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.

Introduction Multiple myeloma (MM) accounts for nearly 20% of all hematologic cancers in the US and remains a substantial clinical burden. While BCMA-directed CAR T-cell therapy has improved outcomes, challenges persist. AZD0120 (formerly GC012F) is a first-in-class autologous BCMA/CD19 dual-targeting CAR T-cell therapy using the FasTCAR rapid manufacturing platform. We report preliminary phase 1b results from DURGA-1, an ongoing phase 1b/2 trial evaluating AZD0120 in patients (pts) with relapsed/refractory (RR) MM. Methods This open-label, single-arm, US-based, multicenter study (NCT05850234) evaluated the safety of 2 dose levels (DLs) of AZD0120. Eligible pts were ≥18 y with RRMM (3+ prior lines of therapy [pLOT]), ECOG PS 0–1, and evidence of progressive disease. Prior BCMA-directed therapy ≥6 mo with best response of partial response or better was permitted. Pts received a single infusion of AZD0120 (DL1: 1×105 cells/kg; DL2: 3×105 cells/kg). Phase 1b primary objectives: safety/tolerability, RP2D determination; secondary objectives: efficacy, cellular kinetics (CK), pharmacodynamics. Results At data cutoff (DCO; 18 July 2025), 25 pts received AZD0120 (n=12 DL1; n=13 DL2). Median age was 64 y (range 44–78), median pLOT was 4 (range 3–7), 72% were triple-class refractory, 20% had prior BCMA CAR T-cell therapy, and 28% had high-risk cytogenetic features. Median time from apheresis to infusion was 28 d (range 19–44); 5 pts received bridging therapy. Median follow-up was 1.4 mo (range 0–19.3). No dose-limiting toxicities were reported. Most common treatment-emergent AEs (any grade) were CRS (64%), neutrophil count decreased (56%), and anemia (32%). CRS was reported in 75% (DL1) and 54% (DL2) of pts, with no cases grade ≥3. Median time to CRS onset (DL1/DL2) was 9 d (range 2–11); 12 pts (48%) received tocilizumab to manage CRS. No deaths or cases of ICANSEC-colitis, or secondary primary malignancies were reported. For efficacy-evaluable pts (n=15), overall response rate was 100% and complete response rate was 33%; median time to response was 0.9 mo for both DLs (range 0.6–1.9). All pts evaluable for minimal residual disease (MRD; n=5 DL1; n=3 DL2; DCO 1 July 2025) were MRD negative by next-generation sequencing (10-5 sensitivity). Three pts in DL1 with ≥12 mo follow-up maintained MRD negativity. CK analysis from 16 evaluable pts (DCO 12 June 2025) demonstrated median Tmax of 13 d post-infusion and median persistence of 42 d (range 13–273). Updated clinical data will be presented. Conclusion Preliminary phase 1b results demonstrated AZD0120 was well tolerated, with a low incidence of serious AEs, no grade ≥3 CRS, and no ICANS. FasTCAR-manufactured AZD0120 had controlled in vivo expansion leading to a predictable safety profile. A single infusion of AZD0120 achieved early, deep responses with 100% MRD negativity in triple-class‒exposed pts with RRMM.

In 2019, the American Society for Transplantation and Cellular Therapy (ASTCT) developed consensus definitions and grading criteria for the common immune effector cell (IEC)-associated toxicities of cytokine release syndrome (CRS) and IEC-associated neurotoxicity syndrome (ICANS). These grading scales were widely adopted by clinicians, investigators, and sponsors, allowing a clearer understanding of outcomes across clinical trials and a uniform basis to inform treatment algorithms. Since then, other IEC class effects, such as IEC-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) and non-ICANS attributable neurotoxicity, have been recognized. ASTCT convened experts for 2 tasks. First, to consider updating the previously published ASTCT grading criteria for CRS, ICANS, and IEC-HS. Second, to consider existing definitions and grading criteria, and/or create consensus criteria for emerging toxicities, including immune effector cell-associated hematotoxicity; non-ICANS neurological toxicities such as parkinsonism, cranial nerve palsies, and polyneuropathies; IEC-associated enterocolitis; tumor inflammation-associated neurotoxicity; and on-target, off-tumor toxicities. These updated consensus toxicity definitions and grading criteria can facilitate comparisons of toxicities of IEC and T-cell engager therapy across clinical trials and in real-world settings, as well as aid clinicians in better characterizing the severity of toxicity that can ultimately be tied to management guidelines.

