Combination Of Pomalidomide Research Articles

Elotuzumab in combination with pomalidomide, bortezomib, and dexamethasone in relapsed and refractory multiple myeloma.

Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). The OPTIMISMM study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone (PVd) in relapsed/refractory MM. We therefore studied adding elotuzumab to PVd (elo-PVd) in relapsed/refractory MM in a multicenter phase 2 trial. The primary objective was to determine the overall response rate (ORR). Patients with relapsed/refractory disease and ≥1 prior line of treatment (including lenalidomide and a proteasome inhibitor) were eligible. For each 28 day cycle, elotuzumab was weekly for the first 2 cycles and then every other week; pomalidomide was on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. The trial completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80) and the median number of prior lines was 3 (range 1-9); 25% had high risk FISH. Prior therapies included: pomalidomide (33%), daratumumab (25%), and isatuximab (4%). Best ORR was 56.3% and median PFS was 10 months. In patients with 1 prior line of therapy, ORR was 73.7% and median PFS was 23.4 months. Common grade ≥3 adverse events were neutropenia (33%); infections, any (33%); lung infection (27%); hypophosphatemia (19%); and thrombocytopenia (15%). Elo-PVd is one of the first trials of a quadruplet regimen in relapsed/refractory MM incorporating a monoclonal antibody to show efficacy across diverse prior treatments, including triple class exposed with prior anti-CD38 monoclonal antibody.

Clinical outcomes of pomalidomide-based and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma: A real-world cohort study in China.

Comparative investigations evaluating the efficacy of pomalidomide-based (Pom-based) versus daratumumab-based (Dara-based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real-world studies. This retrospective cohort study included 140 RRMM patients treated with Pom-based or Dara-based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023. The overall response rates (ORR) for Pom-based (n = 48), Dara-based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression-free survival (PFS) was 5.7 months (95% CI: 5.0-6.5) for the Pom-based group, 10.5 months (5.2-15.8) for the Dara-based group, and 6.7 months (4.0-9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double-refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara-based regimens over Pom-based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara-based and DPd regimens (Pom-based 39.6% vs. Dara-based 64.7% vs. DPd 70.8%, p = 0.009). In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy.

Abstract 6046: CFT8634, a BRD9 BiDAC™ degrader, is active in a subset of multiple myeloma cell line models and synergistic when combined with pomalidomide or dexamethasone

Abstract Recent literature has shown that loss-of-function of BRD9, a component of the noncanonical SWI/SNF (ncSWI/SNF) complex, mediated by RNA interference or by BRD9 degrader compounds can inhibit multiple myeloma (MM) cell lines and primary MM cell proliferation in vitro, as well as inhibit mouse MM xenograft tumor growth in vivo. Additionally, in vitro synergy was observed when a BRD9 degrader was combined with either dexamethasone or pomalidomide. CFT8634 is a potent and selective oral BiDAC™ degrader of BRD9 that entered a clinical trial for the treatment of SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null tumors. Pharmacokinetic and pharmacodynamic data from this trial demonstrated dose-proportional human plasma exposure and robust BRD9 degradation in patients. Here we show that CFT8634 has anti-proliferative activity in a subset of MM cell lines that translates into tumor growth inhibition in MM xenograft models at clinically relevant CFT8634 exposures. We observe that cell lines less sensitive to pomalidomide tend to be significantly more sensitive to CFT8634 treatment. As pomalidomide is a SoC treatment in MM, we interrogated the ability to combine CFT8634 and pomalidomide. CFT8634 demonstrates synergy with pomalidomide in MM cell lines where CFT8634 is anti-proliferative as a single agent. We further show that clinically relevant exposures of CFT8634 demonstrate synergy with pomalidomide in vivo in the NCI-H929 mouse xenograft model. This model is relatively unresponsive to pomalidomide alone, suggesting that CFT8634 can render otherwise recalcitrant MM tumors sensitive to the effects of pomalidomide in combination. Pharmacokinetic and pharmacodynamic analyses show that in combination, CFT8634 and pomalidomide do not interfere with the ability to degrade each other’s targets (BRD9 and IKZF1/3, respectively) despite both utilizing the E3 ligase cereblon. As the corticosteroid dexamethasone is another SoC treatment given in combination with pomalidomide, we explored the ability to combine dexamethasone with CFT8634. CFT8634 demonstrates synergy with dexamethasone in the RPMI-8226 in vivo xenograft model. This combination leads to tumor regressions at clinically relevant doses and outperforms the current combination of pomalidomide with dexamethasone. In conclusion, we demonstrate in vitro and in vivo activity in an expanded set of MM models using the clinical oral BRD9 degrader CFT8634 as a single agent and show in vivo synergy between CFT8634 and SoC agents pomalidomide and dexamethasone at clinically relevant doses. Citation Format: Laura L. Poling, David Cocozziello, Minsng he, Eunju Hurh, Riadh Lobbardi, Katrina L. Jackson, Stewart L. Fisher, Roy M. Pollock. CFT8634, a BRD9 BiDAC™ degrader, is active in a subset of multiple myeloma cell line models and synergistic when combined with pomalidomide or dexamethasone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6046.

