ABSTRACT:Belantamab mafodotin (belamaf), an antibody-drug conjugate targeting B-cell maturation antigen, has demonstrated single-agent activity in relapsed/refractory multiple myeloma (RRMM) but is associated with ocular toxicity. This phase 1/2 study evaluated the safety and preliminary efficacy of belamaf administered every 8 weeks in combination with carfilzomib, lenalidomide, and dexamethasone (KRd-b) in patients with RRMM. Eligible patients had received at least 1 previous line of therapy and had not progressed on full-dose lenalidomide. In the dose-escalation phase (3+3 design), belamaf was administered at 1.4 or 1.9 mg/kg every 8 weeks. The recommended phase 2 dose was 1.9 mg/kg, with no dose-limiting toxicities at this level. Among 19 patients treated, the overall response rate was 89.5%, and 78.9% achieved very good partial response or better, with minimal residual disease negativity in all complete responders. At a median follow-up of 19.3 months, 24-month progression-free survival and overall survival rates were 74.3% and 85.1%, respectively. Keratopathy occurred in 94.7% of patients but was mostly grade 1 to 2, reversible, and manageable without permanent discontinuation. Grade ≥3 keratopathy (31.6%) was comparable with historical rates despite the less frequent dosing. Other adverse events, including hematologic and gastrointestinal toxicities, were manageable and consistent with known profiles of KRd or belamaf. The combination demonstrated deep and durable responses, including in patients at high-risk and with lenalidomide maintenance dose-refractory disease. These results support the feasibility of KRd-b with extended-interval belamaf and warrant further evaluation in phase 2 trials to confirm its clinical benefit in RRMM. This trial is registered at www.clinicaltrials.gov as NCT04822337.

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.

Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated remarkable efficacy in RRMM, but some patients experience early relapse. Identifying these patients is critical to guide therapeutic strategies. Methods In this multi-center study, outcomes were evaluated by high-risk (HR) features: functional HR (FHR; relapse ≤18 months of first-line therapy), extramedullary disease (EMD), traditional HR [del 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (del 17p; t(4;14) or t(14;16) with gain 1q or del 1p; gain 1q with del 1p). Multivariable Cox regression was used to examine association of HR features with PFS, adjusting for ferritin, prior BCMA, and ECOG PS ≥2. Predictors of early relapse (≤18 months post infusion) were assessed with logistic regression. Results Among 598 patients treated with cilta-cel, median age was 65 (range 33-83) and median pLOT was 5 (range 1-18, 84% with >3 pLOT). FHR was present in 33%, traditional HR in 43%, adapted IMS HR in 42%, and EMD in 11%. Median follow-up was 10.6 months. ORR and CR rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS HR (ORR: 91% vs 94%, CR: 64% vs 75%), and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS HR (61% vs 80%), and EMD (59% vs 73%). ORR, CR, and 12-month PFS in patients without any HR features vs those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%. In multivariable models, each HR feature (FHR, adapted IMS HR, and EMD) was independently associated with inferior PFS after adjusting for ferritin, prior BCMA, and ECOG PS.However, because early relapse cannot always be identified a priori, we sought to identify predictors of relapse within 18 months of cilta-cel. Notably, FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse ≤18 months, while EMD was not (OR=0.90, 95% CI=0.32, 2.40). We also used a time-varying Cox model to examine the association of each HR feature with PFS at <18 and ≥18 months, while adjusting for the same covariates. FHR and adapted IMS HR were associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion Despite durable responses with cilta-cel, patients with FHR and adapted IMS HR remain at increased risk for early relapse. These findings inform risk-adapted therapeutic strategies to improve outcomes in HR RRMM.

