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.

Extramedullary myeloma with pulmonary and pleural involvement is rare and can present in different ways. Here we present two cases of extramedullary pulmonary disease in relapsed/refractory multiple myeloma. Background: Multiple myeloma remains an incurable disease with unmet need for new treatments for high-risk disease such as extramedullary plasmacytoma. Relapses can occur at different stages due to the heterogeneity of the disease. While relapsed/refractory disease can be challenging to treat, progression can also lead to extramedullary disease which indicates an aggressive form with poor outcomes. Pulmonary extramedullary disease can present in various ways, such as a lung mass, parenchymal infiltrates, pleural mass, or pleural effusion. Objective: Our case series highlights two different presentations of pulmonary extramedullary disease and a review of the treatment of relapsed/refractory myeloma. Our patients highlight the progression of their multiple myeloma due to the aggressive nature of their extramedullary disease. Their cases emphasize the importance of new targeted treatments to treat extramedullary disease and penta-refractory disease as there is no currently accepted standard regimen for this difficult to treat condition.

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: 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.

Background: Lenalidomide maintenance after autologous stem cell transplantation (ASCT) improves progression-free survival (PFS) and overall survival (OS) in multiple myeloma; however, these benefits are attenuated in high-risk multiple myeloma (HRMM). No standard post-transplant maintenance strategy is established for HRMM, and some centers employ doublet maintenance with bortezomib plus lenalidomide (VR). We evaluated outcomes with VR versus lenalidomide alone (R) in HRMM. Methods: We conducted a multicenter retrospective study through the US Myeloma Innovations Research Collaborative (USMIRC), including adults with HRMM who received R or VR maintenance following ASCT between January 2009 and January 2024. HRMM was defined by del(17p), t(4;14), t(14;16), or t(14;20), with or without 1q gain. PFS and OS were estimated using Kaplan–Meier methods. Median follow-up was 91 months. Baseline characteristics, induction regimens, and post-transplant response depth were well balanced between the groups. Median PFS was 51 months (95% CI, 20–NR) with VR and 36 months (95% CI, 31–56) with R (p > 0.05). Median OS was 103 months (95% CI, 90–NR) and 110 months (95% CI, 94–NR), respectively (p > 0.05). VR was associated with numerically longer PFS, although the difference was not statistically significant. No treatment-related mortality occurred within 100 days post-ASCT. Conclusions: In this multicenter real-world analysis of HRMM, VR maintenance did not result in statistically significant improvements in PFS or OS compared with lenalidomide alone. These findings underscore the need for prospective, risk-adapted trials incorporating novel maintenance strategies, including CD38- and BCMA-directed therapies, in high-risk disease.