in the warfarin group: two were major and four were non-major. The two major events were gastrointestinal bleeding (GIB) and a subarachnoid hemorrhage (SAH). Neither event occurred while on concomitant antiplatelet therapy. The GIB required cessation of therapy, hospitalization, and transfusions. The INR at the time is unknown. The SAH was preceded by a fall while INR was in therapeutic range. Both major and two of the non-major bleeding events occurred in the same patient at different time points and accounted for most of the warfarin-related bleeding events. There was one thrombotic event in the DOAC group. The patient had a non-ST segment elevation myocardial infarction (NSTEMI) while on prophylactic-dose rivaroxaban. She was not on concomitant antiplatelet therapy. Arterial thrombotic events are not typically seen with IMiDs, and the NSTEMI was thought to be related to the recent initiation of carfilzomib. There were no thrombotic events in the warfarin group. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs as compared to warfarin in patients on IMiDs. In our study, all bleeding events in the DOAC group were non-major, while patients on warfarin experienced both major and non-major bleeds. Only one thrombotic event was recorded in the DOAC group. DOACs may represent an attractive alternative to warfarin for VTE prophylaxis in these patients, given no need for routine monitoring and fewer dietary restrictions. Prospective studies in this population are warranted. Disclosures No relevant conflicts of interest to declare.
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Chirackal, Sinto Sebastian, Yuan Xiao Zhu, Esteban Braggio, Chang-Xin Shi, Sonali Panchabhai, Gregory Ahmann, Scott A. Van Wier, et al. "Immunomodulatory Drugs Inhibit H2O2 Decomposition in Multiple Myeloma Cells and Its Mediated Cytotoxicity Is Determined By Cellular Antioxidative Capacity." Blood 126, no. 23 (December 3, 2015): 2475. http://dx.doi.org/10.1182/blood.v126.23.2475.2475.
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Abstract Introduction Lenalidomide is an immunomodulatory drug (IMID) used to treat Multiple Myeloma (MM). Although a role for cereblon (CRBN)-mediated degradation of Ikaros proteins (IKZF1 and IKZF3) has been shown, the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated anti-MM activity and/or resistance are undiscovered. Therefore, we aimed to analyze whether IMIDs (thalidomide, lenalidomide, and pomalidomide) are inducing oxidative stress in MM and what determines these drugs varying sensitivity and/or resistance. Methodology Amplex Red Assay has been performed to analyze IMIDs-mediated inhibition of H2O2 decomposition in both, in-vitro and in-vivo assays. Lentiviruses were prepared in 293T cells for CRBN, IgL-λ & IgL-k, and Bim knockdown experiment. Quantification of MM cellular anti-oxidative capacity for determining IMID sensitivity was standardized with H2O2-mediated oxidation of FADH2 and NAD(P)H. To measure apoptosis and gene expression analysis 106 cells were incubated with lenalidomide for 24 to 96 hours before they were examined by annexin-PI and FACS analysis. Gene and protein expression were measured by RT-PCR, western blot, and immunohistochemistry. Results We discovered that IMIDs inhibit peroxidase-mediated decomposition of H2O2 in both, in vitro horseradish peroxidase (HRP) assays and in human MM cell lines (HMCLs). Of the IMIDs analyzed, pomalidomide was the more potent inhibitor. H2O2 treatment effectively degraded IKZF1 and IKZF3 in HMCLs. To confirm the central role of CRBN in IKZF1 and IKZF3 degradation by H2O2-induced oxidative stress, we used CRBN knockdown OPM2 isogeneic cells and the CRBN-overexpressing OCIMY-5 cell line. We treated both sets of isogenic cell lines with lenalidomide and H2O2 for 3 hours, and we showed that H2O2 similarly mediates IKZF1 and IKZF3 degradation in a CRBN-dependent fashion. Next, we tested viability of CRBN present and absent cell lines with increasing concentrations of lenalidomide and H2O2 for 3 days. Lenalidomide-induced cytotoxicity was CRBN dependent, but H2O2 was not after 3 days, as shown by MTT assays. The capacity of MM cells to decompose H2O2 was measured