Real-World Outcomes of Medicare Fee-for-Service Beneficiaries Meeting the Eligibility Criteria for the DREAMM-7 and DREAMM-8 Clinical Trials

Introduction: Belantamab mafodotin (belamaf), an investigational first-in-class B-cell maturation antigen-binding antibody-drug conjugate, has demonstrated deep and durable responses as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM) in the DREAMM-2 and DREAMM-3 trials. Two randomized controlled trials (RCTs) exploring the use of belamaf in combination therapy are ongoing in patients with RRMM treated with at least 1 prior line of therapy (2L+). DREAMM-7 is evaluating the efficacy and safety of belamaf in combination with bortezomib and dexamethasone versus daratumumab in combination with bortezomib and dexamethasone. DREAMM-8 is evaluating the efficacy and safety of belamaf in combination with pomalidomide and dexamethasone versus pomalidomide in combination with bortezomib and dexamethasone. The present study aimed to provide real-world context for DREAMM-7 and DREAMM-8 trial results by reporting treatment outcomes of Medicare Fee-for-Service (FFS) patients with characteristics that meet the inclusion/exclusion criteria for each trial. Methods: A retrospective database analysis was conducted to develop trial-like cohorts (one per trial) using the 100% sample from Medicare FFS administrative claims data spanning 2016-2020. Inclusion/exclusion criteria from each RCT protocol included the presence of an MM diagnosis (based on an ICD-9-CM or ICD-10-CM diagnosis code for MM), ≥1 prior line of therapy (prior lenalidomide treatment required for the DREAMM-8 cohort), and other exclusion criteria related to renal, liver, and cardiovascular function. These criteria were used to identify patients in the Medicare FFS database who would be eligible for trial enrollment. Both RCT protocols restricted the overall study populations to ≤50% of patients with at least 2 prior lines of therapy (3L+). Accordingly, random sampling without replacement was applied across eligible Medicare patient lines of therapy to generate cohorts composed of 50% 2L RRMM patients and 50% 3L+ RRMM patients. Index date was the date the randomized line of therapy was initiated. Overall survival (OS) for each cohort was estimated using time from index date until death. Real-world progression-free survival (rwPFS) for each cohort was estimated as the time from index date until next treatment or death. Results: Overall, 1,911 and 1,280 patients met the DREAMM-7 and DREAMM-8 eligibility criteria, respectively. Following random sampling, the analysis cohorts were composed of 1,232 patients (DREAMM-7) and 1,066 patients (DREAMM-8). For the DREAMM-7 trial-like cohort, median rwPFS was 13.6 months and median OS was 29.6 months(Figure). The most commonly used regimens in this cohort were lenalidomide +/- steroids (21.3%), bortezomib +/- steroids (14.4%), and bortezomib + lenalidomide +/- steroids (8.9%). In the DREAMM-8 trial-like cohort, median rwPFS was 13.2 months and median OS was 30.8 months (Figure). In this cohort, the most common regimens were lenalidomide +/- steroids (21.1%), bortezomib +/- steroids (12.9%), and pomalidomide +/- steroids (8.3%). Over a third of patients in the DREAMM-8 trial-like cohort were retreated with lenalidomide. Conclusions: Real-world outcomes of Medicare FFS patients with RRMM eligible for DREAMM-7 and DREAMM-8 were suboptimal: 57% and 56% died within 3 years of entry into their trial-like cohort, respectively, and median rwPFS was around 1 year for both cohorts. Lenalidomide +/- steroids and bortezomib +/- steroids were most commonly used in each cohort. Retreatment with lenalidomide was common in the DREAMM-8 trial-like cohort. These suboptimal outcomes and frequent retreatment demonstrate a substantial need for new effective treatment modalities to improve patient outcomes and provide further treatment choice in the 2L+ RRMM setting. Funding: GSK (Study 209838). Drug linker technology licensed from Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.