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.

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.

Patients tapering and discontinuing immune suppression (IS) often develop graft vs. host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We prospectively enrolled HCT patients at relevant time points of initiation of taper of last systemic IS agent (cohort 1) or at time of complete IS stop (cohort 2) to identify rates and determinants of failure. Actual IS taper practice was recorded, and patients were followed for scheduled and event-driven clinical data and research blood samples. Success was defined as complete discontinuation of IS and durable freedom from GVHD; failure as GVHD during/after taper (cohort 1), or after IS stop (cohort 2). Median follow-up post-HCT was 53 months (range 10–141). Cohort 1 enrolled at median 15.6 months post-HCT. Failure during IS taper occurred in 43% (60% total considering failure during IS taper and after IS stop). Median time to failure was 8.3 months (range 1.1–39.5), manifesting as acute (26%) or chronic (74%) GVHD. Cohort 2 enrolled at median of 25 months post-HCT. Subsequent failure occurred in 44% at median of 4.5 months (range 0.1-27.1) manifesting as acute GVHD (20%) or chronic GVHD (80%). This prospective cohort study provides new insight into GVHD risk during IS taper/discontinuation and establishes a biologic sample repository for investigation into immune tolerance.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is an established effective treatment strategy for relapsed/refractory multiple myeloma in fifth line or later (5L+) and was recently approved for patients who have received ≥1 prior line of therapy. Although rare, non-immune effector cell-associated neurotoxicity syndrome (ICANS) neurologic events (NEs), including cranial nerve palsy (CNP), parkinsonism, and Guillain-Barré syndrome, may occur post-infusion. This study evaluated the incidence, clinical characteristics, and management strategies of non-ICANS NEs to inform patient care. Methods: This retrospective cohort analysis utilized Loopback Analytics electronic medical records (Feb 2017–May 2025) supplemented with physician chart notes from academic and community centers across the US. Adults treated with cilta-cel in second to fourth line (2L–4L) and 5L+ settings were included if they had ≥1 absolute lymphocyte count (ALC) test within 30 days pre- and post-infusion. Incident non-ICANS NEs were defined as ≥2 ICD-10 diagnoses of the same condition on distinct days within 30 days of each other. Non-ICANS NEs were further verified through manual chart review using unstructured data elements from patient charts to ensure clinical accuracy. Pre-lymphodepletion ALC (x 103/μL; i.e., closest value to cilta-cel infusion),post-infusion peak ALC (x 103/μL), and management strategies for non-ICANS NEs were described along with cilta-cel response and mortality. Interim results are presented; data collection is ongoing with updated analyses planned for additional patients. Results: Among 174 patients (2L–4L cilta-cel: 73; 5L+ cilta-cel: 101), median age was 64 years (range: 37-83 years). With a median follow-up of 6.1 months (2L–4L; range: 0.2-13.3) and 17.2 months (5L+; range: 1.1-33.0), non-ICANS NEs remained rare. CNP occurred in 4 (5.5%) patients in the 2L–4L cohort and 3 (3.0%) in the 5L+ cohort. Parkinsonism and Guillain-Barré syndrome were each reported in 1 patient, both in the 5L+ cohort, with no cases observed in 2L–4L. Among patients without non-ICANS NEs, the median post-infusion peak ALC was 2.1 in the 2L–4L cohort and 2.0 in the 5L+ cohort. In the 2L–4L cohort, 4 CNP cases occurred at a median of 29 days post-infusion. Median pre-lymphodepletion ALC was 0.10, while post-infusion peak ALC was 7.6 (range: 1.2-16.8; median day 11 post-infusion). Management included prednisone and valacyclovir. Over a median follow-up of 6.7 months, 3 (75.0%) patients showed improvement in CNP (median 15 days), and 1 (25.0%) patient experienced full resolution by day 62. In the 5L+ cohort, 3 CNP cases occurred at a median of 25 days post-infusion. Median pre-lymphodepletion ALC was 0.10, and post-infusion peak ALC was 8.8 (range: 8.3-26.9; median day 11 post-infusion). Management reported for one 5L+ CNP patient resulting in full resolution of CNP included prednisone, dexamethasone, and valacyclovir; data on CNP improvement wasn't documented for the remaining