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1
Lopez-Girona, Antonia, Derek Mendy, Karen Miller, et al. "Direct Binding with Cereblon Mediates the Antiproliferative and Immunomodulatory Action of Lenalidomide and Pomalidomide." Blood 118, no. 21 (2011): 738. http://dx.doi.org/10.1182/blood.v118.21.738.738.
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Abstract Abstract 738 Thalidomide, lenalidomide and pomalidomide are therapeutically active in a number of hematological malignant and premalignant conditions including myelodysplastic syndromes, multiple myeloma, and lymphomas. Clinical efficacy is ascribed to a complement of overlapping activities including direct antitumor effects, immune system activation and inhibition of stromal support of tumor growth. Thalidomide has previously been shown to bind cereblon (CRBN) a protein required for the teratogenic effects of thalidomide in zebrafish and chicken embryos (Ito et al). CRBN forms an ubiquitin E3 ligase complex with DNA damage-binding protein 1 (DDB1), cullin 4 (CUL4) and protein Rbx1 and thalidomide treatment has been shown to inhibit the ubiquitin ligase activity of the complex (Ito et al). Using two independent biophysical methods, we demonstrate that lenalidomide and pomalidomide bind to CRBN-DDB1 complex. Fluorescence-based thermal shift analysis was carried out using purified ZZ-CRBN-DDB1. Phthalimide showed no appreciable binding to the CRBN-DDB1 complex while dose-dependent interaction of thalidomide, lenalidomide and pomalidomide was observed. Thalidomide binding showed approximately ten-fold less affinity (∼ 30 μM) than lenalidomide and pomalidomide (each ∼ 3 μM IC50). Following the procedure of Ito et al, we used thalidomide analog-coupled beads (Thal-beads) and demonstrated binding of CRBN in complex with DDB1 from U266B1 myeloma cell extracts. Preincubation of the extracts with lenalidomide (100 μM) prevented CRBN binding to Thal-beads. Furthermore, the binding of CRBN was dose-dependently inhibited by preincubation with either lenalidomide or pomalidomide with IC50s of 2.3 and 2.1 μM, respectively. We then investigated whether CRBN was required for lenalidomide and pomalidomide responses associated with efficacy. First, CRBN expression was reduced in activated human T cells using CRBN siRNAs. After T cell activation, incubation with lenalidomide (1 μM) or pomalidomide (1 μM) resulted in an 11 to 14- fold-increase in IL-2 and a 5 to 10-fold increase in TNF-α. This increase was reduced ∼60% in the presence of siCRBN. Since IL-2 and TNF-α are important cytokines for tumor surveillance by activated T cells, our results indicate that some of the immunomodulatory effects of lenalidomide and pomalidomide are mediated via CRBN. We next determined if CRBN was required for the antiproliferative effect of lenalidomide and pomalidomide in myeloma cells. Multiple siRNAs were used to silence the expression of CRBN in U266B1 cells resulting in the absence of CRBN protein as determined by immunoblot analysis. Propidium-iodide staining showed that depletion of CRBN affected neither cell cycle nor proliferation of U266B1 cells. However, knockdown of CRBN markedly abrogated lenalidomide- and pomalidomide-induced delay of cell cycle progression. In addition, using lentiviral vectors we produced U266B1 cell lines with either 60% or 75% less expression of CRBN and showed that relative to the parental cell line these cells were gene dose-dependently less responsive to inhibition of proliferation by lenalidomide. The U266B1 cells in which CRBN had been decreased were also less responsive to inhibition by pomalidomide, but this compound maintained greater inhibition of proliferation than lenalidomide in the context of decreasing CRBN. Moreover, gene profile changes by lenalidomide and pomalidomide were reversed in the presence of siCRBN. In particular, induction of p21WAF1 cyclin –dependent kinase inhibitor protein was prevented in the absence of the expression of CRBN. Similar results on different myeloma cell lines and using multiple CRBN siRNAs, confirmed the same critical role of CRBN in the antiproliferative response to lenalidomide and pomalidomide of myeloma cells. Finally, we demonstrated that CRBN expression decreases concomitantly with the acquisition of lenalidomide resistance in H929 myeloma cells. Lenalidomide-resistant H929 cells remain responsive to inhibition by pomalidomide despite relatively reduced expression of CRBN. However, in pomalidomide-resistant DF15R myeloma cells, the complete absence of CRBN confers resistance to both lenalidomide and pomalidomide. Our data demonstrate that CRBN is a direct target of lenalidomide and pomalidomide and plays a crucial role in the antitumor efficacy of lenalidomide and pomalidomide. Disclosures: Lopez-Girona: Celgene Corp: Employment, Equity Ownership. Mendy:Celgene Corp: Employment, Equity Ownership. Miller:Celgene Corp: Employment, Equity Ownership. Gandhi:Celgene Corp: Employment, Equity Ownership. Kang:Celgene Corp: Employment, Equity Ownership. Carmel:Celgene Corp: Employment, Equity Ownership. Abbasian:Celgene Corp: Employment, Equity Ownership. Mahmoudi:Celgene Corporation: Employment, Equity Ownership. Jackson:Celgene Corporation: Employment, Equity Ownership. Cathers:Celgene Corporation: Employment, Equity Ownership. Rychak:Celgene Corporation: Employment, Equity Ownership. Richard:Celgene Corporation: Employment, Equity Ownership. Brady:Celgene Corporation: Employment, Equity Ownership. Schafer:Celgene Corporation: Employment, Equity Ownership. Evans:Celgene Corporation: Consultancy. Daniel:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.
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Lacy, Martha Q., and Arleigh R. McCurdy. "Pomalidomide." Blood 122, no. 14 (2013): 2305–9. http://dx.doi.org/10.1182/blood-2013-05-484782.
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Abstract This spotlight review focuses on the second-generation immunomodulatory drug pomalidomide, which was recently approved by the US Food and Drug Administration. This drug was approved for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 days of completion of the last therapy. This review focuses on the clinical trial data that led to approval and provides advice for treating physicians who are now prescribing this drug for patients.
3
Sinha, Shirshendu, Shaji Kumar, Suzanne Hayman, et al. "Response to Salvage Therapies and Outcome of Patients with Multiple Myeloma Relapsing After Pomalidomide Therapy." Blood 116, no. 21 (2010): 1965. http://dx.doi.org/10.1182/blood.v116.21.1965.1965.
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Abstract Abstract 1965 Background: Pomalidomide is an immunomodulatory compound to be used for heavily pre-treated patients with relapse and refractory multiple myeloma and has shown considerable efficacy in recent clinical trials. It is not clear how patients may respond to other therapies, once the disease becomes refractory to pomalidomide. We examined this question among a cohort of patients receiving pomalidomide therapy in phase 2 clinical trials. Methods: Patients enrolled in an ongoing phase 2 clinical trial of pomalidomide (2-4 mg daily) along with dexamethasone (40 mg weekly), in relapsed myeloma, form the study population. Several cohorts of patients (>= 3 prior therapies not specified, lenalidomide refractory, and lenalidomide and bortezomib refractory patients were enrolled sequentially in this trial (Lacy, M.Q., et al., J Clin Oncol, 2009. 27(30): p.5008–14). Only those patients who have gone off study for disease progression were included in the current analysis. Details of subsequent therapies and survival data were obtained from the medical records. Results: Forty-seven patients from among 142 patients enrolled on the clinical trial between November, 2007 and April, 2010 were included in the study. The median (range) duration of pomalidomide therapy was 4 (0.6-16) months. 15 (32%) patients were lenalidomide refractory and 11 (23%) were refractory to both lenalidomide and bortezomib at the time of study entry. The best confirmed response to pomalidomide was MR (Minimal Response) or better in 23 patients (52%). Various regimens were employed following relapse on pomalidomide. The response to the first regimen following relapse in the 34 patients where salvage therapy was initiated is as shown in Table 1. Overall, 81 regimens were employed across 34 patients; median (range) number of regimens per patients was 1 (0-8). The response rates to the different regimens were as shown in the Table 1. The median overall survival (OS) from the time of progression on pomalidomide was 14.7 months (95% CI; 4, NR). The OS was similar between those patients who had a response to pomalidomide (MR or better) and those who did not. However the OS was shorter for patients who were refractory to lenalidomide and bortezomib (2.1 months) compared to those who were lenalidomide refractory only (6.5 months), and the non-refractory group (NR), P=0.06. Conclusions: This study confirms poor outcome of the patients relapsing after all available therapies. It also gives interesting insights into the activity of different regimens among patients who have relapsed after pomalidomide. The findings once again highlight the incurable nature of the disease and warrant further investigation to develop newer effective treatment regimens for this group of patients who presently do not have effective therapeutic options especially in the relapsed setting. Regimens: ASCT: Autologous Stem Cell Transplantation, Bz: Bortezomib, Mel=Melphalan, Dex: Dexamethasone, CRD: Cyclophosphamide, Revlimid (Lenalidomide), Dexamethasone, CTX; Cyclophosphamide, Len; Lenalidomide, Sor: Sorafenib, VDT-PACE: Velcade (Bortezomib), Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide. Response: SD; Stable Disease; Prog; Progression MR: Minimal Response; PR: Partial Response. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Mikhael:Celgene: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.
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Kastritis, Efstathios, Maria Roussou, Maria Gavriatopoulou, et al. "Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone." Blood Advances 3, no. 23 (2019): 4095–103. http://dx.doi.org/10.1182/bloodadvances.2019000539.
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Key Points There was no significant difference in response rates, PFS, or OS among patients that developed resistance to different lenalidomide doses. Longer duration of prior lenalidomide and a longer lenalidomide-free interval are associated with better outcomes with pomalidomide.
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Bartlett, J. B., L. Wu, M. Adams, P. Schafer, G. Muller, and D. Stirling. "Lenalidomide and pomalidomide strongly enhance tumor cell killing in vitro during antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab, cetuximab and rituximab." Journal of Clinical Oncology 25, no. 18_suppl (2007): 3023. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3023.
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3023 Background: Potential mechanisms of action of lenalidomide and pomalidomide (CC-4047) include anti-angiogenic, anti- proliferative and immunomodulatory activities, e.g., enhancement of T cell and NK cell function. Both drugs appear to enhance T cell activation and Th1-type cytokines in cancer patients. Also, both drugs have been shown to enhance rituximab-mediated protection in a mouse lymphoma model. Methods: We have utilized an in vitro ADCC system to assess the ability of these drugs to enhance human NK cell function in response to the approved therapeutic antibodies trastuzumab, cetuximab and rituximab. Results: Pre-treatment of NK cells with either pomalidomide or lenalidomide greatly enhanced IFN-γ production by NK cells in response to IgG in the presence of either IL-2 or IL- 12. In a series of functional ADCC assays, Her2/neu overexpressing breast cancer cells (SKBR3 & MCF-7) pre-coated with trastuzumab, EGFR positive colorectal cancer cells (HCT-116) pre-coated with cetuximab and NHL cell lines (Namalwa, Farage & Raji) pre-coated with rituximab, were exposed to NK cells pre-treated with pomalidomide, lenalidomide or thalidomide. Both pomalidomide and lenalidomide synergistically increased (up to 6-fold) NK cell-mediated killing of antibody coated tumor cells in a dose-dependent manner. Thalidomide had no effect in this system. There was minimal tumor cell killing by antibody alone or in the absence of antibody. The presence of IL-2 or IL-12 was required to see enhanced killing by either drug. Enhanced ADCC was associated with increased signaling in NK cells, specifically with inhibition of the negative regulator SHIP-1. Other downstream effects on signaling pathways are also being investigated. Monocyte-mediated tumor cell ADCC was also enhanced by both drugs. Conclusions: We have shown that pomalidomide and lenalidomide (but not thalidomide) strongly enhance the ability of therapeutic antibodies to induce ADCC via NK cell/monocyte-mediated killing of tumor cells in vitro. These results provide a strong rationale for combination of either lenalidomide or pomalidomide with antibodies to tumor-specific surface antigens in cancer patients. No significant financial relationships to disclose.
6
Rekhtina, I. G., and L. P. Mendeleeva. "Efficiency of pomalidomide therapy in patients with multiple myeloma refractory to lenalidomide." Oncohematology 14, no. 1 (2019): 8–13. http://dx.doi.org/10.17650/1818-8346-2019-14-1-8-13.
