The pivotal clinical trials, CARTITUDE-1 and KarMMa-3, showed promising response rates in relapsed and refractory multiple myeloma (RRMM) with use of BCMA-directed CAR T-cell therapy; however, a major challenge is determining suitability in patients who do not meet trial inclusion criteria due to suboptimal organ function. In this multicenter retrospective study, we evaluated the safety and efficacy of BCMA CAR-T therapy in patients with RRMM and renal impairment (RI), defined as creatinine clearance (CrCL) of less than 45 mL/min. We evaluated 223 patients treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) between May 2021 and April 2024. Outcomes were compared between baseline RI (11.2%) and normal renal function (nRF) cohorts. Response rates were similar at 1 month (p = 0.09), 3 months (p > 0.9), and 6 months (p = 0.8). Progression-free survival (PFS) was 21.9 months in the RI group compared to 15 months in the nRF group (p = 0.32), while overall survival (OS) was 27.9 months for patients with nRF versus not reached for patients with RI (p = 0.87). Patients with RI had higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS) (60% vs. 19%, p = 0.04) and infections (44% vs. 20%, p = 0.008). We found that BCMA CAR-T demonstrated comparable efficacy in RRMM patients with baseline RI, although these patients exhibited increased rates of neurotoxicity and infections.

Background/Objectives: Teclistamab is a bispecific antibody targeting BCMA and CD3, approved for relapsed/refractory multiple myeloma. It is administered continuously until progression or intolerance; however, prolonged use may increase infections and treatment burden. This study compares continuous versus fixed-duration teclistamab to determine whether treatment discontinuation after response is feasible without compromising outcomes. Methods: A multicenter retrospective study was conducted on adults with relapsed/refractory multiple myeloma treated with teclistamab between August 2022 and May 2024. Patients received step-up dosing followed by weekly administration. Those who achieved ≥VGPR and discontinued therapy due to deep response, toxicity, or preference were assigned to the fixed-duration group. Outcomes included response rates, progression-free survival (PFS), overall survival (OS), and adverse events. Results: Eighty-eight patients were included (continuous: n = 72; fixed: n = 16). The fixed group had higher complete response rates (69% vs. 44%) and shorter median time to best response (1 vs. 2 months). Median PFS was 16 months for continuous dosing versus 13 months for fixed-duration. Twelve-month PFS was similar (65% vs. 66%). Twelve-month OS was 83% vs. 81% in the continuous and fixed groups, respectively. Cytokine release syndrome and neurotoxicity rates were similar. Infections were more frequent and severe in the fixed cohort (75% any grade; 69% grade ≥ 3). Conclusions: Fixed-duration teclistamab after deep response appears feasible in appropriately selected patients, with comparable early survival outcomes to continuous treatment. Prospective studies are needed to define selection criteria, immune recovery markers, and optimal discontinuation timing.

