Background B cell repertoire reconstitution following autologous stem cell transplant (SCT) may influence risk of infection and relapse. Minimal residual disease (MRD) testing in multiple myeloma (MM) utilizes next generation sequencing assay to measure clonal frequency of immunoglobulin heavy (IgH) and light chain loci (kappa, KLC and lambda, LLC). In this study, unique IgH, KLC and LLC sequence frequencies reported as a part of MRD testing (ClonoSEQ, Adaptive Biotechnologies) were analyzed in autologous SCT recipients with multiple myeloma. Methods Bone marrow biopsy aspirate samples were collected prior to SCT, at approximately 100 days and one year post-transplant to measure MRD. We analyzed the number of unique IgH, KLC and LLC sequences (clones) reported at these time points and examined trends over time using T test, repeated measures ANOVA, and Spearman’s rank correlation. Results From February 2023 to June 2024, 54 MM patients underwent SCT; 23 patients had high risk disease and median age was 65 years. The median unique IgH sequences pre-transplant, at day 100 and 1 year post-transplant were 15691, 174375 and 123455 sequences, respectively (P < 0.001 for pre-transplant to day 100, P < 0.01 for day 100 to 1 year) (Figure 1). KLC and LLC sequences exhibited similar trends over time, with the median ratios of K/L sequences of 3.6, 2.7 and 2.9 respectively at these times.Consistent post-transplant recovery in the number of unique IgH, KLC, and LLC sequences was seen at day 100, with three different patterns of reconstitution observed when classified by the magnitude on day 100 measurement (RMANOVA P < 0.001) (Figure 2). Administration of CD38 MoAb pre-transplant was associated with lower IgH diversity (RMANOVA P = 0.012) (Figure 3). Age, disease risk, lines of prior therapy, CD34+ cell dose administered and CD38 MoAb given in maintenance did not have a significant effect on B cell recovery. A statistically significant difference in MRD reduction at one year is not evident between the patients with different IgH sequence recovery kinetics. Day 100 IgH sequences correlated with day 180 IgM levels (Spearman’s rank correlation coefficient 0.5). Conclusion Using readily available data in MRD testing reports, significant B cell receptor recovery was observed at 3 months following SCT for MM. The magnitude of clonal IgH sequence reconstitution is potentially impacted by pre-transplant administration of CD38 MoAb. Measuring IgH diversity as a part of next generation sequencing testing is an immunologically relevant biomarker for measuring post-transplant immune recovery. This will be especially germane in standard risk myeloma comparing patients treated with SCT versus CAR T cells where B cell aplasia, impaired vaccine response and infections are common.

Introduction The Endothelial Activation and Stress Index (EASIX), calculated as (creatinine [mg/dL] × LDH [U/L]) / platelets [10⁹/L], reflects endothelial dysfunction and has been associated with toxicities in T-cell–redirecting therapies. The modified EASIX (m-EASIX), replacing creatinine with CRP, has shown predictive value for severe cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in CAR T–cell therapy. We evaluated whether dynamic changes in m-EASIX predict CRS in patients (pts) with RRMM treated with talquetamab (talq). Methods We retrospectively analyzed 25 pts who received talq at a single center by Dec 2024. Talq step-up dosing was given on Days 1, 3, 5, and 7. Daily CRP and m-EASIX were tracked for 9 days, from the first dose through 48 hours post–treatment dose. We evaluated m-EASIX rise as a CRS predictor using a 2 × 2 diagnostic model: true positive (rise before/coinciding with CRS, n=12), true negative (no rise/CRS, n=1), false positive (rise without CRS, n=6), and false negative (rise after CRS, n=2). Sensitivity, specificity, PPV, and NPV were calculated and analyzed on SPSS v29. Results Median age was 66 years (range, 48–86). Eighty percent (20/25) had high disease burden. BCMA-directed bispecific antibody (BsAb) exposure occurred in 64% (16/25), with a median interval of 18.5 days (range, 3–207) from prior BCMA BsAb therapy to talq initiation. CRS occurred in 16/25 (64%) pts: 12 (48%) Grade 1, 2 (8%) Grade 2, and 9 (36%) without CRS. Median CRS onset was Day 3 from first talq infusion (range, 2–6). ICANS occurred in 5/25 (20%) pts—3 overlapped with CRS, and 2 occurred independently (1 patient had recent cranial radiation preceding to talq; 1 with concurrent subdural hematomas post talq). In evaluable pts (n=21) m-EASIX rise typically preceded or coincided with CRS onset, with only a minority showing delayed rise. The model demonstrated sensitivity 85.7%, specificity 14%, PPV 67%, and NPV 33%. Pearson correlation analysis showed a significant positive association between the day of m-EASIX rise and CRS onset (r=0.6, p=0.019; 95% CI, 0.14–0.89). Among pts with m-EASIX rise but no CRS (n=6), potential explanations included low disease burden (2/6), cytokine suppression due to concurrent high-dose steroids or hemodialysis (2/6), and recent BCMA BsAb exposure within 28 days (2/6). While the median interval from prior BCMA therapy did not differ between CRS and non-CRS groups, CRS occurred in 89% (8/9) of BCMA BsAb-naïve vs. 50% (8/16) of not-exposed pts (p=0.08). The best overall response rate (ORR) was 80% (12/15) in those with CRS vs. 50% (4/8) without CRS. Conclusion Dynamic m-EASIX rises are sensitive but nonspecific for CRS during talq step-up dosing. Combining m-EASIX kinetics with disease burden may aid early toxicity detection and guide supportive care and outpatient management, including pre-emptive tocilizumab or steroids.