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Currently, there has been a marked increase in the number of opportunities for relapsed and refractory multiple myeloma treatment due toemergence of new target drugs. These include pomalidomide, a 3rd generation immunomodulator capable of treating double refractory multiple myeloma (to lenalidomide and bortezomib). Efficacy and safety of pomalidomide combined with low doses of dexamethasone have beenestablished in MM-003 and STRATUS trials. The summary presents the data on opportunities to further enhance the efficacy of pomalidomide combined with other antitumor drugs in patients with relapsed and refractory multiple myeloma who previously received 4–5 lines of therapy. It has been shown that triplets based on pomalidomide and dexamethasone combined with cyclophosphamide, bendamustine, daratumumab, carfilzomib, elotuzumab are highly effective in double refractory multiple myeloma patients. A combination of pomalidomide with proteasome inhibitors is a promising treatment provided that there is no refractoriness to bortezomib.
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Siegel, David S., Gary J. Schiller, Christy Samaras, et al. "Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment." Leukemia 34, no. 12 (2020): 3286–97. http://dx.doi.org/10.1038/s41375-020-0813-1.
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AbstractPatients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
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Phan, Vien, Tomoki Ito, Muneo Inaba, et al. "Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses." Blood Advances 4, no. 15 (2020): 3572–85. http://dx.doi.org/10.1182/bloodadvances.2019001410.
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Abstract Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.
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Leleu, Xavier, Michel Attal, Bertrand Arnulf, et al. "Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide–refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02." Blood 121, no. 11 (2013): 1968–75. http://dx.doi.org/10.1182/blood-2012-09-452375.
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Key Points Combination of pomalidomide with dexamethasone is highly active and can salvage end stage myeloma refractory to lenalidomide and bortezomib. Current data suggest pomalidomide 4 mg/day on days 1 to 21 per 28-days cycle with dexmethasone should be studied in future phase 3 trials.
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Bolzoni, Marina, Manuela Abeltino, Paola Storti, et al. "The Immunomodulatory Drugs Lenalidomide and Pomalidomide Inhibit Multiple Myeloma-Induced Osteoclast Formation and RANKL/OPG Ratio In Myeloma Microenvironment Targeting the Expression of Adhesion Molecules." Blood 116, no. 21 (2010): 448. http://dx.doi.org/10.1182/blood.v116.21.448.448.
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Abstract Abstract 448 The increase of osteoclast formation and activation occurring into the bone marrow (BM) area of myeloma cells infiltration is the hallmark of multiple myeloma (MM). The increase of the RANKL/OPG ratio in BM stromal cells (BMSCs) and osteoprogenitor cells, induced by MM cells through the cell-to-cell contact, is critically involved in MM-induced osteoclast formation. In addition, MM cells also up-regulate RANKL expression and secretion by activated T in the MM BM microenvironment. Soluble factors such as CCL3/MIP-1α, IL-3 and IL-7 produced by MM cells contribute to the increase of osteoclast formation either directly or indirectly through RANKL stimulation. Recent data have suggested that thalidomide and the immunomodulatory drugs (IMiDs®) lenalidomide directly inhibit osteoclast formation and maturation. In the present study we have investigated the potential effects of lenalidomide and the more potent IMiD® pomalidomide on MM-induced osteoclast formation. First in a cell-to-cell contact co-culture system we found that both IMiDs® at concentration ranging from 2 to 100 μM significantly blunted RANKL secretion by human BMSC/osteoprogenitor cells induced by MM cells decreasing the RANKL/OPG ratio level with a more potent effect of pomalidomide as compared to lenalidomide. Consistently the pro-osteoclastogenic property of the conditioned medium of MM cells co-cultured with BMSC/osteoprogenitor cells was reduced in the presence of IMiDs®. On the other hand, we did not find any significant inhibitory effect of both drugs neither on the production of soluble pro-osteoclastogenic factors by MM cells as CCL3/MIP-1α, IL-3 and IL-7 nor on RANKL expression and secretion by T lymphocytes. To go further inside to the capacity of IMiDs® to blunt MM-induced RANKL/OPG ratio, we performed a microarray analysis (using Affymetrix, GeneChip®, HG-U133Plus2.0 platform) to investigate the effect of lenelidomide and pomalidomide on the transcriptional profile of both MM cells and BMSCs. We found that 40 and 83 genes were significantly modulated by lenalidomide and pomalidomide, respectively, in MM cells Interestingly, among the genes significantly modulated by IMiDs® we identified the downregulation of the adhesion molecules ITGA4 (CD49d), ITGA8 and ICAM2 (CD102). In human BMSCs, 71 genes and 214 genes were significantly modulated by lenalidomide and pomalidomide, respectively, including those belonging to focal adhesion, cell cycle, BMP2, TGF-beta and IL-6 signaling pathways. Finally, using flow cytometry we confirmed the capacity of lenalidomide and pomalidomide to inhibit the expression of adhesion molecules as CD49d by MM cells co-cultured either in presence or absence of BMSCs showing that this effect is critically involved in the inhibition of RANKL/OPG ratio by IMiDs®. In conclusion our data strongly suggest that lenalidomide and pomalidomide inhibits MM-induced osteoclast formation through the inhibition of RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells. Disclosures: Giuliani: Celgene: Research Funding.
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Gemechu, Yohannes, David Millrine, Shigeru Hashimoto, et al. "Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs." Proceedings of the National Academy of Sciences 115, no. 46 (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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Mark, Tomer M., Peter A. Forsberg, Adriana C. Rossi, et al. "Phase 2 study of clarithromycin, pomalidomide, and dexamethasone in relapsed or refractory multiple myeloma." Blood Advances 3, no. 4 (2019): 603–11. http://dx.doi.org/10.1182/bloodadvances.2018028027.
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Abstract The addition of clarithromycin enhances the efficacy of lenalidomide plus dexamethasone in treatment-naive multiple myeloma (MM). We conducted a phase 2 trial to evaluate the safety and efficacy of clarithromycin, pomalidomide, and dexamethasone (ClaPd) in relapsed or refractory multiple myeloma (RRMM) with prior lenalidomide exposure. One hundred twenty patients with a median of 5 prior lines of therapy received clarithromycin 500 mg orally twice daily, pomalidomide 4 mg orally on days 1 to 21, and dexamethasone 40 mg orally on days 1, 8, 15, and 22 of a 28-day cycle. The overall response rate (ORR) was 60% with 23% achieving at least a very good partial response. There was no statistical difference in response rates for patients who were refractory to lenalidomide (ORR, 58%), bortezomib (ORR, 55%), or both lenalidomide and bortezomib (ORR, 54%). Median progression-free survival (PFS) for the cohort was 7.7 months and median overall survival (OS) was 19.2 months. A history of dual-refractoriness to lenalidomide and bortezomib did not significantly impact either PFS or OS. The most common toxicities were neutropenia (83%), lymphopenia (74%), and thrombocytopenia (71%). The most common grade ≥3 toxicities included neutropenia (58%), thrombocytopenia (31%), and anemia (28%). ClaPd is an effective combination in RRMM with response and survival outcomes that are independent of lenalidomide- or bortezomib-refractory status. Toxicities are manageable with low rates of nonhematologic or high-grade events. ClaPd is a convenient, all-oral option in RRMM with comparable efficacy to other highly active, 3-drug, pomalidomide-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT01159574.
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Zhu, Yuan Xiao, Esteban Braggio, Chang-Xin Shi, et al. "Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide." Blood 118, no. 18 (2011): 4771–79. http://dx.doi.org/10.1182/blood-2011-05-356063.
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Abstract The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.
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Larocca, Alessandra, Vittorio Montefusco, Sara Bringhen, et al. "Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study." Blood 122, no. 16 (2013): 2799–806. http://dx.doi.org/10.1182/blood-2013-03-488676.
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Mark, Tomer M., Melissa Rodriguez, Manan Shah, et al. "ClaPD (Clarithromycin/[Biaxin®], Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma." Blood 118, no. 21 (2011): 635. http://dx.doi.org/10.1182/blood.v118.21.635.635.
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Abstract Abstract 635 Background: The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We hypothesized that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy. We now report the initial results from a phase 2 trial of ClaPD (Clarithromycin/[Biaxin®], Pomalidomide, Dexamethasone) therapy in RRMM. Methods: Fifty-two patients with heavily pre-treated RRMM were enrolled into a single-institution study and received ClaPD. Eligible subjects had at least 3 prior lines therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg on days 1,8,15,22; and pomalidomide 4mg for days 1–21 of a 28-day cycle. All subjects had thromboprophylaxis with aspirin. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results: Forty-six patients had completed at least 1 cycle of ClaPD and were eligible for analysis. The median number of cycles received was 6 (range 2–10). ClaPD responses were progressive disease (PD): 20%, stable disease (SD): 15%, minimal response (MR): 7%, partial response (PR): 33%, very good partial response (VGPR): 20%, stringent complete remission (sCR): 7%, giving an overall response rate (ORR) of 60% and a ≥VGPR rate of 27%. In responding patients, time to PR was rapid at a median of 1.5 cycles (range 1–7). After a median follow up time of 6.7 months, 28 patients (61%) remain on study free from disease progression and 39 patients (85%) are alive. Two patients withdrew from treatment due to regimen toxicity (one due to Grade 3 fatigue, another due to Grade 4 muscular weakness). Conclusions: ClaPD is a highly effective regimen for heavily treated RRMM, particularly in patients with disease progression after prior lenalidomide therapy. When compared to other published Phase 2 data, the addition of clarithromycin in ClaPD appears to enhance the efficacy of Pomalidomide-Dexamethasone in lenalidomide-relapsed patients, (ORR 60% versus 40% - Lacy et. al JCO 2009) without induction of excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained at > 6 months in the majority of subjects. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures: Mark: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: There is no FDA indication for pomalidomide at this time. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding.
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Pegourie, Brigitte, Marie Odile Petillon, Lionel Karlin, et al. "Long-Term Exposure to Pomalidomide-Dexamethasone in Pts with Refractory Myeloma." Blood 124, no. 21 (2014): 3466. http://dx.doi.org/10.1182/blood.v124.21.3466.3466.