two patients in the medical charts. Over a median follow-up of 7.9 months, all 3 patients achieved a complete response to cilta-cel. The one case of parkinsonism in the 5L+ cohort occurred on day 46 post-infusion. Pre-lymphodepletion ALC was 0.60, with a post-infusion peak ALC of 14.5 on day 15. Management for parkinsonism included cyclophosphamide. The patient achieved complete response to cilta-cel within 15.5 months of follow-up. Data on neurologic symptom improvement wasn't documented for this patient in the medical charts. Finally, the case of Guillain-Barré syndrome in the 5L+ cohort occurred on day 105 post-infusion. Pre-lymphodepletion ALC was 0.04, with a post-infusion peak ALC of 8.8 on day 10. During the 15.7 month follow-up period, management included intravenous immunoglobulin and plasma exchange, and the patient achieved complete response post-cilta-cel. Data on neurologic symptom improvement wasn't documented for this patient in the medical charts. Conclusion: In this real-world cohort, CNP, parkinsonism, and Guillain-Barré syndrome cases were infrequent following cilta-cel infusion. Affected patients had higher post-infusion peak ALCs compared to those without non-ICANS NEs, suggesting peak ALC may serve as a potential biomarker for identifying patients at risk for NEs and guiding prophylactic and therapeutic strategies. Despite experiencing non-ICANS NEs, all patients with available response assessments responded to cilta-cel, and no deaths were reported.

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.

BACKGROUND:Data on transplant outcomes of obese patients undergoing allogeneic hematopoietic cell transplant (alloHCT) have demonstrated conflicting results both in regard to the prognostic significance of obesity and appropriate dosing of chemotherapy to balance toxicity and efficacy. OBJECTIVES:We retrospectively evaluated 751 acute myeloid leukemia (AML) patients who underwent alloHCT at the Moffitt Cancer Center from 2010-2021 to compare transplant outcomes of obese (BMI ≥30 kg/m2) and non-obese patients (BMI <30 kg/m2). Transplant related outcomes included time to engraftment, acute graft-versus-host disease (aGVHD), moderate-severe chronic graft-versus-host disease (cGVHD), relapse, non-relapse mortality (NRM), relapse free survival (RFS), and overall survival (OS). STUDY DESIGN:Data was collected via internal database supplemented by direct records review. Univariate Cox regression models were developed using baseline variables, and multivariate Cox regression models were built using significant variables from univariate analysis and backwards selection. Similarly, Fine & Gray subdistribution hazard models were built when competing risks were present. Kaplan Meier curves were utilized to show RFS and OS. The time-to-event outcomes with competing risks were summarized by cumulative incidence curves. In the subgroup of patients with BMI ≥30 kg/m2 receiving melphalan based conditioning (n = 78), we compared outcomes in patients who received melphalan dosed on total body weight versus adjusted body weight. RESULTS:The cohort of 751 patients included 246 (32.8%) with BMI ≥30 kg/m2, and 505 (67.2%) with BMI <30 kg/m2. Median follow up time was 50 months. Engraftment did not differ between groups. The cumulative incidence of grade 2-4 aGVHD was 49% for patients with BMI ≥30 kg/m2 and 44% for patients with BMI <30 kg/m2, (P = .28), while the cumulative incidence of moderate to severe cGVHD was 24% versus 25% (P = .56). The cumulative incidence of relapse at 2 years was 23% versus 27% for patients with BMI ≥30 kg/m2 and BMI <30 kg/m2 respectively (P = .41), and cumulative incidence of NRM at 1 year was 14% versus 15% (P = .94). OS at 2 years was 64% versus 59% for patients with BMI ≥30 kg/m2 and BMI <30 kg/m2, respectively (P = .35). In multivariable analysis, BMI was not shown to affect aGVHD, moderate to severe cGVHD, NRM, RFS, relapse, or OS. In the analysis of obese patients who received melphalan, no significant differences in outcomes were found between those receiving melphalan dosed by total body weight versus adjusted body weight. CONCLUSIONS:In this study of North American AML patients receiving alloHCT with varying conditioning and GVHD prophylaxis, including post-transplant cyclophosphamide, there were no significant differences in clinical outcomes between patients with BMI ≥30 kg/m2 compared to patients with BMI <30 kg/m2.