Introduction: Patients (pts) with soft tissue plasmacytomas noncontiguous with bone (true extramedullary disease [EMD]) have poor outcomes with standard therapies shown by low overall response rates (ORRs), which are not durable. Talquetamab (Tal; anti-GPRC5D×CD3) and teclistamab (Tec; anti-BCMA×CD3) are first-in-class bispecific antibodies (BsAbs) approved as monotherapies for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM). Primary analysis from the RedirecTT-1 (NCT04586426) dedicated phase 2 EMD cohort (March 2025 data cut; median follow-up [mFU] 12.6 mo) showed Tal + Tec elicited an ORR of 78.9% (assessed by independent review committee) and a 12-mo progression-free survival (PFS) of 61.0%. Here, we report updated efficacy, using investigator assessment, and safety results from the phase 2 RedirecTT-1 EMD cohort with Tal + Tec. Importantly, we report EMD location and a novel analysis of tumor burden as a prognostic indicator of ORR. Methods: Pts had TCE RRMM and true EMD defined as ≥1 nonradiated soft tissue plasmacytoma noncontiguous with bone ≥2 cm in 1 dimension (with or without paramedullary plasmacytomas). Nonsecretory/oligosecretory disease was permitted. Prior CAR-T and non-BCMA/-GPRC5D BsAb therapies were permitted. Pts received Tal 0.8 mg/kg + Tec 3.0 mg/kg Q2W, preceded by step-up doses, with a permitted switch to monthly dosing at investigator's discretion after cycle 6 or after cycle 4 with confirmed ≥VGPR. Response was assessed per IMWG; EMD response was assessed by PET-CT or MRI whole-body scans. Tumor burden was assessed by total EMD tumor volume. Results: As of July 2025, 90 pts received Tal + Tec, with a median follow-up of 16.3 mo (range 0.5–23.7). Baseline characteristics were as previously reported; 39% had nonsecretory/oligosecretory disease, 20% had prior anti-BCMA CAR-T therapy, and 9% had prior BsAb therapy (all anti-FcRH5). The median number of plasmacytomas was 2 (range 1–7); 17 (18.9%), 29 (32.2%), and 74 (82.2%) pts, respectively, had ≥1 nodal, organ, or soft tissue EMD, while 11 (12.2%) also had ≥1 additional paramedullary plasmacytoma. Of 268 EMDs across all pts, 95 (35.4%) were nodal EMD, 77 (28.7%) were organ EMD (most commonly liver), and 64 (23.9%) were soft tissue EMD; 32 (11.9%) were paramedullary. Baseline EMD tumor volume was <25 cm2in 43 (47.8%) pts, 25–50 cm2 in 21 (23.3%) pts, and >50 cm2 in 26 (28.9%) pts. Per investigator assessment, ORR (95% CI) was 77.8% (67.8–85.9); 50.0% had a ≥CR. Median duration of response (DOR) was not estimable (NE; 12-mo DOR rate, 60.1%), 12-mo PFS was 55.6%, and median overall survival (OS) was NE (12-mo OS rate 73.8%). ORR was 90.7% (77.9–97.4; ≥CR 60.5%) in pts with EMD tumor volume <25 cm2, 66.7% (43.0–85.4; ≥CR 52.4%) for 25–50 cm2, and 65.4% (44.3–82.8; ≥CR 30.8%) for >50 cm2. Common adverse events (AEs) included CRS (77.8%; no grade [gr] 3/4) and neutropenia (72.2%; gr 3/4 62.2%). Taste changes (78.9%), non-rash skin AEs (68.9%), and nail AEs (55.6%) were all gr 1/2, and rash AEs (30.0%) were mostly gr 1/2. ICANS occurred in 11 (12.2%) pts (gr 3, 1.1%; gr 4, 1.1%). Infections occurred in 72 (80.0%) pts (gr 3/4 40.0%), most commonly upper respiratory tract infection (26.7%; gr 3/4 5.6%); IVIG was highly recommended to prevent and manage hypogammaglobulinemia and infection. Ten (11.1%) pts discontinued Tal + Tec due to treatment-emergent AEs (4 pts due to infections and 6 due to gr 5 AEs). Two pts discontinued Tal only due to AEs. In total, 11 (12.2%) pts had gr 5 AEs (6 due to infections), 6 of which were deemed to be drug related by investigators. Data will be updated with an additional 4 mo of follow-up for the presentation. Conclusions: With longer follow-up in pts with TCE RRMM with true EMD regardless of baseline tumor characteristics, Tal + Tec efficacy exceeded all approved therapies, including T-cell redirecting and cellular therapies, noting limitations of cross-study comparisons. Lower total EMD tumor volume was associated with a higher ORR but low pt numbers in each group and lack of statistical testing limits robust interpretation. The safety profile of Tal + Tec was generally consistent with each monotherapy; AEs were not exacerbated with the combination. These data continue to highlight the clinical benefit of the novel combination of Tal + Tec in pts with true EMD, a population with high disease burden and significant unmet need.