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Abstract Background. The IFM2009-02 study was launched in 2009, and randomized 84 patients (pts) with pomalidomide (oral 4 mg daily) and dexamethasone (oral 40 mg weekly) given either 21 days out of 28 or continuous. Whilst the overall median PFS was 4.6 months - this end stage very advanced RRMM population, we observed that 40% of the patients had a prolonged PFS and subsequently OS in the trial. We sought to analyze the characteristics of 58 pts that had more than 3 months of pomalidomide to study the effect of long exposure to Pomalidomide. Method. IFM 2009-02 was a multicentre phase 2 study of pts with RRMM who had at best a stable disease with the last course of bortezomib and of lenalidomide, or who were refractory to bortezomib and lenalidomide (IMWG). This analysis was performed on the ITT population combining data from the 2 study arms. We have analyzed the characteristics of pts according to duration of treatment with pomalidomide and dexamethasone 3 months to one year (<1 year) or more than one year (≥1 year). Results. 60% and 40% of pts were exposed to pomalidomide for <1 year and ≥1 year, respectively. The ORR for the <1 year group was 43%, the median PFS 4.6 months (CI95% 4;6) with only 6% at 12 months, and the median OS 15 months (4;6) and 65% at 12 months, 40% at 18 months. For the ≥1 year group, the response rate and survival were strikingly different, ORR at 83%, PFS 20.7 months, OS not reached (CI95% 40;-) and 100% at 12 months, 91% at 18 months. Of the pts in the <1 year, 87% have died versus 35% in the ≥1 year group. Of note, death of most pts occurred during the follow up period post pomalidomide therapy , however in a far greater extent for the <1 year group, 96% versus 67%, that could suggest it was more difficult to salvage these pts post pomalidomide. We next sought to identify the characteristics of the 2 groups. Interestingly, the median number of prior lines was similar across groups, 5 (range 1-10), with 89% and 79% of the pts exposed to more than 3 lines and 17% and 22% exposed to more than 6 lines, for the <1 year and ≥1 year groups, respectively. 40% and 48% of pts had Bortezomib as last line, 29% and 43% Lenalidomide, 43% and 26% and alkylating agent. Similarly, 80% and 74% of pts were refractory to Bortezomib, 89% versus 87% to Lenalidomide, 65% versus 75% to alkylating agents, 74% and 87% to the last line of therapy, respectively. 74% and 70% were double refractory (Bortezomib and Lenalidomide) and 60% and 70% were triple refractory (double +last line), respectively. The time from diagnosis to IFM 2009-02 study entry was also similar between cohorts, 5.8 and 6.5 years for <1 year and ≥1 year groups; however with 6% versus 26% of pts, entering the study in less than 3 years since diagnosis. There was no difference in terms of patients characteristics between groups, either patients-based such as gender, age, weight, or myeloma-based characteristics. However, serum beta 2m level was higher at diagnosis in the <1 year compared to the ≥1 year, 54% versus 35%, with a slightly more adverse cytogenetic profile 35% versus 12%, with the limitation that this was not available for all the patients. Presence of plasmacytoma/EMD was also greater in the former group, 20% versus 4%, respectively. It seems that the <1 year had more intrinsic adverse features of the tumor cells compared to the ≥1 year group. There was no clear difference in terms of safety management of pomalidomide and/or dexamethasone, with respect to the daily dose intensity of Pomalidomide (median, 3.0 and 2.9 mg/day), and the relative dose intensity of pomalidomide that was 89% and 84%, respectively; similar to the rate of dose reduction and dose interruption. Conclusion. Pomalidomide and dexamethasone is effective and well tolerated in these heavily pre-treated MM pts refractory to Bortezomib and Lenalidomide, with approximately 40% of the patients having a prolonged exposure to treatment, which translated into a significantly prolonged OS. Our study suggests that patients with more intrinsic adverse features of Myeloma tumor cells could not have prolonged exposure to pomalidomide as they progressed within a year from start of pomalidomide. Future studies should examine optimizing pomalidomide therapy in those patients, such as using multidrug pomalidomide-based combined regimens to prolong exposure to pomalidomide and improve the survival of these patients. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Celgene Jansen: Honoraria.
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Cho, Hearn J., Craig Cole, Thomas G. Martin, et al. "A phase Ib study of atezolizumab (atezo) alone or in combination with lenalidomide or pomalidomide and/or daratumumab in patients (pts) with multiple myeloma (MM)." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS8053. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps8053.
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TPS8053 Background: The advent of proteasome inhibitors and immunomodulatory drugs (IMiDs) have significantly improved outcomes in MM, and the first monoclonal antibodies for MM have been recently approved (daratumumab, elotuzumab). Despite novel therapies and improved disease management, MM is still considered incurable and most pts relapse, confirming the need for additional treatment options. MM cells express PD-L1, with higher levels observed after relapse and with advanced disease. Additionally, PD-L1–expressing immune cells in the microenvironment promote MM cell survival and potential immune escape. However, anti–PD-1 monotherapy did not result in objective responses in the MM cohort of a Ph I study, suggesting that MM pts need combination therapy. Daratumumab has activity as a single agent, as well as in combination with IMiDs plus dexamethasone and bortezomib plus dexamethasone in R/R MM. Immunomodulatory activity for daratumumab has also been reported. Thus, disruption of the PD-L1/PD-1 pathway may be additive or synergistic. The safety and efficacy of atezo (anti–PD-L1) alone or with lenalidomide or pomalidomide and/or daratumumab will be evaluated in a Ph Ib study of MM pts. NCT02431208. Methods: R/R MM pts with ≤ 3 prior therapies will be enrolled in Cohorts A (atezo), B (atezo + lenalidomide), D (atezo + daratumumab) and E (atezo + daratumumab + lenalidomide); MM pts with measurable disease after ASCT (Cohort C: atezo) or ≥ 3 prior therapies (Cohort F: atezo + daratumumab + pomalidomide) will also be enrolled. Cohorts B, D, E and F include a safety run-in (D) or dose escalation phase (B, E, F) and an expansion. Lenalidomide and pomalidomide will be dose escalated and the MTD evaluated in expansion phases. Atezo will be given at 1200 mg IV (A, B, C) or 840 mg IV (D, E, F); pts will get daratumumab at 16 mg/kg IV (D, E, F). All pts will be ECOG PS ≤ 2. Primary endpoints are ORR and the RP2D of lenalidomide and pomalidomide with atezo and daratumumab and the RP2D of lenalidomide with atezo. DOR and PFS are secondary endpoints; safety, PK and the relationship between biomarkers and other endpoints, including efficacy, will be assessed. Pts will be enrolled at 19 US sites. Clinical trial information: NCT02431208.
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Palumbo, Antonio, Alessandra Larocca, Angelo Michele Carella, et al. "A Phase I/II Study of Pomalidomide-Cyclophosphamide-Prednisone (PCP) in Patients with Multiple Myeloma Relapsed/Refractory to Lenalidomide." Blood 118, no. 21 (2011): 632. http://dx.doi.org/10.1182/blood.v118.21.632.632.
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Abstract Abstract 632 Background: Patients with multiple myeloma (MM) relapsed/refractory after immunomodulatory drugs and bortezomib have limited treatment options. Recently, the combination pomalidomide-dexamethasone has led to at least partial response (PR) of 25–42% in relapsed/refractory MM and 32% in patients refractory to lenalidomide. Aims: In this study we evaluate the safety and efficacy of the combination pomalidomide-cyclophosphamide-prednisone (PCP) in patients with MM who received 1–3 lines of treatment and were relapsed/refractory to lenalidomide therapy. Methods: Between August 2010 and July 2011, 41 patients were enrolled; median age was 69 years (range 49–82); 23 patients relapsed after lenalidomide and 18 patients were refractory to lenalidomide. The first 24 patients entered the phase I of the study to define the maximum tolerated dose (MTD) of PCP: 4 dose levels of pomalidomide (1, 1.5, 2 and 2.5 mg/day, days 1–28) were tested in combination with cyclophosphamide (50 mg every other day, days 1–28) and prednisone (50 mg every other day, days 1–28) for six 28-day cycles. Thromboprophylaxis with aspirin (100 mg/day) was recommended, low-molecular weight heparin was given to high risk patients. Dose Limiting Toxicities (DLTs) were defined as: grade 4 neutropenia for more than 3 days, grade 4 thrombocytopenia, grade 3–4 neutropenic fever, any grade 3–4 non-hematologic toxicity. The MTD was achieved when 25% of patients experienced a DLT, using the Bayesian Continual Reassessment Method. In the phase II of the study, the Simon two-stage design was used and 17 additional patients were enrolled and received the MTD of pomalidomide. Results: DLTs occurred in 1/4 patient who received pomalidomide 1.5 mg (grade 4 thrombocytopenia) and in 3/12 patients who received pomalidomide 2.5 mg (grade 3 neuropathy, grade 3 hepatic toxicity and grade 4 thrombocytopenia). The MTD was defined at 2.5 mg/day, with an estimated DLT probability of 0.258 (95% credibility interval: 0.101–0.468). 32 patients received at least one cycle of therapy and could be evaluated for efficacy and safety. At least PR was reported in 19/32 (59%) patients, including 2 complete response (CR), 5 very good partial response (VGPR), 12 PR. In patients refractory to lenalidomide, at least PR was reported in 11/15 (73%) patients, including 1 CR, 2 VGPR, 8 PR. Grade 4 hematologic toxicities were neutropenia (9%) and thrombocytopenia (9%). Grade 3–4 non-hematologic toxicity included infection (9%), rash (9%), neurologic (6%) and hepatic (3%) toxicities. Thromboembolism occurred in 1 patient. Conclusions: At least PR was achieved in 73% of patients refractory to lenalidomide; grade 4 neutropenia and/or thrombocytopenia were less than 10%. The combination pomalidomide (2.5 mg/day), cyclophosphamide (50 mg every other day), prednisone (50 mg every other day) showed high response rates with limited toxicities in patients relapsed/refractory to lenalidomide. Updated data will be presented at the meeting. Disclosures: Palumbo: Amgen: Honoraria; Merck: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Janssen-Cilag: Honoraria. Guglielmelli:Janssen-Cilag: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding; Novartis: Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Berenson, James R., James D. Hilger, Leonard M. Klein, et al. "A Phase 1/2 Study of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma." Blood 120, no. 21 (2012): 2979. http://dx.doi.org/10.1182/blood.v120.21.2979.2979.
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Abstract Abstract 2979 Background: Thalidomide and its immunomodulatory (IMiD) derivatives such as lenalidomide have shown great promise as a treatment option for multiple myeloma (MM) patients. Pomalidomide is a newer IMiD with high in vitro potency that has shown promise as an effective treatment option for relapsed/refractory (R/R) MM patients. Recent data has shown pomalidomide to be effective in combination with dexamethasone, even for patients who are refractory to bortezomib and lenalidomide. It has been demonstrated that the addition of pegylated liposomal doxorubicin (PLD) to lenalidomide and thalidomide is effective for both R/R and frontline MM patients. Our recent trial evaluating lenalidomide in combination with dexamethasone, PLD, and bortezomib (DVD-R) showed that both efficacy and tolerability may be improved by changing the dose and schedule of these drugs. These data imply that the combination of pomalidomide, dexamethasone, and PLD for R/R MM patients may be an effective regimen. We conducted a phase 1/2 trial investigating the safety and efficacy of pomalidomide in combination with IV dexamethasone and (PLD) using a modified dose and longer 28-day schedule for patients with R/R MM. The combination of PLD, dexamethasone and lenalidomide without bortezomib has not been previously evaluated. Methods: For enrollment into the phase 1 dose-escalation portion of the study, eligible pts had to have progressive MM at the time of enrollment that has relapsed following stabilization to at least one anti-myeloma regimen or is refractory defined as progressed while receiving anti-myeloma treatment. For enrollment into the planned phase 2 portion of the study, eligible pts have to be refractory to lenalidomide (singe-agent or in combination) demonstrated by progressive disease while receiving lenalidomide or relapse within 8 weeks of the last dose of lenalidomide. Patients who have received previous pomalidomide treatment were not eligible. Patients must not have received chemotherapy, corticosteroids, immunotherapy, antibody therapy, or treatment with thalidomide, lenalidomide, or bortezomib within 3 weeks of receiving study drug, nor extensive radiation therapy within 4 weeks of receiving study drug. During the phase 1 part of the trial, pomalidomide was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 patients each on days 1–21 of each 28-day cycle. Dexamethasone was administered intravenously at 40 mg over 30 min on days 1, 4, 8, and 11 of each cycle. PLD was administered at 5 mg/m2 as an IV infusion over 30–90 min on days 1, 4, 8, and 11 of each cycle. Pomalidomide doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent patients will be enrolled at that dose. Results: Ten of 40 planned patients have been enrolled to date, all during the phase 1 portion of the trial. Pts received a median of 4 prior treatments (range, 1–8) with a median of 1 prior PLD regimens (range, 0–1). Pts have completed a median of 1 cycle (range: 0–12) with a median of 1.2 months of follow up (range: 0.2–3.6). To date, the trial has enrolled all three cohorts in phase 1 (1 patient in cohort 1 chose to withdraw during Cycle 1 and was replaced). MTD has not yet been reached with no dose limiting toxicities (DLTs) in the first 2 cohorts. The 3 patients in cohort 3 are currently in Cycle 1. Seven patients are currently evaluable for efficacy and the 3 patients in cohort 3 have not yet had response assessment. Best response for evaluable patients is as follows: 3 patients have shown partial response, 2 patients have shown minor response, 1 is exhibiting stable disease (SD) but shows a decreasing monoclonal protein, and 1 has progressed. The incidence of reported adverse events (AEs) so far is low. Only 1 grade 3 or 4 (G3, G4) AE has been observed. The most common AEs were lymphopenia, which occurred in 6 pts (G1: 3; G2: 2; G3: 1), elevated urea nitrogen occurred in 4 pts (all G1), neutropenia occurred in 4 pts (all G1), and leukopenia occurred in 4 pts (all G1). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle may be an effective treatment option with acceptable tolerability for relapsed/refractory MM patients. Disclosures: Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Bondili, Suresh Kumar, Bhausaheb Bagal, Abhinav Zawar, et al. "Real-World Outcomes With Generic Pomalidomide in Relapsed Refractory Multiple Myeloma—Experience From a Tertiary Care Cancer Center." JCO Global Oncology, no. 7 (March 2021): 361–67. http://dx.doi.org/10.1200/go.20.00228.