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 Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are BCMA CAR-T products approved for relapsed/refractory multiple myeloma in 2021 and 2022, respectively, with distinct safety profiles. Objective In the absence of head-to-head trials, use CIBMTR data to compare safety and efficacy of ide-cel and cilta-cel in real-world patients (pts). Methods We included pts who received commercial ide-cel (May 2021–Aug 2023) or cilta-cel (Apr 2022– Dec 2023) with adequate follow-up. We used inverse probability of treatment weighting (IPTW) to reduce confounding and balance baseline characteristics. We used logistic and Cox regression models for multivariable analyses. Results Of 1581 pts, 595 received cilta-cel and 986 ide-cel. Baseline characteristics were somewhat similar, except cilta-cel cohort had lower comorbidity burden, better performance status, less extramedullary disease, less BCMA therapy, and less penta-exposed disease, while a greater proportion achieved ≥ partial response at infusion (Table 1). Median follow-up of survivors was 12.0 months (range 1.1–25.4) for cilta-cel and 12.9 months (range 1.4– 34.6) for ide-cel. Cilta-cel had statistically lower any-grade CRS; grade ≥3 was similar. Any-grade ICANS was less common in cilta-cel; grade ≥3 was similar. 6- and 12-month treatment-related mortality (TRM) were statistically similar. After IPTW adjustment, cilta-cel retained lower odds of any-grade CRS [odds ratio (OR) 0.72, p=0.0004)] and any-grade ICANS (OR 0.75, p = 0.0005), but higher odds of grade ≥3 CRS (OR 1.50, p = 0.041) and no difference in grade ≥3 ICANS (OR 0.97, p = 0.8). The unadjusted cilta-cel cohort experienced 5% non-ICANS neurologic events: Parkinsonism (2.7%) and cranial nerve palsies (2.5%), most commonly the facial nerve (12/15); ide-cel incurred no such events. At 12 months, cumulative overall response (ORR) and complete response (CR) were higher in cilta-cel (Table 1). One-year progression-free survival (PFS, Figure 1) and overall survival (OS) favored cilta-cel. After IPTW adjustment, cilta-cel retained higher odds of ORR (OR 1.68; 95% CI, 1.48–1.90; p < 0.0001), CR (OR 1.72; 95% CI, 1.39–2.11; p < 0.0001), PFS (hazard ratio [HR] 0.47; 95% CI, 0.41–0.53; p < 0.0001), and OS (HR 0.82; 95% CI, 0.70–0.95; p = 0.016). Conclusions In this largest real-world comparison to date, cilta-cel showed deeper responses and improved PFS/OS but was associated with more delayed neurotoxicity—highlighting the need for optimized patient selection and proactive risk mitigation strategies.