via a biochemical test that quantitatively measured cellular anti-oxidative capacity. IMID sensitivity was well correlated with cellular anti-oxidative capacity, likely, cells more efficiently decompose H2O2was resistant and cells were not sensitive to IMID. This result shows that antioxidant capacity determines lenalidomide sensitivity among HMCLs with similar CRBN protein expression. We discovered that lenalidomide-mediated cytotoxicity in MM was attributable to oxidative damage of intracellular immunoglobulin proteins. By using several sets of isogenic cells lines with and without CRBN expression, we confirmed that lenalidomide treatment caused accumulation of IgL dimers only in CRBN-positive cells. Lenalidomide-induced IgL dimerization lead to decreased secretion and consequent intracellular accumulation of IgL, as evidenced by unchanged IgL mRNA expression, increased total intracellular IgL protein, and decreased secretion of IgL. After 72 hours of lenalidomide treatment we found decreased XBP-1u, increased XBP-1s, and over-expressed GRP78/BiP endoplasmic reticulum stress (ERS) marker proteins in CRBN positive cells but not in CRBN knock-down cells. We observed Bim requirement, especially BimEL, after lenalidomide treatment in CRBN-positive lenalidomide-sensitive cells. Our data reveals that lenalidomide-mediated; progressive ERS can positively enhance bortezomib-induced apoptosis in an in-vitro MM model. We pretreated MM cells with lenalidomide and then treated them with bortezomib. OPM2 cells pretreated with lenalidomide for 2 days clearly showed increased sensitivity to bortezomib-induced apoptosis compared with cells that were not pretreated. Conclusion IMIDs inhibit H2O2 decomposition. Ikaros protein degradation is a consequence of H2O2 mediated oxidative stress. Therefore, cells producing high H2O2 and with less antioxidative capacity are more sensitive to IMIDs. On the basis of this discovery, we would be able to predict which patients will benefit from IMIDs-mediated therapy and develop new drugs other than IMIDs that can inhibit intracellular H2O2 decomposition in MM. At present, CRBN may be required for IMIDs to effectively inhibit H2O2decomposition. Disclosures Chirackal: Mayo Clinic: Patents & Royalties: Filed a professional US patent for quantifying cellular anti-oxidative capacity. Fonseca:Mayo Clinic: Patents & Royalties: Filed a professional US patent for quantifying cellular anti-oxidative capacity.
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Fotiou, Despina, Ioannis V. Kostopoulos, Maria Krevvata, Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Pantelis Roussakis, Chrysanthi Panteli, et al. "Evaluation of Efficacy and Immune Modulation Associated with the Addition of IMiDs to Daratumumab Backbone in Patients Refractory to Both Drug Classes." Blood 138, Supplement 1 (November 5, 2021): 1668. http://dx.doi.org/10.1182/blood-2021-150032.
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Abstract Despite significant improvements in myeloma (MM) therapies, patients (pts) refractory to immunomodulatory agents (IMiDs), proteasome inhibitors (PIs) and anti-CD38 monoclonal antibodies (mAbs) have poor prognosis and limited treatment options. Daratumumab (DARA), an anti-CD38 mAb, is active in pts with relapsed/refractory MM through mechanisms that include complement-dependent and antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and immunomodulation. DARA + IMiDs have substantial efficacy, probably through the combination of their immune and microenvironmental effects. The mechanisms of resistance are not fully elucidated but resistance to DARA may be reversed by addition of IMiDs and vice versa, as previously shown (Gavriatopoulou Blood 2019, Nooka Cancer 2019). We prospectively evaluated the combination of DARA + IMiD following refractoriness to both agents, to assess clinical activity but also to longitudinally assess immune cell populations in the peripheral blood (PB) in order to understand the resulting immunomodulation. Consecutive PB samples from 35 pts refractory to an IMiD (LEN or POM) and progressing on DARA monotherapy were analyzed. The last IMiD on which each patient was refractory was added