Introduction: Talquetamab (tal), a GPRC5D-targeting bispecific antibody (bsAb), is approved for treatment of relapsed/refractory multiple myeloma (RRMM). CRS is commonly associated with tal, occurring in up to 80% of patients in the MonumenTAL-1 study. According to IMWG guidelines, tocilizumab (toci) is recommended for treatment of grade 1 and 2 CRS prior to the use of dexamethasone (dex). We conducted a multicenter retrospective study to evaluate the safety and efficacy of dex for CRS management in patients receiving tal. Methods: Seven academic medical centers contributed data on 211 patients with RRMM receiving commercial tal. Patients received pre-medication and step-up dosing (SUD) per package insert. Toxicity management and supportive care followed institutional protocols. CRS and ICANS were graded per ASTCT criteria. Toci was dosed at 8 mg/kg (max 800 mg) and individual dex doses varied by institution (range 4-20 mg). Responses were assessed using IMWG criteria. Outcomes included incidence and severity of CRS events, CRS recurrence, need for additional intervention, treatment delay, and overall response rate (ORR). Results: Among the 211 patients included, median age was 66 years (range 34-87), 18% were Black, and 55% were male. The median number of prior lines of therapy was 6 (range 2-14). Eighty-seven percent were triple-class refractory and 47% were penta-refractory. One hundred twenty-six patients (60%) received prior BCMA-directed therapy with 76 (36%) receiving a prior bsAb. Tal was used as bridging therapy in 53 patients (35%). Most patients (91%) received biweekly tal after SUD and 27 (13%) received prophylactic toci. CRS occurred in 129 (61%) patients, with 43% experiencing grade 1 and 16% grade 2. Two and one patients experienced grade 3 or 4 CRS, respectively. CRS occurred after the first (17%), second (27%), third (29%), and first full dose (7%). Fifty-three patients (25%) experienced a SUD delay due to CRS (median 1 day, range: 0.5-15) and 39 (18%) experienced recurrent CRS after a subsequent SUD. The median duration of CRS was 1 day (range 0-8). ICANS occurred in 29 patients (14%). Of the 129 patients who experienced CRS, dex was the first intervention in 46 patients (36%), toci in 42 (33%), and supportive care (antipyretics, hydration, oxygen) in 37 (29%). Four (3%) received dex + toci simultaneously. Among those receiving dex first, 11 patients experienced concurrent ICANS. The median dose of initial dex was 10 mg. Among 27 patients who received prophylactic toci, CRS occurred in 14 (52%) of patients, primarily grade 1. Within the dex treatment first group, 33 patients (72%) had grade 1 CRS and 11 (24%) had grade 2 CRS. In the toci-first group, 21 patients (50%) had grade 1 and 20 (48%) had grade 2 CRS. Among those who received dex-first, CRS resolved following a single dex dose in 21 patients (46%), with repeat dex doses in 10 patients (22%), a subsequent toci dose in 12 patients (26%), and multiple toci doses in 2 patients (4%). One patient with grade 1 CRS in the dex-first group died after SUD 2 due to respiratory failure vs PE. Of those who received toci treatment first, CRS resolved following a single toci dose in 30 patients (71%), repeat toci doses in 5 (12%), a single dex dose in 2 (5%), and repeat dex doses in 5 (12%). Median duration of SUD delay (1 day, p=0.96) and incidence of delay were similar (48% vs 35%, p=0.28) in the toci and dex groups, respectively. While CRS recurrence after a subsequent SUD was more common in the dex-first group (50% vs. 14%, p=<0.005), repeat events were all grade 1 or 2 and resolved with repeated dex and/or the addition of toci. At a median follow-up of 9.2 months, the ORR of all patients was 77%, with 50% of patients achieving a very good partial response (VGPR) or better. Median PFS and OS were 7.6 and 17.7 months in the entire group and 6.1 and 16.4 months when excluding patients who received tal as bridging prior to CAR T. Best ORR was similar (86% vs 90%, p=0.74) between dex and toci groups and overall population of 77%. Conclusion: Although more patients in the dex-first group experienced recurrent CRS, recurrent CRS was low grade and manageable. When compared to the toci group, the dex group had similar efficacy outcomes. Considering potential advantages of utilizing dex over toci with respect to availability and cost, this study highlights the feasibility of dex for the management of grade 1 or 2 CRS in patients receiving tal.