Prolonged cytopenias are a well-recognized complication following CAR-T therapy. Autologous SCB offers a potential strategy to promote fast hematologic recovery. We conducted a retrospective multi-institutional comparing outcomes of SCB versus supportive care alone in patients with prolonged cytopenias after CAR-T infusion. Patients were included if they received SCB within 1 year following commercial CAR-T between 6/2021 and 3/2024. To identify matched controls, we reviewed 590 CAR-T recipients and selected patients with ANC and platelet thresholds representing the 75th percentile of cytopenia severity in the SCB cohort. Hematologic recovery in the SCB cohort was assessed using CIBMTR engraftment criteria. For the non-SCB (nSCB) group, cell counts were analyzed cross-sectionally at day 60 and 90 post-CAR-T and compared to the SCB cohort with Kruskal-Wallis tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier methods. Of 590 patients, 91 patients (15.4%) developed prolonged cytopenias, 39 of whom received SCB. Median CD34+ cell dose was 2.9 million/kg (range: 1.8-23.6) administered at a median of 53 days post-CAR-T (range 24-265). All but one patient (97.4%) in the SCB group achieved hematologic recovery, with median time to recovery of 24 days (range 9-87). No new toxicities attributable to SCB were observed. On day 90 post CAR-T infusion, SCB patients had higher median Hb (10.6 vs. 8.7g/dL, p = 0.002), and platelet counts (135 vs. 35K/L (p < 0.001). After a median follow-up period of 12.6 months in the SCB cohort and 11.6 months in the nSCB arm, the mPFS was 11.0 months and 8.2 months, respectively. Median OS was not reached vs. 12.3 months in the SCB vs. nSCB groups, respectively. Overall, SCB lead to rapid and successful hematologic outcomes in nearly all patients. Compared to matched controls, Hb and platelets were significantly improved by day 90 post-CAR-T infusion.

Introduction BCMA targeted CAR-T therapy in multiple myeloma (MM) results in deeper, more durable responses and a higher frequency of minimal residual disease (MRD) negativity when compared to standard of care. Many patients, however, will relapse after initially achieving a response. We evaluated outcomes of MRD positive patients following ciltacabtagene autoleucel (cilta-cel) to determine the expected outcomes in this population. Objectives To compare outcomes based on MRD status, and dynamics of CAR-T expansion in these patients. Methods In this multicenter study, we evaluated 317 patients receiving cilta-cel for MM who achieved a VGPR or better response to cilta-cel and had MRD results available at 3 months post cilta-cel infusion using next generation sequencing or next generation flow cytometry with sensitivity of 1 × 10-5 or better. Efficacy outcomes based on MRD status were examined. Median follow-up from the time of CAR-T infusion was 11.93 months. We also evaluated a cohort of cilta-cel patients (n=38) from one center where data on CAR-T expansion by flow cytometry was available. CAR expansion was determined via peripheral blood cilta-cel concentration at day 7, 14, 21, and 28 post-infusion. Results Amongst the 317 patients with VGPR or better response, only 32 (10%) were MRD positive at 3 months post cilta-cel. Median age of the population was 65 years. 52% were male and 14% were black. 33% had high-risk cytogenetics and 34% had EMD. Median prior lines of therapy was 5. Patients who were MRD positive were more likely to have high risk disease (41% vs 32%) and higher baseline ferritin, but no other differences in baseline characteristics were noted. PFS was significantly different based on MRD status (p=0.002), with median PFS of the MRD+ patients at 12.6 months compared to 26.4 months for MRD- patients. 1-year PFS estimates were 51% (95% CI: 31%, 68%) and 81% (95% CI: 75%, 86%), respectively.In the single center cohort with CAR expansion data, 32% (10/31) of patients were MRD+. MRD data was not available for 7 patients. We observed similar trends in PFS with the larger, multi-site cohort. When evaluating the interaction of CAR-T expansion and persistence with MRD negativity, we observed no significant differences in CAR-T expansion at peak (around day 14) or at other timepoints based on MRD status. CAR-T persistence at day 90 was known in 21 patients and was not significantly different based on MRD status. Conclusion Overall, our data confirms that patients who remain MRD positive at 3 months post cilta-cel are at significantly higher risk of early relapse with median PFS of 12.6 months. This is likely independent of CAR-T expansion or persistence, but should be confirmed in a larger dataset. Importantly, there is an urgent need for clinical trials of bridging and consolidation strategies to prevent early relapse in patients who remain MRD positive following cilta-cel.