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PURPOSE The prognosis of relapsed and refractory multiple myeloma (RRMM) that is refractory to bortezomib and lenalidomide is very poor wherein the median survival is between 3 and 9 months. We did this retrospective analysis to study the pattern of utilization, tolerance, and outcomes with pomalidomide in these patients having RRMM. MATERIALS AND METHODS Retrospective analysis of all the patients who were treated with generic pomalidomide at Tata Memorial Centre, Mumbai, during the period of May 2017 to March 2019 was done. Patients with secretory disease and who had completed at least one cycle of pomalidomide were analyzed for response rates, toxicity, and survival outcomes. RESULTS A total of 81 patients received pomalidomide-based therapy during this study period, out of which 75 were included in the survival analysis. Forty-eight patients (59.3%) were refractory to both lenalidomide and bortezomib. Overall response rate was 58.7%. Five patients (6.7%) achieved complete response, very good partial response was seen in 13 patients (17.3%), and partial response was seen in 26 patients (34.7%). After a median follow-up of 11 months (range 2-27 months), median progression-free survival was 9.1 months (95% CI, 5.4 to 12.9 months). Median progression-free survival for patients who were refractory to both lenalidomide and bortezomib versus nonrefractory was 5.5 and 12.6 months, respectively, which was significant statistically ( P = .04, hazard ratio, 0.35, 95% CI, 0.28 to 0.97). The median overall survival was not reached. Important toxicities included anemia (28%), neutropenia (16%), pneumonia (16%), and venous thrombosis (5%). CONCLUSION Generic pomalidomide-based therapy is an effective option and is well tolerated in patients with RRMM. Higher response rates and longer survival seen in our study are possibly because of heterogeneity of the study population.
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Tagoug, Ines, Adriana Plesa, Julie Vendrell, and Charles Dumontet. "Effect of Imids on Gene Expression Profiles of Fresh Human Myeloma Cells." Blood 116, no. 21 (2010): 5013. http://dx.doi.org/10.1182/blood.v116.21.5013.5013.
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Abstract Abstract 5013 Immunomodulatory drugs represent a major therapeutic advance in the treatment of patients with multiple myeloma. While these agents appear to exert various effects on the microenvironment, including effect on immune cells and angiogenesis, a direct effect on the tumor cells themselves is also likely. To describe and compare the effect of the three clinically available agents (thalidomide, lenalidomide, pomalidomide) we analyzed the gene expression profiles of fresh human myeloma cells exposed to thalidomide, lenalidomide or pomalidomide, using high density DNA arrays. Fresh human myeloma samples were obtained from bone marrow aspirates of patients with myeloma, and myeloma cells were immunopurified using anti CD138 magnetic beads. Purified myeloma cells (1.106 cells/ml) were incubated for 24 hours in RPMI 1640 medium supplemented with 10% fetal calf serum under each of the four following conditions: 1) DMSO; 2) thalidomide 40 microM; 3) lenalidomide 1 microM; 4) pomalidomide 100 nM. These levels are achievable in the plasma of MM pts. Pangenomic array experiments were performed usingWhole Human Genome 4 × 44K Agilent one-color microarrays. Data were normalized using the quantile normalization method. Samples were analysed for differentially expressed genes, taking into account both the level of significance and the fold-change. Ten evaluable samples were processed. Exposure to thalidomide, lenalidomide and pomalidomide induced differential expression of 36, 50 and 75 genes, respectively, in comparison to DMSO-exposed controls, the total list including 101 genes. Twelve of these were found to be differentially expressed after exposure to all of the three agents, including trophoblast glycoprotein, WAS protein family member 1, dickkopf homolog 1, pentraxin-related gene, CD28, interleukin 12B, tissue factor pathway inhibitor 2, phospholipase A2, dehydrogenase/reductase (SDR family) member 9, hypothetical LOC145788 and betacellulin. These commonly altered genes could be mechanistically involved in themultiple activities of these agents in multiple myeloma or may represent epiphenoma mechanistically unrelated to drug-induced cell death. Genes differentially expressed between the treatment with each of these agents could be indicative of the different and non-overlapping actions these agents have in multiple myeloma. An example of this is the recent demonstration that pomalidomide is clinically active in lenalidomide refractory patients. These results suggest that exposure to IMIDs induce various intracellular signalization pathways in myeloma cells which might be involved in the cytotoxic activity of these compounds. Disclosures: Dumontet: Celgene: Research Funding.
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Mo, Clifton C., and Paul G. Richardson. "Pomalidomide in lenalidomide‐refractory multiple myeloma: Far from futile." British Journal of Haematology 188, no. 4 (2019): 483–85. http://dx.doi.org/10.1111/bjh.16214.
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Milrod, Charles J., Frances Blevins, David Hughes, et al. "Incidence of skin hyperpigmentation in Black patients receiving treatment with immunomodulatory drugs." Blood 137, no. 21 (2021): 2987–89. http://dx.doi.org/10.1182/blood.2021010853.
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In a retrospective single-center review of patients with myeloma treated with the immunomodulatory drug thalidomide, lenalidomide, or pomalidomide, the authors report that marked hyperpigmentation occurred in 40% of Black patients, compared with 3.5% of White patients. Since only 2% of the participants in the original pivotal trial of lenalidomide were Black, this unexpectedly high rate was not previously recognized.
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Lacy, Martha Q., Jacob B. Allred, Morie A. Gertz, et al. "Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease." Blood 118, no. 11 (2011): 2970–75. http://dx.doi.org/10.1182/blood-2011-04-348896.
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Abstract Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with multiple myeloma (MM). We opened 2 sequential phase 2 trials using the pomalidomide with weekly dexamethasone (Pom/dex) regimen at differing doses to study the efficacy of this regimen in patients who have failed both lenalidomide and bortezomib. Pomalidomide was given orally 2 or 4 mg daily with dexamethasone 40 mg weekly. Thirty-five patients were enrolled in each cohort. Confirmed responses in the 2-mg cohort consisted of very good partial response (VGPR) in 5 (14%), partial response (PR) in 4 (11%), minor response (MR) in 8 (23%) for an overall response rate of 49%. In the 4-mg cohort, confirmed responses consisted of complete response (CR) in 1 (3%), VGPR in 3 (9%), PR in 6 (17%), MR in 5 (14%) for an overall response rate of 43%. Overall survival at 6 months is 78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression was the most common toxicity. This nonrandomized data suggests no advantage for 4 mg over the 2 mg daily. Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896.
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Das, Deepika Sharma, Durgadevi Ravillah, Arghya Ray, et al. "Synergistic Anti-Myeloma Activity of a Proteasome Inhibitor Marizomib and IMiD® Immunomodulatory Drug Pomalidomide." Blood 124, no. 21 (2014): 2099. http://dx.doi.org/10.1182/blood.v124.21.2099.2099.
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Abstract Background and Rationale: Proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that a novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities (Chauhan et al., Cancer Cell 2005, 8:407-419). We also showed that marizomib triggers synergistic anti-MM activity in combination with lenalidomide (Chauhan et al., Blood 2010, 115:834-45). Pomalidomide, like lenalidomide, is an analogue of thalidomide with potent immunomodulatory activity, and has been approved by FDA for treatment of RRMM patients who have received at least two prior therapies including lenalidomide and bortezomib and showed disease progression on or within 60 days of completion of the last therapy. Approval of treatment is based on progression-free survival. Here we utilized in vitro and in vivo models of MM to examine the anti-MM activity of combined marizomib and pomalidomide. Materials and Methods:MM celllines, patient tumor cells, and peripheral blood mononuclear cells (PBMCs) from normal healthy donors were utilized to assess the anti-MM activity of marizomib and pomalidomide. Cell viability, apoptosis, and migration assays were performed using WST/MTT, Annexin V staining, and Transwell Inserts, respectively. Synergistic/additive anti-MM activity was analyzed by isobologram analysisusing “CalcuSyn” software program. Proteasome activity was measured, as previously described (Chauhan et al., Cancer Cell 2005, 8:407-419). In vitro angiogenesis was assessed using matrigel capillary-like tube structure formation assays. MM.1S-tumor-bearing mice were treated with vehicle control, marizomib, pomalidomide or marizomib plus pomalidomide at the indicated doses for 21 days on a twice-weekly schedule for marizomib and 4 consecutive days weekly for pomalidomide. Statistical significance was determined using a Student’s t test. Pomalidomide was purchased from Selleck chemicals, USA; and marizomib was obtained from Triphase Inc., USA. Results: MM cell lines (MM.1S, MM.1R, INA-6, RPMI-8226, Dox-40, U266, LR5, ANBL6.WT, and ANBL6.BR) and primary patient MM cells were pretreated with DMSO control or with pomalidomide for 24h; marizomib was then added for an additional 24h, followed by assessment of cell viability. A significant decrease in viability of all cell lines and patient cells was observed in response to treatment with combined low doses of marizomib and pomalidomide, compared with either agent alone. Isobologram analysis confirmed the synergistic anti-MM activity of these agents (CI < 1.0). Tumor cells from 5 of 7 patients were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, the cytotoxicity of combination therapy was observed in MM cell lines sensitive and resistant to conventional (dex, doxorubicin, melphalan) and novel (bortezomib) therapies. No significant decrease in viability of PBMCs from normal healthy donors was observed in response to treatment with combined low doses of marizomib and pomalidomide, suggesting selective anti-MM activity and a favorable therapeutic index for this combination regimen. Furthermore, marizomib plus pomalidomide inhibits proliferation of MM cells even in the presence of BM stromal cells. Mechanistic studies showed that marizomib plus pomalidomide-induced apoptosis was associated with: 1) activation of caspase-8, caspase-9, caspase-3, and PARP; 2) downregulation of Cereblon, IRF4, c-Myc, and Mcl-1; and 3) enhanced inhibition of chymotrypsin-like, caspase-like and trypsin-like proteasome activities versus single agent alone. Furthermore, combined low doses of marizomib and pomalidomide blocked migration of MM cells and angiogenesis. In vivo studies using a subcutaneous human MM xenograft models show that combined low doses of marizomib and pomalidomide are well tolerated, inhibit tumor growth, and prolong survival. Conclusion: Our preclinical studies in MM disease models support a clinical trial of combined marizomib and pomalidomide to improve outcome in patients with relapsed and refractory MM. Disclosures Richardson: Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Trikha:Triphase Accelerator: Employment. Chauhan:Triphase Accelerator: Consultancy. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership.
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Zhu, Yuan Xiao, Esteban Braggio, Chang-Xin Shi, et al. "Cereblon Expression Is Required for the Anti-Myeloma Activity of Lenalidomide and Pomalidomide." Blood 118, no. 21 (2011): 127. http://dx.doi.org/10.1182/blood.v118.21.127.127.