OBJECTIVE:To compare the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between two different step-up dosing (SUD) schedules with talquetamab, the standard SUD schedule of Days 1, 4, 7, and 10 and a condensed SUD schedule of Days 1, 3, 5, and 7. METHODS:We conducted a multicenter retrospective study across seven academic medical centers in the United States and included patients who received talquetamab for the treatment of relapsed/refractory multiple myeloma. The incidence and grade of severity of CRS and ICANS were compared between patients receiving the standard SUD schedule and the condensed SUD schedule. RESULTS:A total of 144 patients were included in our analysis; 33 received the standard SUD schedule and 111 received the condensed SUD schedule. The incidence of CRS (76% vs. 56%; p = 0.101) and ICANS (9% vs. 16%; p = 0.41) was similar between the standard and condensed SUD cohorts. There was no significant difference in the severity of CRS and ICANS between both cohorts. CONCLUSION:Shortening the interval between talquetamab SUDs appears feasible and well-tolerated in routine clinical practice.

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:Primary plasma cell leukemia (pPCL) represents the most aggressive plasma cell dyscrasia with a poor prognosis and survival of <3 years. The International Myeloma Working Group (IMWG) adopted more inclusive diagnostic criteria for pPCL in 2021, including patients with 5% or more circulating plasma cells (down from 20%). Most published studies of pPCL do not include patients who meet the criteria for pPCL based on the newer diagnostic guidelines, and the data on the optimal treatment of pPCL is scarce. In our multi-center retrospective analysis, we report data on treatment regimens used in 67 pPCL patients to characterize outcomes in this population. METHODS:We included patients with newly diagnosed pPCL between 2010 and 2023 based on the 2021 IMWG definition at one of three academic centers. RESULTS:Our results suggest significant improvement in overall response rate (ORR) and progression-free survival (PFS) with the use of autologous stem cell transplant, but without additional benefit for a tandem transplant. The presence of high-risk cytogenetics was an independent risk factor for progression in the cohort. CONCLUSIONS:Our dataset represents one of the largest cohorts to date using the expanded definition of pPCL adopted by the IMWG in 2021 and stresses the importance of taking pPCL patients to transplant. Unfortunately, our study was not powered to determine the efficacy of individual induction and maintenance regimens, and many patients diagnosed with pPCL are ineligible for transplant based on end-organ damage at diagnosis or from disease that is refractory to induction therapy, underscoring the need for early diagnosis and treatment in hopes of preserving transplant eligibility.

INTRODUCTION:Patients with relapsed/refractory multiple myeloma (RRMM) now receive sequential lines of therapy over many years, generating cumulative toxicities, functional decline, and symptom burden that conventional trial endpoints and episodic clinic-based monitoring fail to capture. A synthesis of contemporary real-world monitoring strategies in RRMM is therefore needed to guide clinical practice. AREAS COVERED:This review examines real-world monitoring strategies for RRMM, encompassing patient-reported outcome (PRO) instruments, real-world data (RWD) sources (electronic health records, claims, registries, patient-driven platforms), and digital health technologies enabling continuous between-visit assessment. Literature was identified through structured searches of PubMed and MEDLINE from January 2000 through April 2026, supplemented by manual review of reference lists and abstracts from major hematology meetings. We evaluate how these strategies complement conventional disease assessment, inform treatment sequencing in the era of CAR T-cell therapies and bispecific antibodies, and address equity gaps in monitoring access. EXPERT OPINION:Integrating PROs, RWD, and digital health tools into routine RRMM care is a necessary evolution toward continuous, personalized disease management; coordinated investment in interoperable data infrastructure, rigorous real-world evidence frameworks, and equity-conscious implementation will be essential to translate these strategies into improved survival and quality of life for all patients.

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.

Talquetamab, a GPRC5D-targeting bispecific antibody, shows promising activity in relapsed-refractory multiple myeloma. However, real-world outcomes in patients with extramedullary disease (EMD) remain poorly described. We studied 360 patients treated with talquetamab at 15 U.S. centers by Dec 2024. Soft tissue plasmacytomas (STP) were classified as EMD (not contiguous with bone) or paraskeletal disease (PSD; contiguous with bone). If both were present, patients were assigned to the EMD category. Of those, 97 (27%) had EMD, 22 (6%) had PSD, and 241 (67%) had No-STP. Median follow-up was 12.8 months. Overall response rates were 68% in EMD, 63% in PSD, and 65% in No-STP (p = 0.8). Median progression-free survival was 4.3, 4.5, and 7.8 months, respectively (p = 0.009), and median overall survival was 10.3 months, 13.0 months, and not reached (p = 0.070). These findings demonstrate that EMD and PSD are associated with preserved response rates but shorter PFS and OS with talquetamab. While systemic markers of tumor burden and inflammation—particularly lactate dehydrogenase (LDH) and ferritin—emerged as independent predictors of inferior PFS, elevated LDH also retained independent prognostic significance for OS. While EMD was associated with shorter PFS and OS on univariate analysis, it did not retain independent prognostic significance on multivariable analysis, suggesting that inferior outcomes are driven by aggressive disease biology rather than by lesion anatomy alone. These findings are hypothesis-generating and require prospective validation. Talquetamab retains clinical utility in this high-risk population with EMD, though outcomes are suboptimal with a need for further refinement of treatment approaches.