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.

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.

Elranatamab, a BCMA-CD3 bispecific antibody, has demonstrated robust activity in relapsed/refractory multiple myeloma (RRMM), but real-world outcomes remain poorly defined. We conducted a multicenter retrospective study of 130 patients treated with commercial elranatamab across nine U.S. academic centers. The cohort was heavily pretreated (91% triple-class refractory, 49% penta-refractory), with 49% previously exposed to BCMA-targeted therapies. Only 22% would have met eligibility for MagnetisMM-3 cohort A. The overall response rate (ORR) was 65%, including ≥CR in 36%. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 14.6 months, respectively, shorter than MagnetisMM-3. Elevated LDH and low hemoglobin independently predicted poor outcomes and were incorporated into the novel ALPS (Anemia-LDH Prognostic System) score, which stratified patients into distinct risk groups for ORR, OS, PFS, and duration of response. Prior BCMA exposure reduced depth of response, with inferior OS observed in those treated within one year of prior therapy. Infections occurred in 38% of patients. Intravenous immunoglobulin supplementation, modeled as a time-dependent covariate, was associated with improved infection-free survival and PFS. While the incidence of CRS was modestly lower than in MagnetisMM-3, ICANS occurred more frequently in this real-world cohort. These findings highlight the efficacy, limitations, and supportive care needs of elranatamab in a frailer, more heterogeneous real-world RRMM population.

B-cell maturation antigen (BCMA)-targeted therapies have emerged as promising treatment options for patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. However, comprehensive data on their efficacy and safety remain limited. We conducted a systematic descriptive pooled analysis of published studies reporting outcomes of BCMA-directed therapies including chimeric antigen receptor T-cell (CAR-T) therapies, bispecific antibodies (BsAbs), and antibody-drug conjugate (ADC). The analysis included 256 patients. CAR-T therapy was administered to 89 patients (35%), BsAbs to 82 patients (32%), and ADCs to 85 patients (33%). The pooled overall response rate (ORR) was 83%, with CAR-T demonstrating 92% ORR, BsAbs 89%, and ADCs 68%. Deep hematologic responses (≥VGPR) were achieved in approximately 70% of CAR-T and BsAb recipients and 64% of ADC recipients. Minimal residual disease negativity was documented in 75% of evaluable CAR-T patients and in 86% evaluable BsAb patients with reported data. Organ responses were observed in 30% of evaluable patients, with cardiac responses in 41%. Cytokine release syndrome occurred in 74% of CAR-T and 49% of BsAb patients, predominantly grade 1-2. Grade ≥3 CRS was rare (9% CAR-T, 1% BsAb). Ocular toxicity was the predominant adverse event in ADC recipients (84% any grade, 29% grade ≥3). Grade ≥3 infections occurred in 13% of CAR-T, 20% of BsAb, and 6% of ADC patients. BCMA-targeted therapies result in high response rates with manageable safety profiles in heavily pretreated AL amyloidosis patients, supporting continued investigation and clinical application of these approaches.