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Abstract Abstract 127 The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. A landmark paper has recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. We hypothesized that this protein would also be required for myeloma (MM) cytotoxicity. To examine this issue we first tested 12 MM cell lines: 4 of which (OCIMY5, OPM1, SKMM2 and KMS12 PE) were very resistant to treatment with both lenalidomide and pomalidomide. Of these, OCIMY5 and OPM1 showed CRBN gene expression levels at the bottom 10% across the human MM cell lines. We next used CRBN shRNA lentiviral expression constructs to knock down CRBN in 5 human-derived myeloma cell lines (HMCLs) (KMS18, MM1.S, H929, OPM2 and JJN3). HMCLs infected with CRBN shRNAs have a significant reduction of CRBN expression and subsequent diminished cell viability (reduced 65–78%). Surviving MM cells with CRBN knock down demonstrate an acquired (essentially complete) resistance to lenalidomide when compared with controls but retained sensitivity to melphalan, dexamethasone and bortezomib. Gene expression changes induced by lenalidomide were dramatically suppressed in those CRBN depleted cells, e.g., OPM2 cells only showed 30 down regulated (3% of control) and 150 up-regulated genes (24% of control) after lenalidomide treatment, further emphasizing that CRBN is required for lenalidomide activity. We next compared by array comparative genomic hybridization the differences between MM1.S (lenalidomide sensitive) and its isogenic lenalidomide resistant line (MM1.S res), generated by culturing MM1.S in gradually increasing concentrations of lenalidomide. Only three structural abnormalities were noted differentiating the two lines one of which was deletion of CRBN. In fact the baseline MM1.S cell line has a minor population of 9% of cells with CRBN depletion which becomes dominant after lenalidomide treatment. However, further scrutiny of CRBN status in additional HMCLs and MM patients (irrespective of therapy and stage) suggested that copy-number abnormalities affecting this gene are uncommon events in MM, with 12% of HMCLs (7 out of 60) and only 1.2% of MM patients (3 out of 238) showing CRBN monoallelic deletion. Next, we examined by quantitative polymerase chain reaction (Q-PCR) ten MM patients who had become resistant to lenalidomide therapy. CRBN expression level by Q-PCR in 8 of 10 patient samples had a significant reduction (20% to 90% reduction compared to baseline) at time of drug resistance, suggesting CRBN expression as a potential biomarker to predict IMiD response. Notably however some clearly resistant patients have normal CRBN, demonstrating that while CRBN is absolutely required for response, multiple resistance mechanisms are likely present. By gene and protein expression downstream targets of CRBN were examined and included interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. In summary, we demonstrate here that CRBN is essential for IMiD activity and preliminary data support that low levels of CRBN predict for poor drug response. In addition, our data suggest that CRBN is a critical molecule but not the unique source of IMiD resistance. We suggest that the “IMiDs” be renamed Cereblon binding small molecules to more accurately reflect their mechanism of action. Disclosures: Orlowski: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Ma, Zi, Rui bo Zhang, Li He, et al. "Induction of CRBN(Cereblon) mRNA Expression by Baicalein." Blood 120, no. 21 (2012): 5025. http://dx.doi.org/10.1182/blood.v120.21.5025.5025.
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Abstract Abstract 5025 The CRBN gene that encodes the cereblon protein is found on the short arm at position p26. 3 of human chromosome 3. Cereblon is a primary target of thalidomide teratogenicity and required for the anti-myeloma activity of lenalidomide and pomalidomide. CRBN depletion myeloma cells become highly resistant to both lenalidomide and pomalidomide. Baicalein, a component of Scutellaria radix from HLJDT, not only suppressed proliferation and induced apoptosis of myeloma cells by down-regulating interleukin −6(IL-6) and XIAP gene expression, but also inhibited the signaling cascades mediated by IL-6 and facilitated myeloma cell inhibition induced by dexamethasone. In clinic, we found that treatment of thlidomide- or lenalidomide-resistant myeloma patients by applying Huang-Lian-Jie-Du-Tang (HLJDT) can induce hematological remission. The precise molecular mechanism of HLJDT exerts its anti-tumor effects remains unclear. Here, by RT-PCR, we demonstrated that treatment of U266 cells and primary myeloma cells with 20μM baicalein can induce CRBN mRNA expression in time-dependent manner. As lenalidomide and thlidomide are effective drugs for maintenance therapy with the advantage of oral administration. It was particularly active in patients with higher cereblon expression. Thus, the combination of HLJDT with thlidomide or lenalidomide may be a novel strategy of maintenance therapy for myeloma patients. Disclosures: No relevant conflicts of interest to declare.
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Richardson, P. G., C. C. Hofmeister, N. S. Raje, et al. "Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma." Leukemia 31, no. 12 (2017): 2695–701. http://dx.doi.org/10.1038/leu.2017.173.
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Abstract This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1–4 mg days 1–14), bortezomib (1–1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1–8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.
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Grosicki, Sebastian, Martyna Bednarczyk, Agnieszka Barchnicka, and Olga Grosicka. "Elotuzumab in the treatment of relapsed and refractory multiple myeloma." Future Oncology 17, no. 13 (2021): 1581–91. http://dx.doi.org/10.2217/fon-2020-1088.
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Multiple myeloma (MM) is still considered an incurable disease. However, drugs with different mechanisms of action that can improve the efficiency of treatment offer hope. Still, there are concerns about an unacceptable increase in toxicity with such regimens. The results of recently published clinical studies of elotuzumab in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone confirm previous hopes to improve the effect of that treatment. Humanized monoclonal antibodies aimed at SLAMF7 stimulate natural killer cells to fight against MM cells. Elotuzumab used in combination with lenalidomide/dexamethasone or with pomalidomide/dexamethasone is approved by the US FDA to treat patients with relapsed and/or refractory MM. The article is a summary of the recent knowledge about the possibility of using elotuzumab in the treatment of relapsed and/or refractory MM and shows its potential uses in the future.
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Lopez-Girona, Antonia, Courtney G. Havens, Gang Lu, et al. "CC-92480 Is a Novel Cereblon E3 Ligase Modulator with Enhanced Tumoricidal and Immunomodulatory Activity Against Sensitive and Resistant Multiple Myeloma Cells." Blood 134, Supplement_1 (2019): 1812. http://dx.doi.org/10.1182/blood-2019-124338.
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Lenalidomide- and pomalidomide-based therapies are effective drugs in the treatment of patients with multiple myeloma (MM), however most patients with MM eventually relapse or become resistant. CC-92480, a novel cereblon (CRBN) E3 ligase modulator (CELMoD) with multiple activities including potent immunomodulation and single-agent antiproliferative effects, is being investigated in a phase 1 clinical trial (CC-92480-MM-001; NCT03374085) for patients with relapsed/refractory MM (RRMM). The present study investigates the preclinical data and mechanism of action of CC-92480 in MM models. CELMoD agents bound to CRBN confer differentiated substrate-degradation specificity on the CRL4CRBN E3 ubiquitin ligase. CRBN-modulator agents mediate destruction of Ikaros and Aiolos, transcription factors that contribute to myeloma cell survival. CC-92480 was found to produce rapid, deep, and sustained degradation of Ikaros and Aiolos, with superior antimyeloma activity. Accordingly, in a CRBN protein competitive binding assay, CC-92480 displaced a Cy-5-labeled CELMoD analog from CRBN with a 50% inhibitory concentration (IC50) value of 0.03 μM, whereas lenalidomide competed with an IC50 value of 1.27 μM in the same assay, demonstrating a higher binding affinity of CC-92480 for CRBN. Additionally, CC-92480 promoted the recruitment of Ikaros to the CRBN E3 ligase complex more effectively than pomalidomide in 2 orthogonal CRBN/Ikaros binding assays; it also triggered a more extensive cellular ubiquitination of Ikaros, and a faster, more efficient depletion of cellular Ikaros and Aiolos than pomalidomide. In various MM cell lines, including those with acquired resistance to lenalidomide or pomalidomide and low levels of CRBN, CC-92480 produced robust degradation of Ikaros and Aiolos followed by strong reduction of 2 additional and highly critical transcription factors, c-Myc and interferon regulatory factor 4, which are linked to the induction of apoptosis as measured by cleaved caspase-3. The tumoricidal activity of CC-92480 was shown to be CRBN dependent, since the effect was prevented by complete loss of CRBN or by the stabilization of Ikaros and Aiolos. CC-92480 displayed broad and potent antiproliferative activity across a panel of 20 MM cell lines that are either sensitive, have acquired resistance, or are refractory to lenalidomide or pomalidomide; the cell lines also contained diverse chromosomal translocations and oncogenic drivers typically found in MM patients. Approximately half of the MM cell lines evaluated were highly sensitive to CC-92480, with IC50 values for antiproliferative activity ranging from 0.04 to 5 nM; only 2 cell lines had IC50 values > 100 nM. CC-92480 inhibits cell proliferation and induces apoptosis in MM cell lines that are not sensitive to lenalidomide or pomalidomide. This panel of cell lines includes both refractory cell lines and resistant cell lines generated through continuous exposure to lenalidomide and pomalidomide that acquired low levels of CRBN protein or mutations in the CRBN gene. CC-92480 also induced deep destruction of Ikaros and Aiolos in cultures of peripheral blood mononuclear cells (PBMCs), which led to the activation of T cells and increased production of the cytokines interleukin-2 and interferon gamma. These responses occurred at the range of CC-92480 concentrations that show potent tumoricidal effect against MM cells. The T cell activation and enhanced cytokine production by CC-92480 led to the potent and effective immune-mediated killing of MM cells in co-cultures with PBMCs. CC-92480 is a potent antiproliferative and proapoptotic novel CELMoD with enhanced autonomous cell-killing activity in MM cells that are either sensitive, resistant, or have acquired resistance to lenalidomide and pomalidomide. CC-92480 has a unique and rapid degradation profile stemming from the enhanced efficiency to drive the formation of a protein-protein interaction between Ikaros and Aiolos and CRBN, inducing cytotoxic effects in a CRL4CRBN-dependent fashion that leads ultimately to the induction of apoptosis, even in the context of low or mutated CRBN protein. Additionally, similar to lenalidomide, CC-92480 conserves immunomodulatory activity against MM cells. These data support the clinical investigation of CC-92480 in patients with RRMM. Disclosures Lopez-Girona: Celgene Corporation: Employment. Havens:Pfizer: Employment, Equity Ownership; Celgene: Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Rychak:Celgene Corporation: Employment, Equity Ownership. Mendy:Celgene Corporation: Employment. Gaffney:Celgene: Employment. Surka:Celgene: Employment, Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Matyskiela:Celgene corporation: Employment. Khambatta:Celgene: Employment. Wong:Celgene Corporation: Employment, Equity Ownership. Hansen:Celgene Corporation: Employment. Pierce:Celgene Corporation: Employment, Equity Ownership. Cathers:Global Blood Therapeutics (GBT): Employment; Celgene Corporation: Equity Ownership. Carmichael:Celgene plc: Employment, Equity Ownership.
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Xu, Yibing, Jianwu Li, Gregory D. Ferguson, et al. "Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases." Blood 114, no. 2 (2009): 338–45. http://dx.doi.org/10.1182/blood-2009-02-200543.
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Abstract IMiDs immunomodulatory drugs, including lenalidomide and pomalidomide represent a novel class of small molecule anticancer and anti-inflammatory drugs with broad biologic activities. However, the molecular mechanism through which these drugs exert their effects is largely undefined. Using pomalidomide and primary human monocytes, we report that pomalidomide rapidly and selectively activated RhoA and Rac1, but not Cdc42 or Ras, in the absence of any costimulation. Consistent with the activation of Rho GTPases, we found that pomalidomide enhanced F-actin formation, stabilized microtubules, and increased cell migration, all of which were blocked by selective inhibitors of ROCK1 and Rac1. Further, we showed that in Swiss 3T3 cells, pomalidomide only activated RhoA, not Rac1 or Cdc42, and potently induced stress fiber formation. The pomalidomide effect on actin cytoskeleton was blocked by the ROCK1 inhibitor, but not Rac1 inhibitor. Finally, we demonstrated that pomalidomide was able to regulate the activity of Rho GTPases and the formation of F-actin in primary human T cells as it did in monocytes and showed that the activation of RhoA was essential for pomalidomide-induced interleukin-2 expression in T cells. These novel activities provide what we believe a critical mechanism by which IMiDs drugs function as therapeutic immunomodulatory agents.
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Mark, Tomer M., Angelique Boyer, Adriana C. Rossi, et al. "ClaPD (Clarithromycin, Pomalidomide, Dexamethasone) Therapy in Relapsed or Refractory Multiple Myeloma." Blood 120, no. 21 (2012): 77. http://dx.doi.org/10.1182/blood.v120.21.77.77.