without modulating DARA backbone (RESET). In consenting pts, PB samples were collected at the time of DARA initiation, at progression to DARA monotherapy and IMiD addition, at response and at progression to DARA-IMiD. Samples were viably frozen and analyzed using specific two 8-color panels. Panel 1: CD38-FITC, Granzyme B-PE, CD127-PeCy7, CD25-APC, CD4-APCCy7, CD3-BV510, Lag-3-BV421 and 7-AAD as viability dye; panel 2: CD14-FITC, CD56-PE, CD66-b-PeCy7, CD80-APC, CD45-APCCy7, CD3/CD19-BV510, CD16-BV421 and 7-AAD as viability dye. Pts' median age was 73 years (range 52-86; 66% male); median prior treatment lines were 3 (range 1-16); all had prior exposure and refractoriness to at least one PI; all were refractory to LEN and 51% to POM, 40% had prior ASCT. The IMiD added was the last used prior to DARA, i.e., LEN in 49% (17/35) and POM in 51% (18/35). Median duration of DARA monotherapy prior to RESET was 7.9 months (range 1-38) and 64% responded (≥PR) before progression. Median duration of RESET therapy was 5.5 months (range 0.46 to 23.86) and 43% had ≥PR (≥MR: 60%) [including VGPR: 8.6% (n=3), PR: 34.3% (n=12), MR: 17.1% (n=6), SD/NR: 28.6% (n=10), PD: 11.4% (n=4)]. Median PFS was 5 months (95% CI 1.5-8.4) and median OS was 19 months (95% CI 13.5-24.5). Based on response at 3-month landmark, PFS was 9 months for pts who achieved ≥ PR vs 4 months for < PR (p=0.031). PFS and response to RESET were independent of type or dose of IMiD, prior response to DARA monotherapy or IMiD, number of prior treatments, ISS at diagnosis or at time of RESET. Multivariate flow cytometry analysis showed significant heterogeneity between pts (n=20). After DARA monotherapy there was an increase in CD8+ T cells compared to baseline which persisted throughout DARA-containing therapy with CD4+ T remaining at similar levels at all time-points. Total Tregs reduced after DARA start; however, within Tregs the relative proportion of Lag3+ Tregs tended to increase during DARA monotherapy. NK cell levels were significantly reduced after DARA and remained low throughout DARA therapy, with no recovery after IMiD addition; within NKs, we noticed an increase of CD16-/CD56+ immunomodulatory/cytokine producing and, to a lesser extent, of CD56-/CD16+ cytotoxic subsets compared to mature CD56+/CD16+ NK cells which tended to decrease, especially during DARA monotherapy. Although the samples at response to DARA/IMiD combination are few (n=10), CD56-CD16+ NK cell percentages at the time of progression to DARA were associated with response to DARA/IMiD. Finally, there was a noticeable increase in M1- and a decrease in M2-type macrophage subsets at response to DARA/IMiD. In conclusion, retaining DARA backbone therapy may be associated with clinically relevant activity (ORR 43%, 5 months median PFS) among pts refractory toDARA and IMiD, when these drugs are combined. Longitudinal evaluation of PB immune cell composition showed DARA-specific immunomodulation, which was not altered after addition of IMiDs, but may be related to restoration of sensitivity to the DARA/IMiD combination. Further investigation is in progress to reveal potential immune signatures of clinical relevance. Disclosures Krevvata: Janssen: Current Employment. Gavriatopoulou: Genesis: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Amgen: Honoraria. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria.
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Jakobsen, Theresa, Mette Dahl, Konstantinos Dimopoulos, Kirsten Grønbæk, Jørgen Kjems, and Lasse Sommer Kristensen. "Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells." Cancers 13, no. 3 (January 20, 2021): 365. http://dx.doi.org/10.3390/cancers13030365.
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Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance.
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Cuddihy, Andrew R., Parisa Asvadi, Rosanne Dunn, Tiffany T. Khong, and Andrew Spencer. "The Anti-Kappa Monoclonal Antibody MDX-1097 Synergizes with Immunomodulatory Drugs to Enhance Antibody-Dependent Cell Cytotoxicity of Multiple Myeloma Cells." Blood 120, no. 21 (November 16, 2012): 4012. http://dx.doi.org/10.1182/blood.v120.21.4012.4012.