Renal Response of Selinexor, Pomalidomide, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study

Background Renal impairment (RI) is one of the cardinal features of newly diagnosed multiple myeloma (NDMM), contributing to dismal outcomes and high risk of early death. Improved renal function is associated with prolonged survival for NDMM. The triplet combination of pomalidomide with bortezomib and dexamethasone (PVD) has been proven to be effective in MM patients with RI [1] (The manuscript in preparation). However, the best renal overall response rate (ORR) was 78.8% and 21.2% of patients had no renal response to PVD. Here we reported an interim analysis to evaluate the renal and hematologic response of SPVD (Selinexor, pomalidomide, bortezomib, dexamethasone) regimen as first-line therapy in NDMM with RI in this prospective, open-label, multicenter, phase 2 study (ChiCTR2200064695). Methods Eligible NDMM with RI (defined as estimated glomerular filtration rate (eGFR) by MDRD < 40ml/min) were enrolled in the study. Sample size was designed to recruit 62 patients. RI caused by other reasons than tubular nephropathy was excluded. Patients received SPVD (Selinexor 40mg on days 1,8,15, pomalidomide 4mg on days1-14, bortezomib 1.3mg/m2 on days 1,4,8,11, and dexamethasone 20mg on day of and after bortezomib, 21days/cycle) for a maximum of 9 cycles. Autologous stem cell transplantation (ASCT) was administrated after 3 to 6 SPVD cycles for transplant-eligible patients. The primary endpoint was renal ORR at 3 months. Secondary endpoints included major renal response (≥partial response) at 3 months, hematological ORR, minimal residual disease (MRD), progression-free survival (PFS), overall survival (OS), and safety. The definition of both hematological response and renal response was according to the International Myeloma Working Group (IMWG) criteria. Results Between Oct 28, 2022 and Jun 23, 2023, 31 patients were enrolled across 17 centers, with a median age of 61 years (range: 45-80). The proportion of R-ISS III was 35.5%. Median serum creatine level and eGFR were 365μmol/L [interquartile range (IQR): 214.5-508] and 14.5 mL/min (IQR: 10.5-22.64), respectively. There were 10/31 (32.3%) patients requiring dialysis at diagnosis and 8 patients with high-risk cytogenetic abnormalities [t(4;14), t(14;16), or del(17p)]. At the data cut-off date of July 11, 2023, the median number of SPVD treatment cycles was 3 (range: 1-8). The median follow-up time was 4 months. Two patients received first-line ASCT after induction therapy. The primary endpoint of renal ORR at 3 months was 74.2%, including 6.5% renal PR, and 25.8% renal CR (Table 1). The ORR of the best hematological response was 70.9% (45.1% ≥VGPR, 16.1% CR)(Table 1). The most common treatment emergent adverse events (TEAEs) (incidence >10%) were infection (45.2%), myelosuppression (45.2%), hepatic impairment (12.9%), nausea (12.9%), and hypokalemia (12.9%) (Table 2). Grade 3 or more hematologic toxicity was seen in 35.5% of the patients, the most common being thrombocytopenia (19.4%)(Table 2). Dose reduction or interruption of pomalidomide occurred in 5 patients due to myelosuppression and infection events. Three patients had dose reduction of selinexor due to nausea or vomiting. Notably, among non-hematologic toxicities, 4 patients developed hepatic impairment, and of those, one patient suffered tumor lysis syndrom, hepatic failure and severe infection and then died. Median PFS and OS were not reached. Conclusion This study demonstrated SPVD is an effective combination in NDMM patients with RI. The toxicity profile was consistent with the reported research, but hepatic impairment during treatment should be noted with caution. Reference [1] JIAN Y, CHANG L, SHI M, et al. Renal Response of Pomalidomide with Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients with Renal Impairment: A Prospective, Open-Label, Multicenter, Phase 2 Study [J]. Blood, 2022, 140(Supplement 1): 10167-9. doi:10.1182/blood-2022-159361.

Efficacy of Carvykti in CARTITUDE-4 Versus Other Conventional Treatment Regimens for Lenalidomide-Refractory Multiple Myeloma Patients Using Inverse Probability of Treatment Weighting