PURPOSE This phase I-Ib trial evaluated a novel CD40L blocking antibody, BMS-986004, for the prevention of graft-versus-host disease (GVHD) after unrelated donor allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS A total of 34 patients were treated at three centers. The safety and biologic activity of single-dose BMS-986004 (675 mg [n = 6] and 1,500 mg [n = 6]; one-time dose) were evaluated. Safety of prolonged dosing was then examined in separate cohorts (drug administration every 2 weeks × 3 [n = 3], 5 [n = 3] or 7 doses [n = 16]). Included patients received 8/8 HLA-matched unrelated donor peripheral blood stem-cell HCT and sirolimus/tacrolimus GVHD prophylaxis. Comprehensive HCT outcome data were collected through 2 years, inclusive of GVHD outcomes, immune reconstitution and infections, and biologic correlative studies. RESULTS BMS-986004, a single, one-time dose of 1,500 mg was identified as the safe and biologically active single-dose regimen, and prolonged dosing cohorts demonstrated safety through the seven-dose duration regimen. In phase Ib (n = 16), grade II-IV acute GVHD was 25% with no grade III or IV acute GVHD. Moderate-severe chronic GVHD at 2 years was 18.4%. Considering all patients (n = 34), a total of five deep venous thrombosis (DVT) events occurred and no significant association was detected between DVT and serial D-dimer and TAT levels. There was no evidence for excess infectious complications or cytomegalovirus reactivation. Two-year estimates were the following: Non-relapse mortality 15.3% (95% CI, 5.4% to 29.8%), relapse 22% (95% CI, 9.5% to 37.8%), and overall survival 77.8% (95% CI, 58.7% to 88.8%). CONCLUSION This trial demonstrates that next-generation CD40L blocking antibodies can be used safely in HCT recipients and supports initial clinical efficacy in the prevention of GVHD. Further study is needed in larger populations to verify these outcomes.

Introduction: Patients with relapsed/refractory multiple myeloma (RRMM) who receive BCMA or GPRC5D-directed bispecific antibodies (BsAb) commonly experience low-grade cytokine release syndrome (CRS). Based on limited data, IMWG and mSMART guidelines recommend CRS management with tocilizumab and/or dexamethasone. However, as most CRS is low-grade, we evaluated the safety and efficacy of CRS management with supportive care alone compared to alternative management strategies. Methods: Data on 555 patients with RRMM who initiated elranatamab, teclistamab, and/or talquetamab as of March 1st, 2025, were collected by 7 US academic medical centers. All patients received standard pre-medications and BsAb step-up dosing (SUD) per the package insert. Toxicity management and supportive care were based on institutional standards. Supportive care consisted of antipyretics, hydration, and/or oxygen supplementation. Tocilizumab was dosed at 8mg/kg (maximum 800mg) and dexamethasone ranged from 4-20mg per dose. CRS and ICANS were graded per ASTCT criteria. Outcomes included CRS incidence, severity, recurrence, and duration of hospitalization. Results: Of 555 patients, 36 received elranatamab, 307 received teclistamab, and 212 received talquetamab. Eighteen patients received both a BCMA BsAb and talquetamab at separate time. Median age was 68 years, 52% were male, and 22% were African American. Median prior lines of therapy was 5 (range 2-18), 30% had extramedullary disease and 65% of patients would have been ineligible for registrational trials. Forty-two (7.5%) patients received SUD in the outpatient setting. Overall incidence of CRS was 55% (n=306) (grade 1: 38%, grade 2: 15%). Eight patients experienced grade 3 CRS (1.4%) and two patients experienced grade 4 CRS. Median duration of CRS was 1 day (range 0.5-8 days). Of 29 patients who received prophylactic tocilizumab, 52% (n=15) experienced CRS (grade 1: 13, grade 2: 1, grade 4: 1). Incidence of ICANS was 15% (grade 1: 7%, grade 2: 4%, grade 3: 2.2%, grade 4: 1.3%). There were no CRS-related deaths. Three deaths were possibly related to neurotoxicity and/or progressive disease. Median PFS and OS were 8.3 months and 19 months, respectively. Among patients with CRS, 87 (28%) were managed with supportive care alone. The remaining 219 patients