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Abstract Abstract 77 Background: The addition of clarithromycin has been reported to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is a distinct IMiD® immunomodulatory agent with a significant response rate in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have shown initial results that clarithromycin may similarly enhance the activity of pomalidomide + dexamethasone in patients with RRMM after prior lenalidomide therapy (Rossi et al, ASCO 2012). We now report updated results from a phase 2 trial of large group of patients treated with ClaPD in RRMM. Methods: One hundred patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPD. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1–21 of a 28-day cycle, and dexamethasone 40mg on days 1,8,15,22. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results: Ninety-seven patients had completed at least 1 cycle of ClaPD and were eligible for disease response and safety analysis. Patients had undergone a median of 5 (range 3–15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide +bortezomib) refractory were 73%, 70%, and 64% respectively. The median number of ClaPD cycles received was 4 (range 1–23). Response to ClaPD was progressive disease (PD): 9.3%, stable disease (SD): 32%, minimal response (MR): 5.2%, partial response (PR): 32%, very good partial response (VGPR): 17.5%, stringent complete remission (sCR): 4.1%, giving an overall response rate (ORR, ≥PR) of 53.6% and a ≥VGPR rate of 21.6%. Clinical benefit (≥SD) was achieved in 90.7%. Median time to PR and maximum response was 1 (range 1–7) and 2 (range 1–14) cycles, respectively. After a mean follow up time of 10.1 months, 41 patients (42%) remain on study free from disease progression, with a median progression free survival of 8.2 months (95% CI: 5.1, 10.3). Median overall survival has not been reached with 72 patients (74%) alive at last follow-up. The most common grade 3 and 4 toxicities included anemia (25%), neutropenia (40%), hyperglycemia (11%), and fatigue (6%). Febrile neutropenia was uncommon at 2%. There were 4 cases of lower extremity venous thrombosis (4.1%, 1 at grade 1, 3 at grade 2) and no instances of pulmonary embolism. There was no treatment related mortality. Conclusions: ClaPD is a highly effective regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPD is rapid and sustained at > 8 months in the majority of subjects. The tolerability profile is comparable to lenalidomide and incidence of thromboembolic events was low with low-dose aspirin prophylaxis. These data support the use of pomalidomide therapy in RRMM that has progressed after lenalidomide. Disclosures: Mark: Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium Inc.: Speakers Bureau. Off Label Use: Pomalidomide is not indicated to treat multiple myeloma. This drug is a next-generation immunomodulatory agent. We are investigating its activity and safety for use in relapsed or refractory myeloma. Zafar:Celgene Corp: Speakers Bureau. Pekle:Celgene Corp: Speakers Bureau. Coleman:Celgene Corp: Speakers Bureau. Niesvizky:Onyx, Millenium, Celgene. Speakers bureau: Millenium and Celgene: Consultancy, Research Funding.
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Ruchelman, Alexander L., Hon-Wah Man, Weihong Zhang, et al. "Isosteric analogs of lenalidomide and pomalidomide: Synthesis and biological activity." Bioorganic & Medicinal Chemistry Letters 23, no. 1 (2013): 360–65. http://dx.doi.org/10.1016/j.bmcl.2012.10.071.
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Rossi, Adriana C., Tomer Martin Mark, Melissa Rodriguez, et al. "Clarithromycin, pomalidomide, and dexamethasone (ClaPD) in relapsed or refractory multiple myeloma." Journal of Clinical Oncology 30, no. 15_suppl (2012): 8036. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8036.
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8036 Background: Clarithromycin has been shown to enhance anti-myeloma activity of lenalidomide+dexamethasone in the upfront treatment of multiple myeloma (MM). Pomalidomide is an immunomodulatory agent effective in relapsed/refractory MM (RRMM). We hypothesized that clarithromycin may similarly enhance pomalidomide + dexamethasone in RRMM. We now report updated results from a phase 2 trial of ClaPD in RRMM. Methods: 73 patients with RRMM were enrolled in a single-institution phase 2 study of ClaPD. All subjects had ≥ 3 prior lines of therapy, one of which must have included lenalidomide. ClaPD is clarithromycin 500mg twice daily; dexamethasone 40mg weekly; and pomalidomide 4mg for days 1-21 of a 28-day cycle. All patients had VTE prophylaxis with aspirin. Monthly disease response evaluation included immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM responses. Treatment continued as tolerated until disease progression. Results: The 66 patients who completed ≥ 1 cycle of ClaPD are reported. Median number of cycles was 6 (range 1-17). Responses were progressive disease: 10%, stable disease: 21%, minimal response: 12%, partial response: 33%, very good partial response: 18%, stringent complete remission: 5%, for an overall response rate (ORR) of 56% and ≥VGPR rate of 23%. Median time to PR was 1.25 cycles (range 1-8). Median PFS was 5 months. Response and PFS were not different in patients refractory to lenalidomide (85%), bortezomib (82%), or double-refractory patients (76%). After a median follow up of 12 months,28 pts (42%) remain on study without progression and 56pts (85%) are alive. Two pts withdrew due to toxicity (1 Grade 3 fatigue, 1 Grade 4 muscular weakness). One patient withdrew consent. Conclusions: ClaPD is highly effective for heavily pre-treated RRMM, particularly in lenalidomide-refractory disesase and compares favorably to previously published Phase 2 data of Pom/Dex (ORR 56% vs 40% - Lacy et. al JCO 2009) without excess toxicity. Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects. These data support the clinical efficacy of pomalidomide based regimens in RRMM.
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Anderson, Sarah M., Bradley Beck, Susan Sterud, Robin Lockhorst, and Surachat Ngorsuraches. "Evaluating the use of appropriate anticoagulation with lenalidomide and pomalidomide in patients with multiple myeloma." Journal of Oncology Pharmacy Practice 25, no. 4 (2018): 806–12. http://dx.doi.org/10.1177/1078155218758500.
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Background Lenalidomide and pomalidomide are two immunomodulatory medications with the potential to improve outcomes for patients with multiple myeloma; however, a black box warning for venous thromboembolism exists. Purpose The purpose of this study was to assess overall adherence to guideline recommendations for anticoagulation therapy with lenalidomide and pomalidomide in multiple myeloma patients. Methods This retrospective study at an ambulatory oncology clinic utilized chart reviews from the calendar years 2013–2016. The primary endpoint was prescription of appropriate anticoagulation upon initiation of therapy based on a list of predetermined risk factors. Secondary endpoints included incidence of deep venous thromboembolism, pulmonary embolism, myocardial infarction, stroke, and major bleed; initial anticoagulant prescribed; and whether or not anticoagulation was prescribed for another disease state. Results A total of 130 patients met inclusion criteria: 70.8% (n = 92) and 29.2% (n = 38) were prescribed lenalidomide and pomalidomide, respectively. A total risk score of two was most common (n = 54, 41.5%). Aspirin 81 mg oral tablet was prescribed most often (n = 53, 40.8%), followed by no anticoagulation (n = 30, 23.1%). Overall, 27 patients (20.8%) were prescribed anticoagulation in accordance with National Comprehensive Cancer Network guidelines. Incidence of deep venous thromboembolism was the most common adverse event (n = 4, 3.1%), followed by major bleed (n = 1, 0.8%). No reports of pulmonary embolism, myocardial infarction, or stroke were documented. Conclusions Overall, a disparity exists between appropriate prescribing of prophylactic anticoagulation and current practice guidelines. However, documentation of thromboembolic events was lower than recorded in previously published literature.
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Jimenez Zepeda, Victor H., Peter Duggan, Paola E. Neri, and Nizar J. Bahlis. "Pomalidomide and Dexamethasone Is an Effective Regimen for Advanced-Stage Relapsed/Refractory Multiple Myeloma: Experience of a Single Center." Blood 124, no. 21 (2014): 5747. http://dx.doi.org/10.1182/blood.v124.21.5747.5747.
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Abstract Introduction Almost all patients with MM eventually relapse, and the remission duration in relapsed MM decreases with each regimen. Pomalidomide is an IMiD with antiproliferative, anti-inflammatory and anti-angiogenic effects that was recently approved for the use of relapsed MM failing lenalidomide and bortezomib. Based on these findings, we aimed to evaluate the efficacy of pomalidomide and dexamethasone (PD) for heavily-pretreated relapsed or refractory MM (RRMM) at our Institution. Methods We retrospectively reviewed the records of all patients with RRMM treated with PD at Tom Baker Cancer Center between 01/10 and 06/14. Eligible patients were age 18 years or older; had RRMM after two or more prior therapies (including lenalidomide, bortezomib or thalidomide); and had an Eastern Cooperative Group performance status of 0 to 2. Patients received oral pomalidomide 2-4 mg/d on days 1-21, and dexamethasone 20 mg or 40 mg on a weekly basis. Definitions of response and progression were used according to the EBMT modified criteria. The primary endpoint of the study was to assess the efficacy and feasibility of PD in this group of patients. All analyses were performed using the SPSS 20.0 software and all p-values were 2-sided and statistically significant if <0.05 Results Between 01/10 and 06/14, 31 patients were identified for the study. Clinical and laboratory characteristics are listed in Table 1.The median age for this cohort of patients was 64 years (46-81). Seventy-one percent of patients had IgG isotype, 19.4% had IgA, and 9.7% had light chain only disease. The median number of therapies prior to PD was 4 (2-11). All patients received lenalidomide and bortezomib prior to PD; 11 patients had bortezomib, 8 had lenalidomide and 7 had both prior to PD. Six patients out of 11 receiving bortezomib prior to PD responded (54%) versus 12.5% (1/8), 14% (1/7), and 20% (1/5) for those receiving lenalidomide, lenalidomide/bortezomib and other regimens respectively prior to PD. (p=0.07) Two patients received pomalidomide at a dose of 3 mg, 1 at 2 mg and 28 at 4 mg. After a median of 5 cycles, the ORR was 29% (9/31) with 1 patient achieving nCR and 8 patients (25.8%) PR. (Table 2 ) The median time to first response was 8 weeks with majority of cases achieving at least PR after 2 cycles of therapy. Stable disease was seen in 22.6% and progression in 29% of cases. FISH cytogenetics at relapse were available in 24 patients with 6 cases exhibiting high risk disease (25%). At a median follow-up of 20 months, 16 patients (51.6%) are alive and 21 (67.7%) had already progressed. Median OS was 19.1 months and median PFS 5.6 months. Median PFS was 6.5 months in the group with SR cytogenetics compared to 3.1 months for the HR group. (p0.2) Median OS was similar between SR and HR (19.4 vs 23 months) (p=0.14) With regards to toxicity, 9 patients experienced grade 3/4 hematological toxicity. Eight patients required blood transfusion and one patient discontinued therapy due to grade 4 thrombocytopenia. In conclusion, Pomalidomide is an efficacious drug for the treatment of RRMM. The current report confirms the ORR seen in previous studies and the benefit in HR disease. Further combinations with pomalidomide in the setting of HR disease and for those patients who immediately progressed on IMiD therapies should be considered. Table 1. Clinical and Laboratory characteristics for RRMM patients treated with Pomalidomide and Dexamethasone Characteristic N Median Range % Age (years) 31 64 46-81 Gender -Male -Female 14 17 45.2% 54.8% ISS Stage I II III 5 14 12 16.1% 45.2% 38.7% Heavy chain IgG IgA Free light chain only Light chainKappa Lambda 22 6 3 25 6 71% 19.4% 9.7% <![if !supportEmptyParas]> <![endif]> 80.6% 19.4% Hemoglobin (g/L) 31 113 75-142 Creatinine (µmol/L) 31 86 50-290 Calcium (µmol/L) 31 2.3 2.06-2.64 LDH (IU/L) 31 189 84-489 B2-microglobulin (mg/L) 31 4.2 1.36-16.3 Albumin (g/L) 31 33 21-42 BMPC (%) 31 30 8-98 FISH Cytogenetics Standard risk High risk 24 18 6 75% 25% Prior Therapies ASCT Thalidomide Lenalidomide Bortezomib Carfilzomib 21 13 31 31 6 67.7% 41.9% 100% 100% 19.4% Table 2. Response rates for RRMM patients treated with Pomalidomide and Dexamethasone Characteristic Median (Range) N % Number of cycles 5 (1-31) Overall Response rate 9/31 29% Near Complete Response Complete Response 1 0 3.2% 0% Very Good Partial Response 0 0% Partial Response 8 25.8% Stable Disease 7 22.6% Minimal Response 6 19.4% Progression 9 29% Alive 16 51.6% Disclosures Jimenez Zepeda: Janssen Ortho: Honoraria. Bahlis:Celgene: Honoraria, Research Funding.
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Bjorklund, Chad C., Jian Kang, Ling Lu, et al. "CC-220 Is a Potent Cereblon Modulating Agent That Displays Anti-Proliferative, Pro-Apoptotic and Immunomodulatory Activity on Sensitive and Resistant Multiple Myeloma Cell Lines." Blood 128, no. 22 (2016): 1591. http://dx.doi.org/10.1182/blood.v128.22.1591.1591.