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) who have received one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. CARTITUDE-4 demonstrated superiority of cilta-cel over PVd and DPd on progression-free survival (PFS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or stringent CR]). Other available therapies for the treatment of this patient population where individual patient data was available for analysis include: daratumumab in combination with bortezomib and dexamethasone (DVd), bortezomib in combination with dexamethasone (Vd), carfilzomib in combination with daratumumab and dexamethasone (DKd) or dexamethasone alone (Kd), and pomalidomide in combination with dexamethasone (Pd). This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm (i.e., patients apheresed or infused with cilta-cel) in CARTITUDE-4 vs each of these regimens in the same target population. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd and Vd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs. Patients who met CARTITUDE-4 eligibility criteria were identified from the above mentioned RCTs. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease, and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, ORR, VGPR or better, and CR or better were compared between patients in the cilta-cel arm and the comparator regimens. Relative efficacy of cilta-cel vs comparator regimens were estimated with hazard ratios (HRs) and 95% confidence intervals (CIs) from weighted Cox proportional hazards models for PFS, and response rate ratios (RRs) and 95% CIs from weighted logistic regression models for ORR, VGPR or better, and CR or better. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained. Across the comparative trials, 44 patients treated with DVd, 46 patients treated with Vd, 98 patients treated with DKd, 46 patients treated with Kd, and 92 patients treated with Pd met the inclusion criteria of CARTITUDE-4. Baseline covariates were similar across the cohorts after IPTW. Patients randomized to the cilta-cel arm showed significant improvements in PFS (adjusted HRs from 0.11 vs Vd to 0.51 vs DKd), VGPR or better (adjusted RRs from 1.51 vs DKd to 5.13 vs Vd), and CR or better rate (adjusted RRs from 2.90 vs DKd to 35.24 vs Pd) (Table). Improvements in ORR were also observed against all comparator regimens (adjusted RRs from 1.22 vs DKd to 1.90 vs Pd), though were marginally not statistically significant vs DVd and Kd. Treatment with DKd consistently yielded the best results out of all comparator regimens, but results were still in favor of cilta-cel. Results of cilta-cel benefit were consistent across sensitivity analyses, yielding adjusted HRs below 1.00 and RRs above 1.00 in all cases against other comparator regimens. Conclusions: Data from CARTITUDE-4 and these analyses demonstrate the benefit of cilta-cel over additional regimens commonly used in clinical practice, highlighting its potential to become a new standard of care option for patients with RRMM, who have received one to three prior lines(s) of therapy, including an IMiD and a PI, and who are refractory to lenalidomide. These comparisons provide valuable information to contextualize the efficacy of CARVYKTI in countries where standard of care may be different from DPd/PVd.

CFT8634, a Clinical Stage BRD9 Bi DAC™ Degrader, Is Active in a Subset of Multiple Myeloma Cell Line Models and Synergistic When Combined with Pomalidomide

Recent literature has shown that loss-of-function of BRD9, a component of the noncanonical SWI/SNF (ncSWI/SNF) complex, mediated either by RNA interference or by BRD9 tool degrader compounds can inhibit multiple myeloma (MM) cell lines and primary MM cell proliferation in vitro, as well as inhibit mouse MM xenograft tumor growth in vivo. Additionally, in vitro synergy in MM proliferation assays was observed when a tool BRD9 degrader was combined with the standard of care (SoC) agents, dexamethasone or pomalidomide. Given the continued unmet need of the MM patient population, we explored the therapeutic potential of CFT8634 in this indication. CFT8634, a potent and selective oral BiDAC™ degrader of BRD9, is currently in a Phase 1/2 clinical trial (NCT05355753) for the treatment of SMARCB1-perturbed cancers, including synovial sarcoma and SMARCB1-null tumors. Pharmacokinetic and pharmacodynamic data to date from the ongoing trial of CFT8634 has demonstrated dose-proportional human plasma exposure and robust BRD9 degradation in patient tumor samples thereby establishing proof of mechanism in patients. Here we show that CFT8634 has anti-proliferative activity in a subset of MM cell lines that translates into tumor growth inhibition in MM xenograft models at clinically relevant CFT8634 exposures. We observe that cell lines less sensitive to pomalidomide tend to be significantly more sensitive to CFT8634 treatment. As pomalidomide is a SoC treatment in MM, we interrogated the ability to combine CFT8634 and pomalidomide. CFT8634 demonstrates synergy with pomalidomide in MM cell lines where CFT8634 is anti-proliferative as a single agent. We further show that clinically relevant exposures of CFT8634 demonstrate synergy with pomalidomide in vivo in the NCI-H929 mouse xenograft model (Figure 1). This model is relatively unresponsive to pomalidomide alone, suggesting that CFT8634 can render otherwise recalcitrant MM tumors sensitive to the effects of pomalidomide in combination. Pharmacokinetic and pharmacodynamic analyses show that in combination, CFT8634 and pomalidomide do not interfere with the ability to degrade each other's targets (BRD9 and IKZF1/3, respectively) despite both utilizing the E3 ligase cereblon. In conclusion, we demonstrate in vitro and in vivo activity in an expanded set of MM models using the clinical oral BRD9 degrader CFT8634 as a single agent and show in vivo synergy between CFT8634 and pomalidomide at clinically relevant doses. Our findings suggest that combining CFT8634 with pomalidomide may be a viable therapeutic strategy in treating MM patients.