received pharmacologic intervention: dexamethasone (n=68, 22%), tocilizumab (n=85, 28%), or both dexamethasone and tocilizumab (n=66, 22%). Patients received a median of 5 dexamethasone doses (range 1-34). In those receiving both dexamethasone and tocilizumab, 30 patients (45%) had concomitant ICANS. Supportive care consisted of acetaminophen (90%), hydration (30%), and supplemental oxygen (5%). Thirteen patients in the supportive care group (15%) received prophylactic tocilizumab. There was no difference in age, baseline LDH, presence of extramedullary disease, or performance status between those managed with supportive care versus those managed with pharmacologic intervention. Ten patients in the supportive care group and 14 patients in the pharmacologic intervention group initiated SUD outpatient (p=0.134); of them, 3 and 9 patients were admitted for CRS (p=0.114). Patients treated with supportive care experienced more grade 1 CRS (92% vs 61%, p<0.001) and less grade 2 CRS (8% vs 35%, p<0.001) compared to those receiving pharmacologic intervention. Duration of CRS was 1.3 days for supportive care vs 1.8 days for pharmacologic intervention (p=0.003). There was no difference in incidence of dose delay due to CRS (33% vs 36%, p=0.304) or recurrent CRS (26% vs 32%, p=0.306) in the supportive care and pharmacologic intervention groups, respectively. Doses were delayed by a median of 2 days in those treated with supportive care and 1 day in those treated with pharmacologic intervention (p=0.458). Median duration of hospitalization for SUD was 9 for both groups (p=0.809). Conclusion: In this large real-world cohort of patients with RRMM receiving bispecific antibodies, most CRS events were low grade and short duration. Supportive care alone was associated with comparable outcomes to pharmacologic intervention with dexamethasone and/or tocilizumab for low grade CRS (particularly grade 1), including similar rates of dose delay, recurrent CRS, and duration of hospitalization. These findings suggest that supportive care may be an appropriate management strategy for low-grade CRS, reducing the need for immunosuppressive therapy and cost avoidance.

Background: Ciltacabtagene Autoleucel (Cilta-cel), an anti-BCMA CAR-T cell therapy, is approved for relapsed/refractory multiple myeloma (RRMM) based upon the results of several pivotal clinical trials. Frail adults are known to be under-represented in clinical trials. To ensure cilta-cel is effectively utilized in this subgroup, there is a need to understand both the efficacy and safety of cilta-cel among frail adults treated in the real-world. Methods: We conducted a retrospective cohort study of patients (pts) with RRMM treated with standard of care cilta-cel reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). Eligible pts had received ≥4 prior lines of therapy (LOT) between Mar 2022-Aug 2024 and completed a 100-day follow up form. Frailty was defined using the simplified frailty index (Facon et al., Leukemia, 2020), incorporating age, performance status, and comorbidities (hematopoietic cell transplantation specific comorbidity index score ≥2, 1 point). Pts with a frailty score ≥2 were classified as frail. Efficacy outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Safety outcomes included CRS, ICANS, prolonged cytopenia (>3 months), clinically significant infections, and treatment-related mortality (TRM). We used multivariable regression to assess the independent impact of frailty on outcomes, adjusting for key patient- and disease-related variables. Results: Among 595 treated pts, frailty status was available for 541, of whom 183 (33.8%) were categorized as frail and 358 (66.2%) as non-frail. Median ages were 65.5 years (range, 38 – 84; ≥70 years, 35%) in the frail group and 63 years (range, 34 -80; ≥70 years, 15.6%) in the non-frail group. Overall, median prior LOT were 7 (range 4–24), 25.1% pts had high-risk cytogenetics, and 7.6% had prior BCMA exposure with no statistically significant differences between frail and non-frail pts. At a median follow up of 12 months, the best ORR in the frail group was 82.9% versus 88.5% in non-frail pts. The 12-month PFS in frail pts was 62.7% (95% CI, 53.6-71.3%) versus 