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Abstract Background: CC-220 is a Cereblon (CRBN) binding compound currently under clinical investigation for systemic lupus erythematosus. Comparable to other Cereblon-binding agents, ex vivo treatment of CC-220 on B-cells, T-cells and monocytes leads to the degradation of the hematopoietic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).(1) Currently, CC-220 is being investigated in a phase Ib/IIa study CC-220-MM-001 (clintrial.gov trial #NCT02773030) as a single agent, or in combination with dexamethasone in relapsed/refractory multiple myeloma (RRMM) in patients who may have previously been exposed to pomalidomide. Here, we provide pre-clinical data and mechanistic rationale for the clinical development of CC-220 in heavily pre-treated RRMM. Results: In order to evaluate the ability of CC-220 effects on MM cells in vitro, we generated a large panel of MM cell lines (~69) that consist of 5 categories, including lenalidomide-sensitive (LS; n=26), intrinsically lenalidomide-resistant (ILR; n=7), acquired lenalidomide-resistant (ALR; n=12), acquired lenalidomide/dexamethasone-dual-resistant (ALDR; n=12), and acquired-pomalidomide-resistant (APR; n=12). Cell proliferation by 3H-thymidine incorporation at concentration between 0.01-100 μM was assessed by the area under the curve (AUC) for both CC-220 and pomalidomide. The average AUC was significantly reduced by 65% vs. 52% (p<0.01) for LS, 33% vs. 20% (p<0.01) for ILR, 30% vs. 20% (p<0.01) for ALR, 25% vs.10% (p<0.01) for ALDR, and 23% vs. 8% (ns) for PR cells for CC-220 vs. pomalidomide respectively. Apoptosis was analyzed by flow cytometry and AnnV+/ToPro3+ staining where CC-220 significantly (p<0.01) induced an average of 36% apoptotic cells compared to 30% for pomalidomide in LS cells, and 18% vs. 6% (p<0.5) in PS cells. Importantly, CC-220 showed anti-proliferative and pro-apoptotic activity in PR cells where Cereblon was still expressed. Additionally, both proliferation inhibition and apoptosis were synergistically enhanced across all cell line categories when CC-220 was used in combination with dexamethasone. We next evaluated the immunmodulatory effects on peripheral blood mononuclear cell (PBMCs)-stimulated killing of MM cells. Following a 72 hr incubation with CD3-stimulated PBMCs, CC-220 significantly induced the death of MM cells (~60%, across all cell type categories) within 4 hr, at concentrations more than 10-fold lower than pomalidomide. The observed CC-220-stimulated PBMC co-culture killing of MM cells closely correlated with dose-dependent increases in IL-2 secretion and Granzyme B release. Notably, CC-220 induced PBMC-mediated death of MM cells lacking observable Cereblon protein expression. Lastly, we evaluated the mechanism of action of CC-220 in MM cells in vitro. In the absence of Cereblon, as shown by shRNA knockdown or downregulation in a subset of PR cells, there is very little if any cell autonomous activity of CC-220, implicating Cereblon-dependency for its effects. Downstream of Cereblon, CC-220 stimulates the complete proteasomal degradation of both Ikaros and Aiolos in as little as 6 hr. Measurement of the half maximal time for 50% degradation of both Ikaros and Aiolos is kinetically faster from 1.9-2.9 vs. 2.4-6.9 hr depending on the MM cell line at a 10-fold lower dose for CC-220 compared to pomalidomide, respectively. CC-220 is also more efficient than pomalidomide at causing downregulation of the c-Myc/IRF4 axis, which has been shown to be essential for the cytotoxic effect of pomalidomide.(2) Conclusions: CC-220 is a potent anti-proliferative and pro-apoptotic compound that shows activity in several MM cell line categories with differing sensitivity to lenalidomide, pomalidomide and dexamethasone. Importantly, CC-220 induces PBMC-mediated killing of all MM cell lines regardless of the level of Cereblon expression and cell autonomous sensitivity. Mechanistically CC-220 acts through binding of Cereblon, leading to the degradation of the hematopoietic transcription factors Ikaros and Aiolos, followed by disruption of the MM promoting c-Myc/IRF4 axis. Taken together, these data support the clinical investigation of CC-220 in relapsed/refractory MM patients,who have previously been exposed to pomalidomide. Disclosures Bjorklund: Celgene Corporation: Employment, Equity Ownership. Kang:Celgene Corporation: Employment, Equity Ownership. Lu:Celgene Corporation: Employment, Equity Ownership. Amatangelo:Celgene: Employment, Equity Ownership. Chiu:Celgene Corporation: Employment, Equity Ownership. Gandhi:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Klippel:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership.
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Schafer, Peter H., Emily Rychak, Derek Mendy, et al. "Targeting Cereblon with the High Affinity Immunomodulatory Compound CC-220: A Novel Therapeutic Agent for B Cell Dyscrasias." Blood 120, no. 21 (2012): 1055. http://dx.doi.org/10.1182/blood.v120.21.1055.1055.
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Abstract Abstract 1055 Background: Cereblon (CRBN) is a component of the E3 ubiquitin ligase complex including CUL4A, DDB1, and ROC-1, and was found to be the molecular binding target of thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide. CC-220 is a novel immunomodulatory compound developed with increased potency and is currently in development for the treatment of immune conditions. The effect of CC-220 on CRBN binding, ubiquitination, and cell proliferation was profiled. Methods: Binding studies to CRBN were conducted using thalidomide analog-conjugated beads in a competitive assay. Endogenous CRBN from human U266 multiple myeloma (MM) cells was measured by incubating cell extracts with varying concentrations of either CC-220 or pomalidomide as a positive control. Affinity beads coupled to a thalidomide acid analog were incubated with the U266 extracts and, after extensive washing of the beads, the bound proteins were eluted. CRBN binding to the thalidomide-coupled affinity beads was determined by quantitative CRBN immunoblot determination. CRBN ubiquitination was measured in HEK293T cells, which were transfected with an amino-terminal His-biotin-tagged CRBN construct, then preincubated with compounds for one hour followed by treatment with the MG132 proteasome inhibitor (to arrest degradation of ubiquitinated proteins). Cells were lysed and processed to measure CRBN ubiquitination by SDS-PAGE and immunoblot analysis using an anti-ubiquitin antibody. Cell proliferation studies were conducted in lenalidomide-sensitive and -refractory multiple myeloma cells. Lenalidomide-resistant or -sensitive H929 MM cell lines were treated with CC-220 for 5 days, and then cell proliferation and viability were assessed by 7-aminoactinomycin D (7-AAD) staining. T-cell costimulation was measured in purified primary human T cells stimulated using immobilized anti-CD3 antibody in cell culture for 2 days, and cytokine secretion was measured by ELISA. Immunoglobulin M and G (IgG and IgM) production was measured from normal donor peripheral blood mononuclear cells by culturing in the presence of the B cell differentiation factors recombinant human IL-2 (20 U/mL), IL-10 (50 ng/mL), IL-15 (10 ng/mL), His-tagged CD40 Ligand (50 ng/mL), polyHistidine mouse IgG1 antibody (5 μg/mL), and ODN 2006-Human TLR9 ligand (10 μg/mL) for 4 days, followed by IL-2, IL-10, IL-15, and IL-6 (50 ng/mL) for an additional 3 days. IgM and IgG were measured by ELISA. Results: In the competitive CRBN binding studies, preincubation with pomalidomide at a concentration of 3 μM resulted in approximately 50% less CRBN bound to the affinity beads, while CC-220 at a concentration of 0.1 μM resulted in similar CRBN binding. CRBN ubiquitination studies in the transfected HEK293T cells resulted in the following potencies: CC-220 IC50 = 0.19 μM; lenalidomide IC50 = 12.9 μM; and pomalidomide IC50 = 21.6 μM. The IC50 value for inhibition of proliferation by CC-220 shifted from 0.01 μM in the parental H929 cell line and 0.04 μM in the DMSO-treated subclone to 0.51–1.58 μM in the lenalidomide-resistant subclones. A 50% decrease in cell cycle (S-phase) was evident after 24 hours of treatment of H929 cells with CC-220. At 48 hours, CC-220 decreased expression of survivin and retinoblastoma protein (pRB) and increased expression of the cyclin-dependent kinase inhibitor p27. CC-220 costimulated IL-2 production by T cells with an EC50 of approximately 0.29 nM, compared with 10 nM for pomalidomide. CC-220 inhibited IgM and IgG production with an IC50 of 0.35 and 2.1 nM, respectively, compared to 17 nM and 63 nM for pomalidomide. Conclusions: The results indicate that CC-220 binds to CRBN with approximately 30-fold higher affinity than pomalidomide, and inhibits CRBN ubiquitination with approximately 110-fold greater potency than pomalidomide in this system. CC-220 is approximately 34-fold more potent than pomalidomide for costimulating IL-2 production by T cells, and is 30- to 48-fold more potent than pomalidomide for inhibiting immunoglobulin production. In summary, CC-220 is a novel high affinity CRBN ligand with cellular potencies 1 or 2 orders of magnitude greater than that of pomalidomide, and is currently in development for the treatment of immune conditions, including those involving B cell dyscrasias. Disclosures: Schafer: Celgene: Employment, Equity Ownership. Rychak:Celgene: Employment, Equity Ownership. Mendy:Celgene Corp.: Employment, Equity Ownership. Parton:Celgene Corp: Employment, Equity Ownership. Capone:Celgene Corp: Employment, Equity Ownership. Lopez-Girona:Celgene Corp: Employment, Equity Ownership. Daniel:Celgene Corporation: Employment. Chopra:Celgene Corp: Employment, Equity Ownership.
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Tsang, Mazie, Joseph Cleveland, Miguel Carlos Cerejo, Huimin Geng, and James L. Rubenstein. "Survival and Patient-Reported Outcomes of Older Adults with Primary Central Nervous System Lymphoma on Low-Dose Lenalidomide." Blood 136, Supplement 1 (2020): 21–22. http://dx.doi.org/10.1182/blood-2020-143070.
