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: 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.

Background: Carfilzomib, a second-generation proteasome inhibitor, is widely used in multiple myeloma (MM) treatment but has been associated with cardiovascular adverse events (CVAEs). Real-world data evaluating the incidence and risk factors are limited. Methods: We conducted a multicenter retrospective cohort study of 385 adult MM patients treated with carfilzomib between January 2020 and August 2024 at three U.S. institutions. The primary objective of this study was to determine the incidence of carfilzomib-associated CVAEs. The secondary objectives included the identification of risk factors, characterization of cardiovascular events, and time-to-onset analysis. Results: Carfilzomib-associated CVAEs occurred in 25 patients (6.5%). The median time to event was 114 days. Heart failure was the most common manifestation (86%), followed by arrhythmias (32%) and acute coronary syndromes (8%). Patients with baseline heart failure had a significantly increased risk of CVAEs (HR 1.61, p = 0.042), whereas arrhythmias showed a trend toward significance. Traditional cardiovascular risk factors were not independently associated with an increased risk. CVAEs were associated with numerically inferior overall survival (45.7 vs. 97.3 months; HR 1.316, 95% CI 0.728–2.377, p = 0.361). Partial recovery of the left ventricular ejection fraction was observed following treatment discontinuation. Conclusion: Carfilzomib-associated CVAEs were infrequent but clinically meaningful in this multicenter cohort. These findings support consideration of a risk-adapted cardio-oncology approach, particularly in patients with pre-existing cardiac dysfunction, where closer surveillance and early intervention may help mitigate clinically significant cardiotoxicity.

Background: Several B-cell maturation antigen (BCMA)-directed therapy (BDT) modalities have been approved by the US Food and Drug Administration (FDA) for relapsed-refractory multiple myeloma (RRMM). Ideal sequencing of these therapies remains unknown. Methods: We report one of the largest multicenter retrospective patient cohorts in this real-world analysis of patients receiving a BDT in both BDT-naïve and exposed settings at major academic centers. Results: In the BDT-naïve setting, which included 276 patients, 169 (61%) received chimeric antigen receptor T-cell therapy (CAR-T), whereas 107 (39%) received bispecific antibodies (BsAbs). Median progression-free survival (PFS) in the BDT-naïve setting was significantly longer with CAR-T than with BsAbs (16.1 vs. 13.5 months, p = 0.007) with a higher overall response rate (ORR) (87 vs. 68%). Multivariable Cox regression analysis revealed that receiving CAR-T (hazard ratio [HR] = 0.41), cytokine release syndrome (CRS) of any grade (HR = 0.50), achieving a best response of ≥very good partial response (VGPR) (HR = 0.12), and high-risk cytogenetic abnormalities (HRCA) (HR = 2.29) were all significant prognostic indicators of PFS. Similarly, HRCA (HR = 2.32), CRS (HR = 0.36), and a best response of ≥VGPR (HR = 0.16) were all independent prognostic factors of overall survival (OS). Of the 80 patients who received prior BDT, 22 received CAR-T (28%) and 58 (72%) received BsAbs. The median PFS was 6.3 months in the CAR-T group, with 64% ORR, vs. 4.4 months in the BsAb group, with 53% ORR (PFS HR, 0.93). Only the best response, ≥VGPR (HR = 0.20), achieved significance in the multivariable model. Conclusions: CAR-T led to more durable responses in the BDT-naïve setting than BsAbs. Responses to either modality were weaker in the BDT-exposed setting. These results highlight the importance of sequencing BDT in RRMM.

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.