Background: High-risk cytogenetic multiple myeloma (HRMM) confers inferior outcomes despite significant therapeutic advances. Real-world data characterizing contemporary treatment patterns across lines of therapy in this population are limited. Methods: We conducted a multicenter retrospective study of 205 patients with HRMM diagnosed between January 2009 and January 2024. High-risk cytogenetics were defined according to the International Myeloma Working Group (IMWG) and Revised International Staging System (R-ISS) criteria as the presence of del(17p), t(4;14), t(14;16), t(14;20), and/or gain/amplification of 1q21. Treatment regimens were categorized by the number of agents (doublet, triplet, quadruplet), mechanism of action (proteasome inhibitor [PI]-based, immunomodulatory drug [IMiD]-based, and anti-CD38 monoclonal antibody-based), and specific regimen composition. Treatment patterns were analyzed across three treatment eras and stratified by age (<70 vs. ≥70 years). Results: The cohort included 205 patients (median age, 62 years [interquartile range [IQR], 54–68 years]; 78.5% aged <70 years). Double-hit and triple-hit cytogenetics were present in 60.0% and 7.3% of patients, respectively. For first-line induction, triplet therapy predominated (81.0%, n = 166), followed by quadruplet (8.8%, n = 18), doublet (5.9%, n = 12), and multi-agent chemotherapy (2.9%, n = 6). By mechanism of action, PI + IMiD combinations were the most common (63.4%, n = 130), followed by PI-based (19.0%, n = 39), anti-CD38-based (10.2%, n = 21), and IMiD-based (2.9%, n = 6) regimens. Era-stratified analysis revealed a significant increase in quadruplet utilization from 3.2% in Era 1 (2009–2015) to 20.3% in Era 3 (2020–2024), with anti-CD38-containing frontline regimens administered to 26.6% of patients in the contemporary era (p < 0.001). Second-line induction was required in 50 patients (24.4%), with anti-CD38-based triplets comprising the most common approach (30.0%). Autologous stem cell transplantation (ASCT) was performed in 75.1% of patients overall, with significantly higher utilization in those aged <70 years (83.9% vs. 43.2%). Maintenance therapy was administered to 71.7% of patients (n = 147), with IMiD-based regimens predominating (53.1%), followed by PI + IMiD combinations (27.9%) and anti-CD38-containing regimens (10.2%). Despite intensive therapy, 69.4% of patients on maintenance experienced disease relapse, with higher rates observed in younger patients (74.8% vs. 41.7%). Conclusions: In this real-world HRMM cohort, the PI + IMiD triplet regimen remained the predominant induction approach, with a significant shift toward quadruplet and anti-CD38-containing regimens in the contemporary era. However, substantial relapse rates during maintenance underscore the continued unmet need in HRMM and support the early integration of novel therapeutic strategies, including quadruplet induction and BCMA-directed agents, in this population.

Background: Idecabtagene vicleucel (ide-cel) has demonstrated substantial activity in relapsed/refractory multiple myeloma (RRMM), but outcomes in real-world patients remain heterogeneous. Extramedullary disease (EMD) is an adverse phenotype, and prolonged cytopenias may complicate post-CAR-T recovery. We synthesized real-world standard-of-care ide-cel evidence to characterize EMD-associated efficacy outcomes and prolonged hematotoxicity. Methods: We performed a focused evidence synthesis of real-world ide-cel studies reporting EMD-stratified outcomes, cytopenias, hematopoietic interventions, or safety in RRMM. Data were extracted into a structured workbook. Because several US datasets were derived from potentially overlapping registry or consortium populations, primary EMD prevalence and progression-free survival (PFS) synthesis was restricted to non-overlapping EMD-stratified cohorts. Progression-free survival (PFS) was analyzed in parallel across contributing cohorts rather than pooled mathematically. Cytopenia outcomes were summarized descriptively at day 30/month 1 and day 90/month 3. Results: Five real-world studies were included. Across two non-overlapping ide-cel-only EMD-stratified cohorts, 111 of 510 infused patients had reported EMD, corresponding to a combined study-reported prevalence of 21.8% (17.0% in the French registry and 23.9% in the US cohort). Median PFS was shorter with EMD in both contributing cohorts: 6.21 versus 14.82 months in FENIX/DESCAR-T and 5.3 versus 11.1 months in the US EMD-focused cohort. Across both independent cohorts, presence of extramedullary disease was consistently associated with significantly inferior progression-free survival: median PFS was 6.21 months (95% CI: 4.01–NR) versus 14.82 months (95% CI: 11.30–18.37) in the French FENIX/DESCAR-T cohort (adjusted HR 3.15, 95% CI: 1.82–5.47; p < 0.0001), and 5.30 months (95% CI: 4.10–6.90) versus 11.10 months (95% CI: 9.20–12.60) in the US cohort (adjusted HR 1.50, 95% CI: 1.10–2.20; p = 0.02). In the US EMD-focused cohort, day-90 ORR was 52% with EMD versus 82% without EMD. EMD independently predicted inferior PFS in both adjusted analyses. A multicenter cohort evaluating both ide-cel and ciltacabtagene autoleucel (cilta-cel) contributed supportive evidence, with ide-cel-treated EMD patients achieving a best overall response rate (ORR) of 61% (≥PR per IMWG criteria). In the cytopenia-focused cohort, grade ≥ 3 cytopenia was present in 64.7% at day 30 and 40.4% at day 90. Grade ≥ 3 thrombocytopenia was present at day 90/month 3 in 20.8–27.7% across ide-cel-only hematotoxicity studies. Conclusions: Real-world ide-cel data identify EMD as a high-risk phenotype associated with inferior response durability and approximately halved median PFS. Prolonged grade ≥ 3 cytopenias are common after standard-of-care ide-cel, particularly thrombocytopenia and neutropenia. These findings support pre-infusion risk stratification incorporating true EMD status, marrow disease burden, and hematopoietic reserve.