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Abstract Abstract 4012 Multiple Myeloma (MM) is a cancer caused by the proliferation of malignant clonal plasma cells in the bone marrow and accounts for 10% of all hematologic malignancies. Recent advances have been made in the treatment and management of MM, however, despite these advances the majority of patients will ultimately relapse and die from their disease within 3–5 years from diagnosis. Several novel therapeutic approaches, including the use of antibody-based therapies, are being investigated to further improve the treatment of MM. MDX-1097 is a chimeric monoclonal antibody being assessed as a single agent in a Phase 2 clinical trial for the treatment of kappa light-chain restricted (κ-type) MM. MDX-1097 binds to the kappa myeloma antigen (KMA), a tumor-specific membrane-associated protein expressed on malignant plasma cells from patients with K-type MM. Previously we have demonstrated that MDX-1097 exerts its anti-tumour effects through multiple mechanisms, including antibody-dependent cell cytotoxicity (ADCC) in the presence of either normal human peripheral blood mononuclear cells (PBMCs) or purified natural killer (NK cells). The immunomodulatory drugs (IMiDs) lenalidomide (Revlimid) and pomalidomide (Actimid) are currently in use or being assessed for the treatment of MM. These IMiDs have been shown to exert their anti-tumor effects both directly, via apoptotic mechanisms, and indirectly via a number of different mechanisms including the augmentation of NK-dependent cellular cytotoxicity. In this study we report that IMiDs and MDX-1097 co-operate to promote enhanced ADCC of MM cells. In vitro treatment of normal PBMCs with IMiDs led to a 1.4-fold higher level of ADCC-mediated cell death of MDX-1097 spiked JJN3 cells (a κ-type MM cell line) compared with vehicle-treated PBMCs from the same donor. Similarly, in vivo lenalidomide exposed PBMCs isolated from a MM patient were, on average, 1.8-fold more effective in killing MDX-1097 spiked JJN3 cells in vitro compared to PBMC obtained from the same patient prior to lenalidomide treatment. Treatment of JJN3 cells with IMiDs resulted in significantly increased cell surface expression of KMA (lenalidomide: 1.9-fold, p < 0.001; pomalidomide: 2.3-fold, p < 0.01). These IMiD-treated JJN3 cells, when spiked with MDX-1097 were 1.7-fold more susceptible to ADCC-mediated cell death in the presence of untreated PBMCs, compared to JJN3 cells treated with vehicle alone. This difference in sensitivity to ADCC mediated cell death is presumably due to increased KMA expression resulting in more binding sites for MDX-1097, therefore facilitating recruitment of PB immune effector cells. Furthermore, combining IMiD-treated PBMCs with IMiD-treated, MDX-1097 spiked JJN3 cells resulted in a further increment in ADCC-mediated JJN3 cell death. This study demonstrates that in vivo and in vitro treatment of PBMCs with IMiDs engages the PB immune effector cells, leading to increased ADCC-induced κ-type MM cell death in vitro in the presence of MDX-1097. IMiDs also increase cell surface expression of KMA, leading to increased MDX-1097 binding and in turn also enhancing ADCC-induced MM cell killing. Our data provides a rationale for the clinical evaluation of a combination therapy involving both IMiDs and MDX-1097 for the treatment of k-type MM. Disclosures: Cuddihy: Immune System Therapeutics Ltd: Research Funding. Asvadi:Immune System Therapeutics Ltd: Employment. Dunn:Immune System Therapeutics Ltd: Employment, Equity Ownership. Spencer:Immune System Therapeutics Ltd: Research Funding.
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Volkers, A., L. Wieske, K. van Dam, M. Steenhuis, E. Stalman, L. Kummer, Z. van Kempen, et al. "DOP27 Humoral immune response after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases treated with immunosuppressive therapy - a Target to B! study." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i079. http://dx.doi.org/10.1093/ecco-jcc/jjab232.066.
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Abstract Background The aim of this study was to investigate the effect of various immunosuppressants on the humoral immune responses after vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods The Target to B! SARS-CoV-2 study is a multicentre study, taking place in 7 Dutch academic hospitals. Patients with the following IMIDs were recruited: Crohn’s disease (CD), ulcerative colitis (UC), auto-immune hepatitis, rheumatic (e.g. rheumatoid arthritis), neurological (e.g. multiple sclerosis) and dermatological IMIDs (e.g. atopic dermatitis). Patients were recruited based on immunosuppressants (table 1) and previous SARS-CoV-2 infection. The control group consisted of healthy subjects and IMID patients without immunosuppressants. SARS-CoV-2 receptor binding domain (RBD) antibodies were measured 28 days after completed SARS-CoV-2 vaccination. Seroconversion was defined as anti-RBD IgG >4 AU/mL. In this abstract, we focus on therapies relevant for inflammatory bowel diseases (IBD) and present results for these treatments from patients with IBD, but also other IMIDs. Results Numbers of recruited patients with each immunosuppressant are shown in table 1. Amongst these patients, 312 patients had CD and 176 UC, the rest was diagnosed with another IMID. Seroconversion was reduced in patients receiving sphingosine 1-phosphate (S1P) modulators (all multiple sclerosis patients) while seroconversion was similar to controls in the other treatment groups. However, use of Anti-tumour necrosis factor (TNF), methotrexate, janus kinase (JAK) inhibitor monotherapy and all combination therapies (except for corticosteroids combined with other immunosuppressants) were associated with reduced Sars-CoV-2 antibody titres. Patients with a previous SARS-CoV-2 infection had higher median antibody titres after second vaccination than those without a previous SARS-CoV-2 infection. The type of IMID did not affect seroconversion rates. Conclusion No immunosuppressant, registered for IBD, reduced the rates of seroconversion after vaccination against SARS-CoV-2. Some immunosuppressants were associated with lower antibody titres. However, the clinical relevance of lower antibody titres remains unknown. S1P modulators, had a clear negative impact on the humoral response against SARS-CoV-2 after vaccination. This might be relevant in the future as this therapy is currently being approved for UC. Disease aetiology did not impair immunity against SARS-CoV-2 immunity after vaccination. Disclaimer: Absolute numbers of antibody titres and rates of seroconversion will be reported at the conference and are not reported in this abstract as this might negatively impact the current submission process.