Efficacy and Safety of Replacing Lenalidomide with Pomalidomide for Patients with Multiple Myeloma Refractory to a Lenalidomide-Containing Combination Regimen

The combination of pomalidomide with dexamethasone is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2, multicenter, open-label, non-randomized study investigated pomalidomide as a replacement for lenalidomide for 45 patients with RRMM refractory to a lenalidomide-containing combination regimen containing steroids and ≥1 other anti-myeloma agent administered using the same schedule(s), dose(s), and drug combination. Pomalidomide was administered on days 1-21 of a 28-day cycle for ≤8 cycles at doses of 2, 3 or 4 mg. Overall response rates (ORR) and clinical benefit rates (CBR) were 33% and 44%, respectively and were higher among those who received 4 mg pomalidomide (ORR 41% and CBR 50%). Median progression-free survival and overall survival were 8 and 16 months, respectively. Adverse events were consistent with the established safety profiles for the individual agents and the replacement of lenalidomide with pomalidomide did not appear to result in greater toxicity. Overall, this study indicates that pomalidomide can be an effective and safe replacement for lenalidomide among patients with RRMM refractory to the latter immunomodulatory agent without requiring additional changes to the combination regimen. #NCT02188368.

Trial in Progress: Pomalidomide Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PRIDE)

Backgrounds: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Patients generally receive salvage therapy as rituximab, ifosfamide, carboplatin and etoposide (R-ICE), followed by consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). However, only approximately 50% of patients can proceed to ASCT and only half of these achieve durable remission post-transplant. New therapeutic strategies are needed to improve response rates and to prevent recurrence following ASCT. The immunomodulatory agent lenalidomide has demonstrated direct anti-tumor effects in lymphoma. Some studies found that the addition of lenalidomide to the widely used R-ICE salvage regimen is feasible and results in promising response rates in R/R DLBCL patients. Pomalidomide is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) with an acceptable toxicity profile. We aim to determine the safety, tolerability and efficacy of pomalidomide in combination with R-ICE in R/R DLBCL patients.Study Design and Methods: PRIDE (ChiCTR2100049327) is a phase I/II trial of pomalidomide plus R-ICE (PR-ICE) as a salvage regimen for first-relapse or primary refractory DLBCL. In phase I of the study, patients receive escalating doses of pomalidomide (2mg, 3mg or 4mg daily on d1-10) along with R-ICE therapy every 21 days by standard 3+3 design until the MTD has been determined. In stage II, all subjects receive three cycles of R-ICE plus pomalidomide, dosing as RP2D. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. Key eligibility criteria are as follows: histologically confirmed DLBCL; relapsed or refractory after one prior treatment for DLBCL; age 18-75 years; absolute neutrophil count >1500 /mm 3; platelet count > 75,000/mm 3; calculated creatinine clearance of over 60 mL/min by Cockroft-Gault formula; total bilirubin < 1.5×ULN; AST and ALT < 3×ULN. The primary endpoint of phase II is the CR rate after PR-ICE induction treatment. The CR rate for R-ICE in R/R DLBCL was estimated to be approximately 35%. We hypothesize that the addition of POM to R-ICE could increase the CR rate by approximately 20%. For phase II, it requires a sample size of 44 evaluable patients (one-sided alpha = 0.05, power 80%, dropout rate of 15%). Eligible patients who receive at least one dose of PRICE will be included in the efficacy and safety analyses. The 95% CI of CR was calculated using Clopper-Pearson method. The Kaplan-Meier method was used to estimate PFS and OS. All these analyses were conducted using SAS 9.4 software. Enrollment for phase I will begin in Q4 of 2021. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Pomalidomide is indicated for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy in China. The abstract presents the rationale for the use of generic pomalidomide in combination with R-ICE, a combination that is not approved in China at present.

Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Part 1 Results of a Dose-Finding Study of Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma (RRMM)

Bortezomib-Pomalidomide-Dexamethasone (VPD) As Novel Induction Therapy in Newly-Diagnosed Multiple Myeloma: Early Safety Data from an Ongoing Single Arm Phase-II Investigator-Initiated Clinical Trial (PRIME Study)