Background Corticosteroids (CS) are frequently used to manage CAR-T-related toxicities, yet their optimal dosing, cumulative exposure and clinical consequences remain uncertain. Methods We retrospectively evaluated 417 commercial BCMA CAR-T (n=230 ide-del, n=187 cilta-cel) recipients (5/2021-12/2024) at two academic centers. Patients were grouped by CS exposure within 30 days post infusion (CS, n=154) vs. none (NCS, n=263); CS patients were stratified by cumulative dex dose equivalents (mg): low=LD (£60, n=106), intermediate=ID (61-200, n=32), and high=HD (>200, n=16). Baseline features, toxicities, infections, and PFS/OS were compared. Results Baseline differences included higher BM plasma cell burden >50% in CS vs. NCS (33.8% vs 11.8%; p<0.001), inferior response to bridging (8.7% vs. 16.8;p=0.04) and a higher baseline ferritin (336 vs 180;p<0.05). Rates of HR cytogenetics, prior LOT and R-ISS stage distribution were similar. The median dex equivalent dose (mg) was 10 (range: 10-60) in the LD group, 110 (range: 70-180) in the ID group, and 395 (range: 204-1485) in HD group. EMD was more prevalent (43.8%) with higher baseline ferritin (670, range: 27-9,215) in the HD dex group. Use of tocilizumab/anakinra occurred more frequently in CS patients. Toxicity pattern showed clear dose dependence with HD dex group exhibiting greater rates of Gr ³3 CRS (18.8%), Gr ³3 ICANS (43.8%) and IEC-HS (31%) compared to LD and NCS groups (all p<0.05). Infections by day 100 were similar overall for CS vs. NCS (any infection 43.5% vs 43.3%; p=0.97) although bacterial infections were highest in the HD group (50.0%). Non-ICANS NT occurred in 9 patients in the CS (2 Parkinson and 7 CN palsies) and in 8 patients in the NCS (1 Parkinson, 1 CIDP, 6 CN palsies) groups. Day 30 responses were comparable between CS and NCS (ORR 66% vs 56%, CR 27.9% vs 28.5%). After a median F/U of 40.7 mo, mPFS was 15.8 mo for CS vs 17.9 for NCS (p=0.19), whereas OS favored the CS cohort (40.7 vs NR, p=0.037). Within the CS group, survival declined sharply with cumulative steroid dose; median PFS 21.2, 9.4 and 1.7 mo, and OS NR, 28.7 and 3.6 mo for LD, ID, and HD groups (global p<0.0001). The non-relapse mortality (NRM) rate was 4.6% and 11.0% in the NCS and CS groups, respectively. In the HD group, the death rate was high at 68.8% (11 deaths: 2 myeloma, 3 infections, 1 IEC-HS, 3 ICANS, 1 CRS, 1 NINT). Conclusion CS use in general within 30 days of CAR-T did not compromise PFS or disease control, however, inferior outcomes in the HD subgroup were attributable to greater inflammatory burden, higher rates of infections and NRM in addition to direct steroid effect. These findings indicate that CS requirement and cumulative dose exposure is a surrogate for severe toxicity. Utilization of lowest and shortest duration of steroids should be encouraged, supporting selective toxicity-guided steroid use in BCMA CAR-T recipients to avoid inferior outcomes.

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) is a hematologic malignancy characterized by the clonal proliferation of plasma cells and a rapidly evolving treatment landscape. Bispecific antibodies targeting B-cell maturation antigens (BCMA) have emerged as promising therapeutic options for relapsed and/or refractory multiple myeloma (RRMM). METHODS:This retrospective study evaluated the efficacy and safety of teclistamab, a BCMA-directed bispecific antibody, in patients with RRMM with renal impairment (RI) at baseline compared to those without. Conducted across seven academic centers, the study included 195 patients with RRMM, of whom 34 had baseline RI. RESULTS:Performance status, previous lines of treatment, and prior BCMA exposure were identified as significant predictors of progression-free survival. Notably, patients with RI demonstrated overall response rates and toxicity profiles comparable to those without RI, although they required more packed red blood cell transfusions. No statistically significant differences were observed in adverse events, including cytokine release syndrome and infections. CONCLUSIONS:Overall, the findings support the efficacy and safety of teclistamab in patients with RRMM and RI, highlighting the need for prospective clinical trials to optimize the treatment strategies for this population.