75.9% (95% CI, 70.4-81.1%) in non-frail adults (log-rank p<0.01). Similarly, the 12-month OS was 72.8% (95% CI, 64.9-80.0%) in the frail group versus 90.4% (95% CI, 86.6-93.7%) in non-frail pts (log-rank p<0.01). The 12-month TRM was 6.8% (95% CI, 3.4-11.2%) in frail pts versus 3.6% (95% CI, 1.8-6.1%) in non-frail pts (p=0.11). A total of 82 pts (15.2%) died during the follow up period (frail, n=45; non-frail, n=37). Progression was the most common cause of death in both groups (57.8% and 62.2%), followed by infections (13.3% and 8.1%). Two pts died from ICANS, and one pt died from CRS in the frail group. There were no ICANS-related deaths in the non frail group; one pt died from CRS. In terms of toxicity, 434 (80.2%) pts developed CRS, with grade 2+ CRS in 22.4% frail versus 17.9% of non-frail pts. A total of 141 patients (26.1%) developed neurotoxicity with rates of grade 2+ neurotoxicity being higher in frail (n=21, 11.5%) versus non-frail (n=18, 5%). More specifically, any-grade ICANS was noted in 32.2% of frail versus 17.6% non-frail pts. Cranial nerve palsies and parkinsonism developed among 2.6% and 2.8% of frail and non-frail pts. Rates of prolonged cytopenia were 30.6% in frail versus 21.2% in non-frail pts. Other toxicities including macrophage activation syndrome/hemophagocytic lymphohistiocytosis (3.7%) and clinically significant infections (47.0%) did not differ between frail and non-frail adults. A total of 23 pts (4.5%) developed a secondary malignancy, with no differences between frail and non-frail pts. After adjusting for patient- and disease-related factors in a multivariable model, frailty was not significantly associated with response or risk for CRS grade 2+. However, frail pts experienced significantly worse PFS (HR 1.67, 95% CI 1.16-2.40, p=0.0059) and OS (HR 2.46, 95% CI 1.57-3.87, p <0.0001). Additionally, frailty doubled the odds of developing any-grade ICANS (OR 2.01, 95% CI 1.32-3.08, p=0.0012). Conclusion: This study represents the largest cohort to-date examining outcomes of frail adults treated with cilta-cel. Frail pts experienced inferior survival and increased risk for ICANS compared to their non-frail counterparts. These findings highlight the urgent need for tailored CAR-T strategies and prospective studies focused on this vulnerable population

Background: B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, responses to CAR-T in RRMM are heterogenous and CAR-T infusion product (IP) features determinant of efficacy remain poorly defined. We performed single-cell RNA sequencing (scRNA-seq) on idecabtagene vicleucel (ide-cel) infusion product of RRMM patients to elucidate transcription profiles associated with CAR-T efficacy. Methods: ScRNA-seq libraries were generated from 40 patient IPs using Cell Ranger (v7.1.0, 10X Genomics), and aligned against a modified GRCh38 reference containing the ide-cel construct. Poor quality cells and doublets were then removed. CD4 and CD8 cells were identified and analyzed separately using an established in-silico gating method (Li, Cancer cell 2023). Harmony within Seurat v5 allowed integration, and cell subtype clusters were annotated by highly expressed genes. Samples collected shortly before CAR-T were analyzed by flow cytometry, including material used to make ide-cel (pre-treatment apheresis) and the tumor microenvironment (TME; bone marrow depleted of CD138+ cells), with the latter also being subject to Nanostring PanCancer Immune Profiling gene expression. Patients were stratified as durable response (DR) if still alive and without progression at 9 months or a non-durable response (NDR) if they died or had evidence of disease progression prior to this cutoff. For NF-κB inhibition assays, BCMA CAR-T with CD3z/4-1BB co-stimulatory domain resembling ide-cel, were manufactured from healthy donor T cells. After manufacture, cells were treated for two hours with BMS-345541, a selective IKKβ inhibitor, or left untreated. NF-κB activation was assessed by quantifying phosphorylation of the p65 subunit at Ser536 using the PathScan® Phospho–NF-κB p65 (Ser536) ELISA in parallel with Total NF-κB p65 ELISA. Results: Following quality control and batch correction, 184,398 cells, including 