Introduction: Pomalidomide is a third-generation immunomodulatory drug approved for relapsed and/or refractory Multiple Myeloma (RRMM). In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone demonstrated superior efficacy in patients with RRMM. PRIME study (CTRI/2019/10/021618) is testing this combination in Newly Diagnosed Multiple Myeloma (NDMM)Aim: To determine safety of Pomalidomide in combination with Bortezomib and dexamethasone (VPD) in NDMMStudy design: A prospective, single arm, phase II study from a tertiary center. Both transplant eligible and ineligible patients with NDMM aged between 18-70 years are being recruited in the study. Patients with Plasma cell leukemia, POEMS and amyloidosis were excluded. The regimen consists of weekly Bortezomib 1.3mg/sq.m (subcutaneous), Tab. Pomalidomide 2-4mg once daily for 21days, and Tab Dexamethasone 20mg twice weekly, with the cycle repeating every 28 days, 9-12 cycles. Here we report the adverse events (AE) by NCI CTCAE v5.0, upon recruiting 26 patients, as predetermined in the study.Results: Of the proposed 45-50 patients, 26 patients were enrolled in the study between April 2020 to May 2021 and 23 (88.4%) have completed 4 cycles of VPD. The median age is 55years (18-70), and gender ratio 1:1. At disease presentation, bone lesions were the commonest (96.2%, n=25), IMWG high risk cytogenetics were seen in 42.4% (n=11), RISS-2 in 69.3% (n=18), IgG kappa paraproteinemia in 54% (n=14) patients and ECOG performance score 2-3 in 57.6%(n=15). Ten (38.5%) patients have completed 9 cycles, and 3 underwent auto-transplant (between Cycle 4 & 6). Protocol adherence was 96.1% (25/26 patients).Table-1 shows drug-induced toxicity, hematological toxicities were the commonest. Two patients withdrew consent in view of bortezomib-induced peripheral neuropathy. Serious adverse events (SAE) were reported in 9 (34.6%) patients and were considered unrelated to the regimen by the safety committee (PSVT=1, Bony pain=2, dyspnea=1, pneumonia=1, constipation=1, diarrhea=1, hypotension=1) and one death due to SARS-CoV2 pneumonia. Treatment delays of 2 weeks in 4 patients (SARS-CoV2 = 3, Syncope = 1)After 4 cycles (n=23), 6 (26%) patients were in stringent Complete Response (sCR), 17(74%) in Very Good partial response (VGPR) and 13 (56.5%) are Measurable Residual Disease (MRD) negative. Of 10 patients who completed cycle 9, 9 were MRD negative and 1 showed disease progression.Conclusion: Safety data from the PRIME study demonstrates that VPD regimen has a favorable tolerance profile in patients with NDMM. Early efficacy signals are encouraging, and recruitment continues. [Display omitted] DisclosuresRadhakrishnan: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emcure Pharmaceuticals: Research Funding; Intas Pharmaceuticals: Research Funding; Janssen India: Honoraria; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca India: Honoraria, Speakers Bureau; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cipla Pharmaceuticals India: Research Funding; Aurigene: Speakers Bureau. Garg: Dr Reddys Laboratories: Honoraria, Speakers Bureau. Nair: Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intas pharmaceuticals: Honoraria, Speakers Bureau; Mylan pharmaceuticals: Honoraria; Novartis India: Honoraria; Fresenius Kabi India: Honoraria; Cipla Pharmaceuticals: Honoraria, Speakers Bureau; Janssen India: Honoraria, Speakers Bureau. Chandy: Janssen: Honoraria; Pfizer: Honoraria; Intas Pharmaceuticals: Research Funding.

Phase II Study of the Combination of Pomalidomide with Dexamethasone As Maintenance Therapy after First Relapse Treatment with PCD Followed or Not By Autologous Stem Cell Transplant in Multiple Myeloma Patients

Phase II Study of the Combination of Pomalidomide with Dexamethasone As Maintenance Therapy after First Relapse Treatment with PCD Followed or Not By Autologous Stem Cell Transplant in Multiple Myeloma Patients

A Phase I/II Trial Of Pomalidomide, Bortezomib and Dexamethasone In Patients With Relpased Or Refractory Multiple Myeloma