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Introduction: Management of primary CNS lymphoma (PCNSL) in patients age &gt;70 represents a significant challenge. In most clinical series, median OS for PCNSL patients age &gt;70 is &lt;1 year (Mendez et al., Neuro-Oncology 2018). Since late 2011, our group has used low-dose lenalidomide as maintenance therapy in older patients with newly-diagnosed PCNSL who had &gt;partial response (PR) to induction chemotherapy or salvage chemotherapy for relapsed disease. A preliminary report by our group supported the feasibility and efficacy of low-dose lenalidomide maintenance for 13 older patients with PCNSL, in lieu of consolidation with radiation or high-intensity chemotherapy (Vu et. al., BJH 2019).Here, we present the outcomes of 22 consecutive older patients with PCNSL (inclusive of updated outcomes on the original 13 patients) treated with low-dose lenalidomide after achieving &gt;PR following induction chemotherapy. In addition, we provide a first report on the impact of maintenance low-dose lenalidomide on quality of life (QOL), overall functioning, and symptom burden. Methods: We performed a retrospective analysis of consecutive patients age &gt;65 years with PCNSL, who achieved &gt;PR to induction methotrexate/rituximab+temozolomide (MTR) chemotherapy and were subsequently treated with low-dose lenalidomide maintenance (5-10 mg/dose) in PR1/CR1. We determined their clinical characteristics, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier. In addition, we obtained correlative data on QOL and symptom burden on a representative sample of older PCNSL patients who were treated with low-dose IMiDs over the course of &gt; 2 months, via the European Organization of Research and Treatment of Cancer (EORTC) QOL questionnaire (QLQ)-C30. Our study was approved by the University of California San Francisco Institutional Review Board with patient informed consent. Results: The median age at diagnosis of the 22 consecutive older newly-diagnosed PCNSL patients was 77 (range 64 - 86). Median Karnofsky Performance Status was 70. Twenty patients received induction MTR (2 received M-R) without consolidative dose-intensive chemotherapy, autologous stem cell transplant, or whole brain irradiation. The median methotrexate dose was 2.5 gm/m2 (range 0.5 - 8). With median follow-up of 47 months, median time on low-dose lenalidomide maintenance was 14 months. Median PFS was 84 months, and median OS has not been reached. (Figure 1). At progression, patients received methotrexate followed by lenalidomide or pomalidomide. Thus far, there have been 3 deaths: one due to PCNSL, one by myocardial infarction, 4 years after discontinuation of lenalidomide, and one without definitive cause. To assess the tolerability of low-dose lenalidomide (and/or pomalidomide) in this population, we determined patient-reported outcomes with respect to quality of life, as measured by the EORTC QLQ-C30. We summarize our findings in Figure 2 on 8 consecutive PCNSL patients age &gt;70 that received maintenance IMiD therapy for at least 2 months. Seven of the 8 patients were treated with maintenance low-dose lenalidomide for a median of 11 months, and one patient was on maintenance pomalidomide (1-2 mg/day) for a total of 76 months. Overall low-dose IMiDs were well-tolerated: mild-to-moderate fatigue and insomnia were the two most commonly reported symptoms. Conclusions: Our experience suggests that low-dose lenalidomide as maintenance therapy after induction chemotherapy in older patients with PCNSL may result in improved PFS and OS. Importantly, our data suggest that QOL and overall functioning as measured by the EORTC QLQ-C30 was comparable, if not better, than QOL as assessed for patients receiving high dose methotrexate-based therapy, autologous stem cell transplant, whole brain radiation therapy, and/or blood brain barrier disruption (Doolittle et. al., Neurology 2013). In conclusion, based on this preliminary assessment, maintenance low-dose lenalidomide (and pomalidomide) appear to be well-tolerated in older PCNSL, with patients reporting good quality of life, low symptom burden, and overall good level of functioning. Survival outcomes remain encouraging. A phase I trial in newly-diagnosed, non-transplant eligible PCNSL that evaluates combination nivolumab with lenalidomide, both as a component of induction therapy and as low-dose lenalidomide maintenance, is in development via Alliance (A051901). Disclosures Rubenstein: Kymera: Research Funding. OffLabel Disclosure: Low-Dose Lenalidomide as Maintenance in Older Patients with Primary CNS Lymphoma
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Lacy, Martha Q., Suzanne R. Hayman, Morie A. Gertz, et al. "Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma." Journal of Clinical Oncology 27, no. 30 (2009): 5008–14. http://dx.doi.org/10.1200/jco.2009.23.6802.
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Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.
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Lacy, Martha Q., Betsy R. LaPlant, Kristina Laumann, et al. "Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of 225 Patients Treated in Five Cohorts Over Three Years,." Blood 118, no. 21 (2011): 3963. http://dx.doi.org/10.1182/blood.v118.21.3963.3963.
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Abstract Abstract 3963 Background: Pomalidomide at doses of 2 or 4 mg/d has demonstrated excellent activity in patients with relapsed multiple myeloma (MM). Between November 2007 and November 2010, we opened 5 sequential phase 2 trials using the pomalidomide at differing doses with weekly dexamethasone (Pom/dex) regimen to study the efficacy of this regimen. Methods: The five cohorts consisted of: Cohort 1 (N=60): relapsed MM with 1–3 prior regimens, 2 mg dose; Cohort 2 (N=34): lenalidomide refractory, 2 mg dose; Cohort 3 (N=35): bortezomib/lenalidomide refractory, 2 mg dose; Cohort 4 (N=35): bortezomib/lenalidomide refractory, 4 mg dose; and Cohort 5 (N=60) lenalidomide refractory, 1–3 prior regimens, 4 mg dose. Pomalidomide was given orally 2 mg daily or 4mg daily on days 1–28 of a 28-day cycle with oral dexamethasone given 40 mg daily on days 1, 8, 15 and 22. Response was assessed by the International Myeloma Working Group Uniform Response criteria. All patients received aspirin 325 mg daily for DVT prophylaxis or full dose anticoagulation. Results: A total of 225 patients were enrolled across all 5 cohorts. One patient was ineligible and excluded from analysis. The median age was 63 years (32.0–88.0). The median time since diagnosis was 53 months. Forty percent had high-risk molecular markers. Eighty-nine percent had received previous IMIDs including thalidomide (53%) and lenalidomide (81%). Sixty-two percent had previous bortezomib and 73% had prior transplant. The median follow-up is 12.6 months, but varies from 9.4 months for the most recent cohort to 30 months for the first cohort. Sixty-nine percent are alive and 30% remain progression free. Toxicities ≥ grade 3 are shown in table 1 and patient outcomes are shown in Table 2. Conclusions: Pom/dex is remarkably active and well tolerated even in heavily pretreated patients. Responses are durable. Response rates and toxicity are similar between the 2 mg and 4 mg doses. Disclosures: Lacy: Celgene: Research Funding. Fonseca:Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.
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Paludo, Jonas, Joseph R. Mikhael, Betsy R. LaPlant, et al. "Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma." Blood 130, no. 10 (2017): 1198–204. http://dx.doi.org/10.1182/blood-2017-05-782961.
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Sonneveld, Pieter, Hervé Avet-Loiseau, Sagar Lonial, et al. "Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group." Blood 127, no. 24 (2016): 2955–62. http://dx.doi.org/10.1182/blood-2016-01-631200.
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AbstractThe International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.
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Harousseau, Jean Luc, and Michel Attal. "How I treat first relapse of myeloma." Blood 130, no. 8 (2017): 963–73. http://dx.doi.org/10.1182/blood-2017-03-726703.
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Abstract The standard treatment of relapsed multiple myeloma has been either lenalidomide-dexamethasone (RD) or bortezomib-dexamethasone (VD) but it is changing rapidly for 2 reasons. First, lenalidomide and bortezomib are currently used in frontline treatment and many patients become resistant to these agents early in the course of their disease. Second, 6 second-line new agents have been recently developed and offer new possibilities (pomalidomide, carfilzomib and ixazomib, panobinostat, elotuzumab, and daratumumab). Recent randomized studies have shown that triple combinations adding 1 of these new agents (except pomalidomide) to the RD or VD regimens were superior to the double combinations in terms of response rate and progression-free survival (PFS). Their place in the treatment of first relapse is discussed here. Among these agents, daratumumab is clearly a breakthrough and daratumumab-based combinations might become the preferred option in the near future. However, all of these drugs are expensive and are not available or affordable in all countries. We propose a decision algorithm for first relapse in fit patients with the objective of achieving the best PFS. The choice of salvage regimen is based on lenalidomide/bortezomib resistance, daratumumab availability, and cost. Autologous transplantation should be considered in younger patients if not used upfront.
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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 (2020): 367. http://dx.doi.org/10.3390/molecules25020367.
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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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Palumbo, Antonio, Alessandra Larocca, Vittorio Montefusco, et al. "Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma." Blood 120, no. 21 (2012): 446. http://dx.doi.org/10.1182/blood.v120.21.446.446.
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Abstract Abstract 446 Background: The outcome of myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide or bortezomib is poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012). The newer immunomodulatory drug pomalidomide, has shown significant activity in these clinical conditions. Aims: We assessed dosing, efficacy and safety of pomalidomide-cyclophosphamide-prednisone (PCP) in MM patients relapsed/refractory to lenalidomide. Methods: Pomalidomide was administered in doses ranging from 1 to 2.5 mg/day on days 1–28, cyclophosphamide at 50 mg every other day on days 1–28 and prednisone at 50 mg every other day on days 1–28 for 6 cycles, followed by maintenance therapy with pomalidomide-prednisone. Thromboprophylaxis with aspirin 100 mg/day or low-molecular weight heparin was recommended at physician's discretion. Results: The maximum tolerated dose (MTD) of pomalidomide was defined as 2.5 mg/day. Fifty-two patients were enrolled at the MTD and evaluated after completing at least 1 PCP cycle. Median age was 69 years (range 41–83). The median time from diagnosis to enrolment was 55 months (range 15–203). Best responses to PCP included 6% of complete response (CR), 19% of at least very good partial response (VGPR), 54% of at least partial response (PR) and 75% of at least minimal response (MR). Time to PR was rapid (median 1.8 months). After a median follow-up of 11 months (range 1–18), 1-year progression-free survival (PFS) and OS rates were 52% and 78%, respectively. PFS was not significantly different in patients with high-risk cytogenetic compared with patients with standard-risk disease and in patients younger or older than 75 years. Toxicities were primarily hematologic and included grade 4 neutropenia (13%) and thrombocytopenia (4%). At least grade 3 non-hematologic toxicities included infections (8%), rash (6%) and neurologic (6%). Thromboembolism occurred in 1 patient. Four patients discontinued treatment for toxicity (2 infections, 1 neurologic and 1 hepatic toxicity). Conclusions: PCP induced high response rates and prolonged PFS after prior exposure to lenalidomide and bortezomib (Table), without adding significant toxicity. PCP could be considered a valuable salvage option for pre-treated MM patients. Disclosures: Palumbo: Celgene: Consultancy, Honoraria. Larocca:Celgene: Honoraria. Sciacca:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Honoraria.
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Montefusco, Vittorio, and Marco Capecchi. "Diarrhea Incidence in Multiple Myeloma Patients Treated With Lenalidomide and Pomalidomide." Clinical Lymphoma Myeloma and Leukemia 17, no. 1 (2017): e46. http://dx.doi.org/10.1016/j.clml.2017.03.082.
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Garderet, Laurent, Frederique Kuhnowski, Benoit Berge, et al. "Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma." Blood 132, no. 24 (2018): 2555–63. http://dx.doi.org/10.1182/blood-2018-07-863829.
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Abstract It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.
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Oka, Satoko, Kazuo Ono, and Masaharu Nohgawa. "Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide." Journal of Clinical Pharmacy and Therapeutics 43, no. 6 (2018): 914–17. http://dx.doi.org/10.1111/jcpt.12740.
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Sivaraj, Dharshan, Michael M. Green, Yubin Kang, et al. "Phase I/II dose expansion of a trial investigating bendamustine and pomalidomide with dexamethasone (BPd) in patients with relapsed/refractory multiple myeloma." Journal of Clinical Oncology 35, no. 15_suppl (2017): 8008. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8008.
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8008 Background: The combination of bendamustine, pomalidomide, and dexamethasone (BPd) displays promising activity in heavily pretreated RRMM. In the Phase I portion, MTD was 120 mg/m2bendamustine/3mg pomalidomide/40mg dexamethasone. We report our combined findings from the additional phase II expansion cohort for the first phase I/II trial of BPd in patients with RRMM (NCT01754402). Methods: All patients had to be refractory to prior lenalidomide as well as be pomalidomide naïve, and must have relapsed or have been refractory to their most recent therapy. Treatment consisted of oral pomalidomide PO QD on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1, and dexamethasone 40mg on days 1, 8, 15, and 22 of a 28-day cycle. Bendamustine was administered at 120 mg/m2 for cycle 1, day 1. Results: A total study population of 38 patients was enrolled, with 34 evaluable for toxicity and 32 for efficacy, with 7 patients still receiving treatment. Data cut-off was January 18, 2017. The median age was 67 years, median number of prior regimens was 5, median time from diagnosis was 3.6 years, and median follow-up was 11.7 months. 82% of patients had a prior stem cell transplant, 100% had prior bortezomib, 32% had prior carfilzomib, and all were lenalidomide refractory. Cytogenetic abnormalities included 6 patients with del(17p), 4 with t(4;14), 7 with del(13), and 7 with t(11;14). Patients received a median of 4 cycles of therapy. Best response assessments in 32 evaluable patients showed 3 sCR, 3 VGPR, 17 PR, 7 SD, and 2 PD for an ORR of 72%. The median PFS and OS were 9.6 months and 21.3 months respectively for the entire cohort, with 16 of 32 still alive at follow-up. Grade ≥3 drug-related AEs included fatigue (8%), neutropenia (45%), anemia (26%), thrombocytopenia (24%), and diarrhea (8%). 71% of patients experienced grade ≥3 AEs including neutropenia, anemia, and diarrhea. Conclusions: The BPd regimen is relatively tolerable and achieves a promising overall response rate (ORR of 72%) and durable responses in a heavily pre-treated lenalidomide–refractory population with prior bortezomib exposure, and a median of 5 lines of prior therapy. Clinical trial information: NCT01754402.