105,951 CD4 and 38,721 CD8 T cells from ide-cel IP were analyzed. Ide-cel was composed of primarily CD4 cells and cell cluster composition differed minimally between DR and NDR patients. One cluster characterized by expression of glycolytic genes was upregulated in NDR patients (p-value 0.0006). Pseudobulk aggregation followed by single-sample gene set enrichment (ssGSEA) of CAR positive (CAR+) CD4 cells from DR patients exhibited increased NF-κB signaling (p-value 0.02) – a pleiotropic activator of cellular responses including survival, proliferation, and inflammation. Pro-survival genes and tonic signaling pathways, and expression of the ide-cel construct, were also upregulated in DR and highly correlated with NF-κB signaling, progression-free survival, and overall survival. Analysis of apheresis samples matched to IP, revealed NF-κB signaling in CAR+CD4 IP cells positively correlated with flow cytometry defined apheresis CD4 T cell central memory cells (CD45RO+ CCR7+), TCF1, and absence of checkpoint ligands (PD1- TIGIT- LAG3-). Conversely lower NF-κB signaling in CAR+CD4 IP negatively correlated with flow defined apheresis CD4 expression of PD1 and CD39. Apheresis BM derived TME phenotypes were similar by flow cytometry. Nanostring of TME demonstrated similar NF-κB pathway correlation with TME CD4 T cell phenotype by flow cytometry, suggesting that NF-κB findings in ide-cel IP are informed by the TME prior to CAR-T manufacture. Pharmacological inhibition of NF-κB reduced CAR T cell function, resulting in impaired cytotoxicity against the H929-GFP-FFL multiple myeloma cell line, as measured by a luciferase-based bioluminescence assay, and decreased secretion of IFN-γ, TNF-α, IL-2, and IL-6, as determined by the ELLA platform. Conclusion: This study presents the first scRNAseq analyses of ide-cel infusion product and elucidates product specific factors that associate with efficacy in RRMM. NF-κB signaling, pro-survival genes, tonic signaling signatures, and ide-cel construct expression in the ide-cel infusion product CD4 CAR-T cells were significantly associated with improved depth and durability of responses. NF-κB signatures were particularly impactful and correlated with apheresis and TME T cells being more central memory-like and less exhausted. This suggests CAR-T product fitness is impacted by the pre-existing T cell fitness and informed by the TME. FLL and CLF contributed equally.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

Data describing outcomes of teclistamab in multiple myeloma patients with prior exposure to BCMA-directed therapy (BCMA-DT) are limited. The goal of this multicenter retrospective analysis was to report the efficacy and safety of standard-of-care teclistamab in patients with prior BCMA-DT. A total of 385 patients were included, of whom 193 (50%) had received prior BCMA-DT, including 47 (24%) patients with prior antibody-drug conjugate (ADC)-only, 99 (51%) with chimeric antigen receptor T-cell therapy (CAR T)-only, 36 (19%) with both ADC and CAR T, 6 (3%) with bispecific antibody-only, and 5 (3%) with other combinations. Most safety parameters between cohorts were comparable. The prior BCMA-DT cohort had a lower overall response rate (ORR: 48.7% versus 61.5%; p = 0.012), and median progression-free survival (PFS: 4.6 versus 8.2 months; p = 0.017) compared to the cohort without prior BCMA-DT. However, in multivariable analysis, despite a clear trend, ultimately receipt of a prior BCMA-DT was not independently associated with ORR or PFS (p = 0.057 and p = 0.1, respectively). No significant differences in PFS were noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Using the maximally selected rank statistics method, the optimal cut-off for time from the last BCMA-DT exposure to teclistamab initiation was identified as 8.7 months. Patients with >8.7 months between their last exposure to prior BCMA-DT and teclistamab initiation had a significantly improved median PFS with teclistamab (8.1 months, 95% CI: 4.6-11.7) compared to patients with <8.7 months (2.5 months, 95% CI: 1.1-5.7), p = 0.001. Altogether, our findings support the use of teclistamab as a viable treatment option in patients previously exposed to BCMA-DT.