BackgroundPomalidomide is a recently approved IMiD® immunomodulatory agent that has been validated and approved in relapsed and refractory multiple myeloma. The combination of IMiDs and proteasome inhibitors together offers the potential for deeper and more durable responses due to enhanced efficacy through biological synergy and reduced overlapping toxicities. The combination of pomalidomide and bortezomib has not been investigated extensively; preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This trial was designed to evaluate the safety and efficacy of the combination of pomalidomide, weekly bortezomib and dexamethasone - Pom-Bor-Dex or “PVD”. Patients and methodsWe designed a phase I/II trial of pomalidomide, bortezomib and dexamethasone in patients with relapsed myeloma who had 1-4 prior lines of therapy, including being resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15,22 IV and dexamethasone 40 mg days 1,8,15,22 PO every 28 days. Dose level 2 increased the bortezomib to 1.3mg/m2. The primary endpoint was to determine the maximum tolerated dose of the combination. The 6 phase I patients treated at dose level 2 will also be included in the phase II portion of the trial. The phase II portion of trial expanded dose level 2 to assess for efficacy. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. As determined a priori, if at least 9 of the first 16 patients responded to therapy, preliminary reporting of efficacy and toxicity would be permitted. ResultsA total of 19 patients have been accrued to the trial: 9 in phase I (3 at dose level 1 and 6 at dose level 2) and 10 additional at dose level 2 for 16 total in phase II. At dose level 1, no DLTs were observed. Two of three patients responded (both CR) and one patient had SD for two cycles then progressed.At dose level 2 (n=16) median age was 66, 50% were female and median time from diagnosis to study was 45 months (15-121). Twenty five percent had mSMART defined high risk status. Median prior lines of therapy was 3 (1-6), with all patients treated with lenalidomide, 75% had stem cell transplant, 31% received thalidomide, and 50% had bortezomib. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. In 14 evaluable patients Grade ≥3 AEs included neutropenia (5), leukopenia (3), lung infection (1), lymphopenia (1) and atrial flutter (1). One DLT has occurred (hospitalization for infection). All patients are alive and remain on therapy (none have progressed). Of 12 patients evaluable for response, 10 (83%) have responded: 1sCR, 3 CR, 3 VGPR and 3 PR. ConclusionsThe MTD of this combination was determined to be pomalidomide 4 mg (day 1-21), IV bortezomib 1.3mg/m2 (days 1,8,15,22) and dexamethasone 40 mg (days 1,8,15,22) every 28 days. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. Pom-Bor-Dex (PVD) is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80% with the enhanced tolerability and convenience of weekly administration of bortezomib. Furthermore, no patients treated at the MTD have progressed thus far. Pom-Bor-Dex (PVD) is a highly attractive option in patients with relapsed and refractory myeloma. Disclosures:Mikhael:Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties. Bergsagel:Onyx: Consultancy. Witzig:Celgene: Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Stewart:Onyx: Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria.

Skuteczność terapii pomalidomidem u pacjenta ze szpiczakiem plazmocytowym opornym na inne leki immunomodulujące

Treatment of patients with refractory or relapse multiple myeloma (MM) is a major therapeutic challenge. The introduction to the therapy of new active drugs, such as immunomodulating drugs (IMiDs) or proteasome inhibitors contributed to a significant increase in the percentage and quality of the obtained responses and, most importantly, to the prolongation of patients’ life. However, MM is a disease with frequent progressions, and choosing the right treatment strategy is much more difficult with each subsequent relapse. The drugs used in the treatment of such patients include pomalidomide — an IMiD, registered in Poland as the third-line therapy for patients with relapsed and refractory MM. The paper presents a case report of a 66-year-old patient diagnosed with IgG lambda MM, who since January 2016 had received 5 lines of treatment with IMiDs, bortezomib and daratumumab, nevertheless she had not met the criteria of response to treatment. In May 2019, the patient was qualified for further treatment with pomalidomide in combination with low doses of oral dexamethasone (POM-DEX). During the treatment, a significant reduction in the level of the monoclonal IgG lambda protein was observed. After receiving two treatment cycles, the patient met the criteria for partial remission, and after 12 cycles the level of monoclonal protein decreased by 78% compared to the period before treatment. The therapy was quite well tolerated. The only side effects observed during treatment were: worse tolerance of physical effort, weight gain and slight edema of lower limbs. Due to the POM-DEX therapy, the patient achieved a durable response to the treatment, despite the rapid relapses of the disease during the previous lines of treatment.

Pomalidomide improves the function of CD133- or HER2-specific CAR T cells

Chimeric antigen receptor (CAR) T-cell therapy is mostly limited to hematological malignancies and has a poor effect on solid tumors. CAR T cells as a kind of immune cell may be affected by some immunomodulatory drugs such as pomalidomide, so the use of pomalidomide may improve the effect of CAR T cells on solid tumors. In this study, CD133- or HER2-specific CAR T cells were chosen to investigate whether pomalidomide can regulate the function of CAR T cells in vitro. We found that pomalidomide can significantly enhance the ability of CD133-CAR T cells and HER2-CAR T cells to kill tumor cells and increase the cytokine secretion of CD133-CAR T cells and HER2-CAR T cells. Also, pomalidomide was shown to induce down-regulation of protein levels of IL-2 transcriptional repressors Aiolos and Ikaros in CAR T cells. This study suggests that the combination of pomalidomide and CAR T cells may be a new strategy for the treatment of solid tumors.

Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide.