Abstract Ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy, was approved in 2022 for heavily pretreated relapsed/refractory multiple myeloma (RRMM). This study evaluates the safety and efficacy of cilta-cel in RRMM patients reported to the Center for International Blood and Marrow Transplant Research registry between March 2022 and December 2023 who met commercial release specifications. Among 595 patients, median age was 64 years, 57% were male, and 70% had ≥1 comorbidity. Extramedullary disease and marrow plasma cell burden ≥ 50% were present in 13% and 14% of patients, respectively. The median number of prior lines of therapy was 7 and 8% had received prior BCMA-directed therapy. Median follow-up was 12 months (range, 1–25 months). Cytokine release syndrome occurred in 80% (≥ grade 3: 4%) and immune effector cell–associated neurotoxicity syndrome (ICANS) in 22% (≥ grade 3: 4%). Non-ICANS neurotoxicity was seen in 5% (n = 31), including Parkinsonism in 2.7% (n = 16) and cranial nerve palsies in 2.5% (n = 15), primarily cranial nerve VII (n = 12/15). Infections occurred in 47% and treatment-related mortality was 5%. The best overall response rate was 87%, with ≥ very good partial response rate in 75%, and ≥ complete response rate in 35%. Estimated 12-month progression-free and overall survival were 73% (95% CI: 68–77%) and 85% (95% CI: 81–88%), respectively. This represents the largest standard-of-care (SOC) study of cilta-cel in RRMM patients to date. Despite advanced disease and high comorbidity burden, cilta-cel demonstrated favorable safety and efficacy, supporting its use in clinical practice.

Introduction Total Marrow and Lymphoid Irradiation (TMLI) is a modality that enables delivery of myeloablative radiation to the bone marrow and lymphoid tissues while maintaining organ-at-risk (OAR) doses at levels comparable to non-myeloablative conditioning in hematopoietic stem cell transplantation (HSCT). This targeted approach allows intensification of cytotoxic effect against hematologic malignancies with limited collateral injury to the OAR. Here, we report the outcomes in a cohort of acute leukemia and MDS patients undergoing TMLI-conditioned HSCT. Methods We analyzed 30 consecutive patients with high-risk hematologic malignancies (14 ALL, 15 AML, 1 high-risk MDS) who underwent HSCT after fludarabine + TMLI conditioning between 2022 and 2025. PTCy, tacrolimus, and Mycophenolate mofetil used as GVHD prophylaxis. Twelve patients received 12 Gy TMLI delivered in 8 fractions twice a day over 4 days, and 18 received 15 Gy, delivered in 10 fractions over 5 days. TMLI treatment planning was done using commercially available treatment planning software and an image-guided delivery capable linear accelerator to allow for dose painting and delivery (Figure 1). Patients received maintenance therapy per standard of care. Results The median age was 47 years (range 23 - 70). High or very high-risk disease was present in 77% of cases per the CIBMTR Disease Risk Index, with 73% of AML patients having ELN 2022 adverse risk disease; 100% of ALL patients had poor-risk disease. Graft source was PBSC from MUD (47%), MMUD (20% Haploidentical (20%), and MSD (13%). The average age of donors was 28 years. After a median follow-up of 192 days (45 - 601), all 30 patients achieved successful engraftment with a median time to and platelet engraftment at 21 days; 100% donor chimerism was measured in granulocytes and T cells at day 100. No treatment-related mortality events or relapses have occurred. Overall survival and LFS (MRD negative) are 100% (Figure 2). GRFS was 90% at 1 year, and 7% patients experienced steroid-sensitive grade 3-4 acute GVHD, and 13% chronic moderate/severe chronic GVHD. Despite the delivery of myeloablative doses of radiation, none of the patients TPN or showed evidence of endothelial injury-related syndromes. Only 6% of patients developed Grade 3 non-hematologic toxicities and Grade 3 infections. Mean OAR doses were reduced by about 40% of the prescribed dose. Conclusion TMLI provides a safe platform for the delivery of myeloablative and immunoablative conditioning with markedly reduced off-target exposure across the age spectrum. These findings support TMLI as a new conditioning paradigm that bridges the intensity gap between reduced-intensity and conventional myeloablative regimens in acute leukemia and MDS, particularly for elderly patients with high-risk malignancies. It can be deployed at any institution equipped with modern linear accelerators.