Introduction: Cytomegalovirus (CMV) reactivation is common following allogenic hematopoietic stem cell transplant and CAR T-cell therapy, but incidence in patients receiving T-cell directed therapies such as bispecific antibodies (bsAbs) is less well known. Use of bsAbs in relapsed/refractory multiple myeloma (RRMM) has increased over the past several years, however there is minimal guidance regarding monitoring or management of CMV in this patient population. This study aims to describe the incidence and risk factors of CMV reactivation in patients with RRMM receiving bsAbs. Methods: A multi-center, retrospective, chart review of 555 patients receiving teclistamab, elranatamab, and/or talquetamab for RRMM was conducted. All treatment was initiated prior to March 2025. ASTCT grading was used for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) grading. CMV serostatus and viral load were checked at the discretion of the treating prescriber. CMV reactivation was defined as any detectable CMV level. Descriptive statistics were utilized for patient and disease characteristics, and incidence of CMV reactivation. Logistic regression model was utilized to evaluate risk factors for CMV reactivation. Results: Of the 555 patients included in the analysis, 308 (55%) patients received teclistamab, 36 (6%) patients received elranatamab, and 211 (38%) patients received talquetamab. Median age of the entire patient population was 68 years (range: 32-89 years), 288 (51%) of patients were male and were predominately Caucasian (420, 76%) and African American (120, 22%). Median prior lines of therapy was 5 (range: 2-18). Intravenous immunoglobulin (IVIG) was administered in 356 (64%) patients and granulocyte colony-stimulating factor was utilized in 83 (15%) patients throughout treatment. Median IgG levels at 30 and 90 days post bsAbs initiation were 463 mg/dL (range: 21-10184 mg/dL) and 674 mg/dL (range: 18-8425 mg/dL), respectively. CRS occurred in 306 patients (55%) and was most commonly grade 1 (38%). ICANS occurred in 81 patients (14.6%), with grade 1 occurring in 39 patients (7%). Tocilizumab was required in 154 patients (27.7%), including 5 patients that received tocilizumab prophylaxis and dexamethasone was required in 160 patients (29%). One hundred and eighteen patients (21%) did not have serostatus checked or status was unknown and were excluded from the subsequent analysis. Two hundred nineteen of the remaining patients (50%) were CMV seropositive. Of patients who were CMV seropositive, 48 patients (22%) had CMV reactivation during treatment, 26 (12%) receiving teclistamab, 2 (0.9%) receiving elranatamab, and 20 (9%) receiving talquetamab. Median time to CMV reactivation was 1.2 months (range: 0-15.4 months) after treatment initiation. Median peak CMV was 289 IU/mL (range: 5-324917 IU/mL). Of the 48 patients that experienced reactivation, 16 patients (33%) received CMV-directed therapy for a median duration of 24 days (range: 5-88). CMV disease occurred in 2 patients, including one case each of disseminated skin and pneumonia, both occurring within the first two months of treatment. Neither patient had prior BCMA exposure or tocilizumab exposure. No treatment interruptions, treatment discontinuations, or deaths occurred due to CMV reactivation. On logistic regression, number of prior lines of therapy, prior BCMA-directed therapy, max CRS grade, tocilizumab treatment, dexamethasone treatment, use of IVIG, and IgG levels at day 30 and day 90 were nonsignificant for predicting CMV reactivation. Conclusion: In this retrospective study, 22% of patients experienced CMV reactivation with approximately a third of those patients requiring CMV-directed therapy. No baseline characteristics evaluated predicted CMV reactivation in patients with RRMM receiving a bsAbs. This incidence may reflect a potential need to provide routine monitoring for patients receiving bispecific antibodies, especially early in treatment. Further guidance on risk factors and thresholds for CMV treatment are necessary to ensure appropriate management of this high-risk patient population.