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Dennert, Robert, Pieter van Paassen, Petra Wolffs, Catrien Bruggeman, Sebastiaan Velthuis, Susanne Felix, Robert-Jan van Suylen, Harry J. Crijns, Jan Willem Cohen Tervaert, and Stephane Heymans. "Differences in Virus Prevalence and Load in the Hearts of Patients with Idiopathic Dilated Cardiomyopathy with and without Immune-Mediated Inflammatory Diseases." Clinical and Vaccine Immunology 19, no. 8 (June 13, 2012): 1182–87. http://dx.doi.org/10.1128/cvi.00281-12.
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ABSTRACTInfections with cardiotrophic viruses and immune-mediated responses against the heart have been suggested to play a dominant role in the pathogenesis of idiopathic dilated cardiomyopathy (DCM). Furthermore, immune-mediated inflammatory diseases (IMIDs) may result in DCM. It has not previously been assessed whether DCM patients with and without an IMID have different prevalences and quantities of cardiotrophic viruses in the heart. Therefore, we compared the profiles of cardiotrophic viruses in heart tissue of DCM patients with and without an IMID. Serum and myocardial tissue samples were obtained from 159 consecutive patients with DCM and 20 controls. Patients were subdivided into three groups, the first two based on the presence (n= 34) or absence (n= 125) of an IMID and the third being a control group. The parvovirus B19 virus genome was detected in equal quantities in the non-IMID DCM patients (100/125) and the control group (15/20) but in lower quantities in the IMID patients (21/34,P= 0.02). Both the non-IMID and IMID DCM patients demonstrated increased myocardial inflammation compared to controls: 12.5 ± 1.8 and 14.0 ± 3.2 CD45-positive inflammatory cells, respectively, versus 5.1 ± 0.7 for the controls (P< 0.05 for both). Importantly, significantly higher parvovirus B19 copy numbers could be amplified in non-IMID than in IMID patients (561 ± 97 versus 191 ± 92 copies/μg DNA,P< 0.001) and control subjects (103 ± 47 copies/μg DNA,P< 0.001). The present study shows decreased parvovirus B19 prevalence and copy numbers in hearts of DCM patients with an IMID compared to those without an IMID. These findings may suggest that DCM patients with an IMID have a different pathophysiologic mechanism from that which is present in the virus-induced form of DCM.
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Li, Ang, Qian Wu, Suhong Luo, Greg S. Warnick, Neil A. Zakai, Edward N. Libby, Brian F. Gage, David A. Garcia, Gary H. Lyman, and Kristen M. Sanfilippo. "Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug–Associated Thrombosis Among Patients With Multiple Myeloma." Journal of the National Comprehensive Cancer Network 17, no. 7 (July 2019): 840–47. http://dx.doi.org/10.6004/jnccn.2018.7273.
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AbstractBackground: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE. Methods: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development. Results: The final RAM, named the “SAVED” score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets. Conclusions: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.
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Firoozmand, Amin, Naveed Ali, Nausheen Ahmed, Pingfu Fu, Shufen Cao, George Brown, Hannah Schmikla, et al. "Low Dose Daily Corticosteroid Tapering Regimen Allows Highly Effective and Practical Desensitization for Multiple Myeloma Patients with Skin Rash after Immunomodulatory Drugs." Blood 136, Supplement 1 (November 5, 2020): 19–20. http://dx.doi.org/10.1182/blood-2020-140800.