Combination Treatment with GSK126 and Pomalidomide Induces B-Cell Differentiation in EZH2 Gain-of-Function Mutant Diffuse Large B-Cell Lymphoma

Simple SummaryTo overcome the potential threat of drug resistance or limit of potency, the combination treatment of drugs is a promising strategy. Around 22% of patients with GCB-DLBCL carry EZH2 gain-of-function mutations and several PRC2 inhibitors are under clinical trials. Herein, we demonstrate that combination of GSK126 with pomalidomide synergistically inhibit tumor growth through inducing B-cell maturation and apoptosis in EZH2 gain-of-function mutant DLBCL. Our study provides the molecular basis of the combination strategy of PRC2 inhibitors and IMiDs in DLBCLs harboring EZH2 hyperactive mutation.Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.

A phase I trial of pomalidomide in combination with liposomal doxorubicin in patients with Kaposi sarcoma with or without other KSHV-associated diseases.

11552 Background: Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus 8 [HHV-8]), is the causative agent of Kaposi sarcoma (KS), a multicentric angioproliferative tumor, a form of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). KS can be difficult to treat when it occurs with KSHV-MCD or KICS; resulting in high mortality rates. Liposomal doxorubicin (LD) is an FDA-approved treatment for KS. Pomalidomide, an oral immunomodulatory drug, is safe and has demonstrated activity in KS, but the activity of the combination (pomalidomide+LD) in KS alone or with KSHV-associated diseases is unknown. Methods: The primary objective was to evaluate safety and tolerability of pomalidomide+LD in two groups of patients with KS requiring systemic therapy: Group I (GI)- KS alone; Group II (GII)- KS with concurrent KSHV-MCD or KICS. Patients received LD at 20 mg/m2 intravenously on day 1 of a 28-day cycle combined with pomalidomide once daily on days 1 to 21 at escalating dose levels (DL) (I - 2mg, II - 3mg, or III- 4mg) in a 3+3 design until plateau of response or other pre-specified criteria. Patients received 81mg of aspirin daily as thromboprophylaxis. KS responses were evaluated using the modified AIDS Clinical Trial Group criteria. Results: Thirty-four cisgender men, all with T1-stage KS [21 patients (62%) in GI and 13 patients (38%) in GII] were treated; 32 (94%) were HIV-infected and 22 (65%) had prior chemotherapy for KS (15/21 GI and 7/13 GII). There were no dose-limiting toxicities (DLTs) at DLIII for GI, and additional patients were treated at DLIII. In GII, grade 3 rash and pharyngeal edema were DLTs observed at 3mg of pomalidomide. Overall a median of 6 cycles were administered; the most common grade 3/4 toxicity was neutropenia. Among evaluable patients receiving &gt;2 cycles,17/21 patients in GI had a response (all partial) (81% [95% confidence interval (CI) 58-95%]) and 5/10 patients in GII had a response (4 partial and 1 complete) (50% [95% CI 19-81%]). Conclusions: Pomalidomide+LD was well-tolerated and active in heavily pretreated patients with KS alone. In patients with KS and other KSHV-associated diseases, activity was noted but less well-tolerated. Clinical trial information: NCT02659930 .

Population Pharmacokinetics and Exposure Response Analysis of Pomalidomide in Subjects With Relapsed or Refractory Multiple Myeloma From the Novel Combination Treatment of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone.

Multiple myeloma is an incurable progressive neoplastic disease that accounts for 10% of all hematologic malignancies. Even though significant progress has been made in the treatment of newly diagnosed multiple myeloma, the disease follows a relapsing course in the majority of patients, and there is a need for more effective therapeutic options for the treatment of relapsed or refractory multiple myeloma. CC-4047-MM-005 and CC-4047-MM-007 were phase 1 and 3 studies to evaluate the novel combination of pomalidomide, bortezomib, and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have already received lenalidomide-based treatments early. This analysis was performed to characterize the population pharmacokinetics (PK) of pomalidomide from the combination treatment and to examine exposure-response relationships. Our analysis showed that pomalidomide concentration-time profiles from the combination treatment were adequately described with a 1-compartment PK model, with first-order absorption and elimination and pomalidomide exhibiting linear and time-invariant PK with moderate variability from the combination treatment. Except for the body surface area, none of the tested covariates had an effect on pomalidomide PK. Although body surface area was identified as a statistically significant covariate of pomalidomide PK, the impact was not deemed clinically relevant. A flat exposure-response curve was observed, consistent with a near-saturated drug effect at the tested exposure range suggesting an appropriately recommended clinical dose of 4mg of pomalidomide for the combination treatment. Finally, pomalidomide exposure was not associated with higher probabilities of dose interruption during cycle 1 or dose reduction during the treatment period.

A Phase II Study of Elotuzumab in Combination with Pomalidomide, Bortezomib, and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.