B-cell maturation antigen (BCMA)-directed therapies (BDTs) have transformed relapsed/refractory multiple myeloma treatment, but optimal post-failure sequencing remains undefined. We evaluated real-world outcomes from three retrospective, multicenter analyses. Study 1 compared BCMA CAR-T and BCMA T-cell engagers (TCEs) in BDT-exposed patients (n = 95). Study 2 evaluated teclistamab in BDT-exposed versus BDT-naïve patients (n = 164). Study 3 examined talquetamab (GPRC5D-targeting TCE) in heavily pretreated patients (n = 68). CAR-T therapy achieved superior outcomes versus TCE (overall response rate [ORR] 79% vs. 51%, p < 0.001; median overall survival [OS] 30 vs. 12 months, p = 0.008). Teclistamab-treated BDT-exposed patients had lower ORR (53% vs. 68%, p = 0.02) and shorter median progression-free survival (PFS; 2.5 vs. 9.7 months, p = 0.01) compared with BDT-naïve patients. Administration < 6 months post-BDT showed inferior outcomes (hazard ratio [HR] 2.5 for PFS; HR 2.9 for OS). Talquetamab achieved an ORR of 68.3% among BDT-exposed patients, with significantly lower response rates when administered < 6 months post-BDT or when BDT was the immediate preceding treatment (56.8% vs. 84.6% and 48% vs. 80.6%, respectively). Treatment-free intervals of ≥6 months between T-cell-redirecting therapies improved efficacy and survival. Post-BDT sequencing should prioritize CAR-T therapy when feasible, allow >6-month intervals before BDT re-challenge, and utilize non-BCMA targets for early relapse or BDT-refractory disease.

Background: Multiple myeloma (MM) has experienced rapid therapeutic innovation over the past two decades, leading to a substantial increase in clinical trial activity. However, the geographic distribution of these trials and the representation of different economic regions remain poorly characterized. We evaluated the global distribution, growth patterns, and phase-specific trends of MM clinical trials and trial sites across different economic settings. Methods: We conducted a retrospective registry-based analysis interventional MM clinical trials registered on ClinicalTrials.gov between January 2006 and January 2026. Trials were categorized based on the economic classification of participating countries using World Bank income groups and Economic Co-operation and Development (OECD) status. Trial characteristics including phase, geographic distribution, number of participating sites, and site-years were analyzed. Population-adjusted trial density and compound annual growth rates (CAGR) were calculated to assess temporal trends and geographic representation. Results: A total of 845 interventional MM clinical trials were identified during the study period. Trial activity was highest in the United States (337 trials, 39.9%), followed by international trials (271, 32.1%), high-income-OECD countries (129, 15.3%), and upper-middle-income countries (103, 12.2%), while high-income non-OECD countries contributed only a small fraction of trials. Trial activity increased substantially over time across all regions with the highest growth observed in upper-middle-income countries (CAGR 18.5%). The US demonstrated the highest population-adjusted trial density (0.99 per million population) and accounted for the largest number of trial sites and site-years. Phase-specific analyses revealed distinct geographic patterns. Phase 1 trials were predominantly conducted in the US and in international collaborative trials. Phase 3 trials were largely international, although the majority of participating sites remained located in the US and High-income countries that are members of the OECD (HIC-OECD). Conclusions: Over the past two decades, MM clinical trial activity has expanded globally but remains highly concentrated in the United States and high income-OECD countries, particularly with respect to trial sites and population-adjusted trial density. Although upper-middle-income countries have shown the fastest growth in trial activity expanding clinical trial infrastructure and strengthening international collaboration will be essential to promote a more equitable global distribution of MM research.