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Introduction: Immunomodulatory drugs (IMiDs) are being frequently used as an integral part of induction regimen as well as maintenance after Bone Marrow Stem cell Transplant (BMSCT) therapy as backbone of therapy for patients with plasma cell neoplasm (PCN) including Multiple Myeloma (MM). Therapy is often complicated by dermatologic adverse effects which may herald a favorable prognosis suggesting a more robust immune stimulation by this class of drugs. The incidence of IMiD-associated rash is up to 27% in some reports and can range from mild to moderate to severe and life threatening skin toxicity including Steven-Johnsons syndrome and toxic epidermal necrolysis. IMiD-associated skin eruptions are thought to result from differential T cell immune modulation. The optimal management strategy for IMiD induced rash is unknown. The European Myeloma Network recommends topical corticosteroids and antihistamines for localized skin reactions. For severe reactions, a desensitization protocol with prolonged 6-week steroid taper is recommended based on a case series of five patients that developed delayed cutaneous adverse effects to IMiD [Lee MJ et al]. Dexamethasone used concomitantly with IMiD as part of the treatment regimen does not decrease the occurrence of skin rash as shown by Sviggum et al. The likely explanation is that concurrent dexamethasone is not effectively able to exert immunosuppressive activity to mitigate the occurrence of cutaneous reactions. Hence, a prolonged, daily steroid protocol is required for effective desensitization. Therefore, we designed a standardized 3-week steroid rash prophylaxis protocol with a low dose daily corticosteroid tapering regimen that allows desensitization and reinstitution of the same IMiD. We assessed the impact of this desensitization regimen on clinical outcomes, by comparing patients with versus without dermatologic manifestations. Methods: Dermatologic adverse effects associated with IMiDs in our study were managed by a single oncologist using a standardized approach. A total of 87 patients were evaluated, 24 patients in the rash group vs 63 controls. A cohort of age- and gender-matched without rash (n = 63) was randomly selected from the institutional database. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling for the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range 2-232 days). The incidence of rash was 27.6% (95% CI: 19.3%-37.8%). All patients were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to controls without rash, there was no significant difference in PFS (p=0.769) or OS (p=0.24) in the multivariable regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in re-instituting IMiDs without recurrence of skin rashes in our cohort. The results of our study indicate that the 30-day prednisone course is practical, well tolerated, effectively desensitizes and allows re-institution of IMiD enabling patients to enjoy comparable outcomes to those without skin rash. Whether development of rash correlates with improved outcomes is unknown. Here, outcomes were similar in both cohorts. Disclosures Caimi: Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Malek:Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Medpacto: Research Funding; Cumberland: Research Funding; Amgen: Honoraria; Clegene: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Janssen: Other: Advisory board, Speakers Bureau.
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Galloway, James, Kevin Barrett, Peter Irving, Kaivan Khavandi, Monica Nijher, Ruth Nicholson, Simon de Lusignan, and Maya H. Buch. "Risk of venous thromboembolism in immune-mediated inflammatory diseases: a UK matched cohort study." RMD Open 6, no. 3 (September 2020): e001392. http://dx.doi.org/10.1136/rmdopen-2020-001392.
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ObjectivesTo describe the risk of venous thromboembolism (VTE), and risk factors for VTE, in people with immune-mediated inflammatory diseases (IMID) (ulcerative colitis, Crohn’s disease (CD), rheumatoid arthritis (RA) and psoriatic arthritis (PsA)), compared with a matched control population.MethodsA total of 53 378 people with an IMID were identified over 1999–2019 in the UK Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database and were matched to 213 512 people without an IMID. The association between the presence of any IMID, and each IMID separately, and risk of VTE was estimated using unadjusted and multivariable-adjusted Cox proportional hazards models. The prevalence of VTE risk factors, and associations between VTE risk factors and risk of VTE, were estimated in people with and without an IMID.ResultsPeople with an IMID were at increased risk of VTE (adjusted HR [aHR] 1.46, 95% CI 1.36,1.56), compared with matched controls. When assessing individual diseases, risk was increased for CD (aHR 1.74, 95% CI 1.45 to 2.08), ulcerative colitis (aHR 1.27, 95% CI 1.10 to 1.45) and RA (aHR 1.54, 95% CI 1.40 to 1.70) but there was no evidence of an association for PsA (aHR 1.21, 95% CI 0.96 to 1.52). In people with an IMID, independent risk factors for VTE included male sex, overweight/obese body mass index, current smoking, history of fracture, and, across study follow-up, abnormal platelet count.ConclusionsVTE risk is increased in people with IMIDs. Routinely available clinical information may be helpful to identify individuals with an IMID at increased future risk of VTE.Observational study registration numberClinicaltrials.gov (NCT03835780).