BACKGROUND:Patients aged ≥ 70 years with relapsed/refractory multiple myeloma (RRMM) face unique challenges due to physiological changes and increased toxicity from treatments. Daratumumab-based regimens have shown efficacy, but direct comparisons in elderly populations are lacking. METHODS:A multicenter retrospective study compared daratumumab, pomalidomide, and dexamethasone (DPd) to daratumumab, carfilzomib, and dexamethasone (DKd) in patients with RRMM aged ≥ 70 years. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and response rates. RESULTS:The study included 150 patients (119 DPd, 31 DKd). Baseline characteristics were similar, but DPd had more lenalidomide-refractory patients (90% vs. 74%, p = 0.035). Overall response rates were comparable (DPd 77%, DKd 74.5%, p = 0.8), but DKd had a significantly higher rate of deep responses (64.5% vs. 36%, p < 0.01). Median PFS was 12 months for DPd and 13 months for DKd (p = 0.6); median OS was 50 months for DPd and 28 months for DKd (p = 0.2). Multivariate analysis identified poor performance status and high-risk cytogenetics as adverse prognostic factors. CONCLUSION:DPd and DKd showed similar efficacy for elderly RRMM patients, with DKd achieving deeper responses. Treatment decisions should consider individual patient factors rather than focusing solely on efficacy differences.

Introduction Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors for DNT and NRM may aid risk mitigation and clinical decision making. Methods In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM, were evaluated by univariable and multivariable analysis. NRM events post-disease progression were censored. Results The median age was 65 (range: 30-88) with median prior lines of therapy (pLoT) being 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLoT) in 16% of patients. High-risk cytogenetics (del 17p, t(14;16), t(4;14)) were present in 39%, with extramedullary disease (EMD) in 27%, and R-ISS stage III in 18%. 86% patients received bridging therapy, with ≥ partial response seen in 33%; median follow-up was 10.1 months, response rate was 92%, and CR rate was 70%.DNT was seen in 10% of patients: Parkinsonism (2.9%, n=22), cranial nerve palsy (4.6%, n=35), other DNT (2.4%). Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, p<0.05). Of 22 Parkinsonism cases, 21 (95%) did not respond to bridging despite achieving post-CAR-T response (ORR 91%, ≥ CR 68%).Absolute lymphocyte count (ALC) was higher in patients with DNT, especially Parkinsonism (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism: 5.88 vs 1.17/uL (p<0.001). Evaluating Parkinsonism risk with ALC thresholds: peak ALC > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19%, > 3000/uL: 68% vs 14% (p<0.001). Absolute Parkinsonism risk with ALC > 3000 vs ≤ 3000/uL: 12% vs 1%, p<0.001; ALC > 2500 vs ≤ 2500uL: 9% vs 1%, p<0.001. Multivariable analysis identified peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) as independent risk factors for Parkinsonism.NRM estimates at 1 and 2 year were 9% and 10% respectively, with infection complications being the most common cause (56%), followed by immune-mediated acute AEs (22%), delayed AEs like DNT and colitis (9.5%), second cancers (8%), and other causes (5%). Multivariable analysis identified non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics, and age ≥ 70 years as independent NRM predictors. Conclusion In a large cohort, we identified potentially modifiable predictors for Parkinsonism and NRM, including non-response to bridging therapy and peak ALC > 3000/uL for Parkinsonism. Peak ALC could be a biomarker to identify patients for interventions. Effective bridging strategies are needed to decrease Parkinsonism and NRM risk with cilta-cel.

ABSTRACT:Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell-redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as active (≥5% circulating plasma cells within 30 days before BsAb initiation) or historical. Patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging to CAR T-cell therapy (Tal Bridge, 11%). Cytokine release syndrome was grade 1 to 2 in 56% and grade 3 to 4 in 4% of patients, whereas neurotoxicity was grade 1 to 2 in 16% and grade 3 to 4 in 5% of patients. The overall response rate was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS values of 1.2 and 1.6 months and mOS values of 8.1 and 3.6 months, respectively (P = .007, P = .023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months vs 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P< .001, P = .002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were well tolerated in PCL, with talquetamab showing superior outcomes compared with B-cell maturation antigen-directed BsAbs.