Extramedullary disease (EMD)-the proliferation of clonal plasma cells in soft tissues without direct bone connection-represents one of the most challenging manifestations of multiple myeloma, associated with aggressive biology, treatment resistance, and poor outcomes. EMD is driven by distinct pathophysiologic mechanisms including downregulation of adhesion molecules, acquisition of high-risk cytogenetic abnormalities (del(17p), gain(1q)), activation of the RAS-MAPK pathway, epigenetic dysregulation such as EZH2 upregulation, and remodeling of the immune microenvironment toward an immunosuppressive, T-cell-depleted phenotype. Conventional therapies, including anti-CD38-based regimens, yield limited efficacy in EMD, with pooled overall response rates of approximately 20% in triple-class-exposed relapsed/refractory disease. T-cell-redirecting therapies have emerged as the most promising treatment strategy. Both chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies have demonstrated clinically meaningful activity in soft tissue EMD, with CAR T-cell therapy providing the deepest and most durable responses, and dual-targeting bispecific combinations showing particularly encouraging efficacy. Central nervous system (CNS) myeloma, the most devastating form of EMD, has historically carried a dismal prognosis. Emerging retrospective data suggest that both CAR T-cell therapy and bispecific antibodies can achieve meaningful CNS responses with acceptable safety profiles, as part of multimodal approaches incorporating CNS-directed therapies. Despite these advances, EMD remains associated with inferior outcomes even in the immunotherapy era, underscoring the need for strategies targeting the immunosuppressive microenvironment, novel therapeutic approaches, and prospective EMD-focused clinical trials. This review provides a comprehensive overview of the biology, classification, and evolving treatment landscape of both non-CNS and CNS EMD in the era of T-cell-redirecting immunotherapy.

Lymphodepleting chemotherapy (LD) enhances chimeric antigen receptor T cell (CAR-T) expansion, persistence, and clinical activity. Fludarabine-cyclophosphamide is most used, but the benefit of alternative agents is unknown. This study compares fludarabine- versus bendamustine-based LD in the real-world setting prior to CAR-T treatment of relapsed or refractory large cell lymphoma (LBCL). We assessed outcomes of patients with LBCL who received commercial CD19 CAR-T therapies during 2017 to 2023, using data from Center for International Blood and Marrow Transplant Research. Of 5256 patients with LBCL treated with axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel, 92% and 9% received fludarabine and bendamustine LD, respectively. Multivariate analyses showed bendamustine had inferior overall response rate (ORR) (hazard ratio [HR] 0.773, P = .0013), but there was no difference in complete response (HR 0.828, P = .0606). The 1-year and 2-year rates of progression-free survival (PFS) were lower for bendamustine (P = .04), and the 1-year and 2-year rates of overall survival (OS) were similar (P = .65) The bendamustine group had lower rates of toxicities than the fludarabine group, including severe cytokine release syndrome (odds ratio [OR] 0.445, P < .0001), immune effector cell-associated neurotoxicity syndrome (OR 0.432, P < .0001), prolonged cytopenia (OR 0.479, P < .0001) Treatment-related mortality (TRM) was lower in the bendamustine group. In a subset analysis adjusting for distribution of LD regimens, the main conclusions were the same. Regardless of CAR-T products used, compared to patients who received bendamustine, patients who received fludarabine LD had higher ORR and PFS, without significant impact on OS. Bendamustine was associated with a reduced incidence of toxicities and TRM. Providers can consider relevant patient characteristics when choosing LD and the trade-off between efficacy and safety. Bendamustine can be considered an alternative LD prior to CAR-T for LBCL.

The assessment of minimal residual disease (MRD) is an important prognostic factor in hematologic malignancies, including multiple myeloma (MM). Historically defined as cancer cells undetectable by conventional morphology, MRD is now more appropriately termed measurable residual disease, reflecting its quantitative and clinically actionable nature. Advances in next-generation flow cytometry and next-generation sequencing have enabled detection of disease at sensitivities as low as 10-6 and even 10-7, redefining the concept of complete response. Nonetheless, challenges remain regarding assay sensitivity, standardization, and interpretation of results. Achieving MRD-negativity is a strong and independent predictor of improved survival outcomes in both newly diagnosed and relapsed/refractory MM. Consequently, MRD negativity has increasingly been accepted by regulatory agencies as an intermediate endpoint supporting accelerated drug approval. This review summarizes MRD detection methodologies, clinically relevant thresholds, and therapeutic implications, highlighting the paradigm shift from "minimal" to measurable residual disease.

PURPOSE Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel. METHODS Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type. RESULTS A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade ≥3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (≥complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell–associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (≥March 2022). CONCLUSION Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.