S199: A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY EVALUATING THE EFFICACY AND SAFETY OF SINGLE AGENT BELANTAMAB MAFODOTIN VS POMALIDOMIDE PLUS DEXAMETHASONE IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (DREAMM-3)
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SUBMITTER: Dimopoulos M
PROVIDER: S-EPMC10428262 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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| S-EPMC11494064 | biostudies-literature
Project description:IntroductionSingle-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678).MethodsAt the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH).ResultsBelamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001).ConclusionSingle-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.
| S-EPMC8523001 | biostudies-literature
Project description:Due to evolving treatment standards for newly diagnosed multiple myeloma, many patients will be triple-class exposed after initial relapses and have poor survival. Novel therapies and combinations are therefore required to improve outcomes. B cell maturation antigen (BCMA)-targeted biologics have emerged as an important new area of therapeutics for relapsed multiple myeloma. The two-part ALGONQUIN trial evaluated various doses and schedules of the anti-BCMA antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone for patients who are lenalidomide refractory and proteosome inhibitor exposed. The primary endpoints, including evaluating dose-limiting toxicities, establishing the recommended Part 2 dose (RP2D) and overall response rate for patients treated at the RP2D, were met. Secondary efficacy endpoints included progression-free survival and overall survival. Patients treated on study (N = 87) had a median of three previous regimens and 55.2% were triple-class refractory. At the RP2D the most common adverse events were decrease in best-corrected visual acuity (71.1%), keratopathy (65.8%), fatigue (57.9%), infection (47.4%; 7.9% grade ≥3), neutropenia (39.5%) and thrombocytopenia (39.5%). For RP2D patients (n = 38), the overall response rate was 85.3%, ≥very good partial response 75.7% and estimated two-year progression-free survival 52.8% (95% confidence interval, 33.9% to 82.4%), at a median follow-up of 13.9 months. The RP2D schedule was associated with manageable antibody-drug conjugate-associated corneal adverse events and improved tolerability without compromising efficacy. Belantamab mafodotin plus pomalidomide and dexamethasone induced durable responses with promising overall survival in relapsed multiple myeloma, the results of which are yet to be confirmed in the phase 3 DREAMM-8 study. ClinicalTrials.gov Identifier: NCT03715478 .
| S-EPMC10878971 | biostudies-literature
Project description:Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.
| S-EPMC11391083 | biostudies-literature
Project description:DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3-72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8-not reached [NR]); median progression-free survival was 5.7 months (2.2-9.7); median overall survival was not reached (8.7 months-NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
| S-EPMC7584571 | biostudies-literature
Project description:DREAMM-11 (NCT03828292) was a Phase 1, open-label, dose-escalation study of belantamab mafodotin in Japanese patients with relapsed/refractory multiple myeloma (RRMM). In Part 1, belantamab mafodotin monotherapy (2.5 or 3.4 mg/kg every 3 weeks) was tolerated and demonstrated clinical activity and a manageable safety profile. Part 2 investigated the tolerability, safety, clinical activity and pharmacokinetics of belantamab mafodotin (2.5 mg/kg on Day [D]1 of each 21-day cycle) plus bortezomib and dexamethasone (Arm A; N = 3) or belantamab mafodotin (2.5 mg/kg on D1 of the first 28-day cycle; 1.9 mg/kg on D1 of subsequent cycles) plus pomalidomide and dexamethasone (Arm B; N = 4) in Japanese patients with RRMM and ≥ 1 prior line of therapy. No dose-limiting toxicities were reported in Arm A; 1 (non-serious liver injury) was reported in Arm B. Safety profiles of each treatment combination were consistent with those of the individual agents and those in Western populations. An overall response was achieved by 3/3 (100%) patients in Arm A and 2/4 (50%) in Arm B. Pharmacokinetics were consistent between Japanese and Western populations. The clinical pharmacokinetics, safety, and efficacy data from this study can inform future use of belantamab mafodotin plus bortezomib/pomalidomide and dexamethasone in Japanese patients with RRMM.
| S-EPMC11782446 | biostudies-literature
Project description:Belantamab mafodotin, a B-cell maturation antigen-targeting antibody-drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses.
| S-EPMC10615937 | biostudies-literature
Project description:IntroductionPatients with relapsed or refractory multiple myeloma (RRMM) are likely to be living with persistent symptoms, especially bone pain and fatigue, and experiencing restrictions in their physical and social functioning, which reduce health-related quality of life.MethodsThis qualitative interview study evaluated patients' perspectives about living with RRMM and their treatment with belantamab mafodotin, using interviews embedded in the Phase II DREAMM-2 trial (NCT03525678) with belantamab mafodotin. Patients consented to participate in up to 2 recorded telephone interviews (at treatment cycle 4 [C4] and at end of treatment [EOT]) comprising open-ended questions.ResultsA total of 142 interviews were conducted with 111 unique patients. At C4, common symptoms included neuropathy, fatigue, and bone or joint pain. Improvements in symptom severity were reported by patients who responded to belantamab mafodotin. Symptoms associated with visual impairment, eye irritation, and eye pain reported during the trial were reported to be at- or near-resolution by the EOT interview. Regarding impacts of underlying MM, patients most commonly expressed concerns about changes in daily performance and lifestyle for both responders (67.5% of all impact expressions) and non-responders (63.2%). Overall, interview participants reported being satisfied with belantamab mafodotin treatment.DiscussionThis qualitative patient interview study provides valuable insight into patients' symptomatic experience with belantamab mafodotin for their RRMM treatment and may help healthcare providers better anticipate their patients' real-world experience and needs when prescribing this novel agent in the clinic.
| S-EPMC10748584 | biostudies-literature
Project description:Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971.
| S-EPMC5570682 | biostudies-literature
Project description:Belantamab mafodotin (belamaf) is an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). Nonlinear mixed-effects models were developed to characterize the population pharmacokinetics (PopPK) of ADC, total monoclonal antibody (mAb), and cysteine-maleimidocaproyl-MMAF (cys-mcMMAF) after 0.03-4.6 mg/kg dosing every 3 weeks in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM; DREAMM-1, n = 73; DREAMM-2, n = 218). Sequential modeling methodology was used. Individual post hoc parameter estimates from the final ADC model were used to develop total mAb and cys-mcMMAF models. Formal covariate selection used a modified stepwise forward inclusion method with backward elimination. A linear, two-compartment PopPK model with a time-varying clearance (CL) described ADC PK. Initial ADC typical value for CL for a DREAMM-2 patient was 0.936 L/day with a half-life of 11.5 days, over time CL was reduced by 28% resulting in a half-life of 14.3 days. Time to 50% maximal CL change was ~ 50 days. Baseline soluble BCMA (sBCMA), immunoglobulin (IgG), albumin, and bodyweight impacted ADC CL. Cys-mcMMAF concentrations were described with a linear two-compartment model linked to ADC; input rate was governed by deconjugation/intracellular proteolytic degradation of ADC represented by an exponentially decreasing MMAF:mAb (drug antibody ratio [DAR]) after each dose. Time to 50% DAR reduction was 10.3 days. Baseline sBCMA and IgG impacted cys-mcMMAF central volume of distribution. In conclusion, ADC, total mAb, and cys-mcMMAF concentration-time profiles in RRMM were well-described by PopPK models, and exposure was most strongly impacted by disease-related characteristics.
| S-EPMC8376139 | biostudies-literature