Locke, Frederick L.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

Objective Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 ( NCT04981119 ), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment. Methods and analysis Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care. Results Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses. Conclusions The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing. Trial registration number NCT04981119 .

ABSTRACT Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of TNFRSF17 (encoding BCMA), while were less enriched for plasma cell–associated transcriptional programs, a phenomenon we term “plasma cell identity escape.” This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.

Abstract Introduction: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness < 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p<0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p<0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p<0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p<0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p < 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p<0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.

Abstract 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.

Abstract Introduction: Elranatamab, a BCMA-CD3 bispecific antibody, has shown efficacy in relapsed multiple myeloma (MM), but real-world data on its safety and effectiveness are limited. Methods: We conducted a retrospective, multi-center study of patients (pts) treated with commercial elranatamab from 8/2023–3/2025 at 9 U.S. academic centers. Logistic and Cox regression were used for binary and time-to-event outcomes, respectively. Multivariable analysis (MVA) adjusted for prior lines of therapy (LOTs), baseline Hgb (per g/dL), and LDH (per 100 U/L) as continuous variables; and for BCMA exposure, extramedullary disease (EMD; extraosseous soft tissue lesions), and ECOG ≥2 as binary variables. Results: Of 130 pts, median age was 71 yrs (range 39–95); 57% were female, 82% white, 13% black, and 35% had ECOG ≥2 (11% ≥3). Median LOTs was 6; 91% were triple-class refractory, 49% penta-refractory, 49% BCMA-exposed (median 15.5 mo [IQR 11.8–20.5] since last exposure), and 49% had prior anti-BCMA CAR-T. Most recent BCMA exposures included: CAR-T (84%), TCE (9.4%), and ADC (6.3%). Only 22% met MagnetisMM-3 cohort A eligibility (which excluded BCMA-exposed pts). High-risk cytogenetics (del(17p), t(4;14), t(14;16), or amp(1q)) were present in 44% (25%, 13%, 6.3%, and 7.9%, respectively). EMD was seen in 22%. Median treatment duration was 4.0 mo (95% CI 2.93–6.3) overall and 7.9 mo (95% CI 5.83–NA) with ≥VGPR. Discontinuation due to toxicity or non-relapse mortality occurred in 12% but was significantly lower among those receiving IVIg (5% vs. 17%, p=0.031); IVIg was given in 47%. The overall response rate (ORR) was 65%, including ≥VGPR in 46% and ≥CR in 36%, consistent with MagnetisMM-3 (ORR 61%, ≥CR 35%; Lesokhin et al. Nat Med. 2023). After median follow-up of 7.5 mo, median PFS was 4.3 mo (95% CI 3.4–11.3), OS was 14.6 mo (95% CI 8.6–NA), and DOR was 12.2 mo (95% CI 6.1–NA). In contrast, MagnetisMM-3 (Prince et al., ASH 2024) reported median PFS and OS of 17.2 and 24.6 mo, respectively, with DOR not reached despite 28.4 mo of follow-up. In univariate analysis, ECOG ≥2 was associated with lower ORR (45% vs. 71%; OR 0.34, 95% CI 0.16–0.73, p=0.006), shorter OS (4.3 mo vs. NA; HR 2.41, 95% CI 1.33–4.35, p=0.004), and shorter PFS (1.7 vs. 6.5 mo; HR 1.77, 95% CI 1.09–2.87, p=0.020). Prior BCMA-directed therapy was linked to reduced odds of ≥VGPR (OR 0.38, 95% CI 0.19–0.77, p=0.008) and ≥CR (OR 0.43, 95% CI 0.20–0.89, p=0.025). Higher baseline LDH was linked to shorter OS (HR 1.37, 95% CI 1.23–1.53, p<0.001) and PFS (HR 1.31, 95% CI 1.18–1.44, p<0.001). Higher baseline Hgb was associated with higher ORR (OR 1.46, 95% CI 1.20–1.81, p<0.001) and ≥CR (OR 1.54, 95% CI 1.26–1.92, p<0.001). Among BCMA-exposed pts, recent exposure (<1 [n=15] vs. ≥1 yr [n=32]) was associated with shorter OS (4.1 mo vs. NA; HR 3.66, 95% CI 1.26–10.6, p=0.017). In MVA, higher baseline LDH remained independently associated with shorter OS (aHR 1.36, 95% CI 1.19–1.54, p<0.001) and PFS (aHR 1.27, 95% CI 1.13–1.43, p<0.001); higher Hgb with greater odds of ≥CR (aOR 1.44, 95% CI 1.14–1.85, p=0.003) and longer PFS (aHR 0.84, 95% CI 0.72–0.99, p=0.034); and BCMA exposure with lower odds of ≥CR (aOR 0.32, 95% CI 0.10–0.91, p=0.037). CRS occurred in 40% (grade ≥2 in 12.3%, grade 3 in 2.3%), and ICANS in 17% (grade ≥2 in 7.7%). These rates contrast with MagnetisMM-3 (no grade ≥3 CRS, 3.4% ICANS). ICANS risk was lower in BCMA-exposed pts (9.4% vs. 24%; OR 0.32, 95% CI 0.11–0.85, p=0.029), and decreased with more LOTs (OR 0.73, 95% CI 0.55–0.92, p=0.016) and higher Hgb (OR 0.71, 95% CI 0.52–0.94, p=0.023). Tocilizumab and steroids were used in 36% (treatment 28%, prophylaxis 9.2%) and 23%, respectively. Steroid use was less common in BCMA-exposed pts (11% vs. 34%; OR 0.23, 95% CI 0.08–0.60, p=0.004) and declined with more LOTs (OR 0.68, 95% CI 0.52–0.85, p=0.002). Infections occurred in 40% of the cohort, more common in pts with CrCl <40 mL/min (59% vs. 36%; HR 2.58, 95% CI 1.02–6.80, p=0.049). IVIg was linked to improved infection-free survival (HR 0.59, 95% CI 0.37–0.93, p=0.023). Conclusions: Elranatamab demonstrated meaningful activity in real-world relapsed MM, though PFS and OS were shorter than in MagnetisMM-3, likely reflecting an older, frailer population with higher disease burden. ICANS was more frequent than in MagnetisMM-3. Baseline anemia and elevated LDH, markers of poor marrow reserve and higher disease burden, were strongly linked to worse outcomes.

Abstract Background: IEC-HS is a potentially life-threatening complication following CAR-T therapy in RRMM. Reliable diagnostic biomarkers are needed to help expeditiously identify cases to initiate prompt treatment and supportive care. Serum ferritin, a routinely available laboratory parameter, is commonly elevated in IEC-HS and has been used to identify cases. However, ferritin can also be elevated in cytokine release syndrome (CRS) or secondary to baseline tumor-related inflammation. The optimal diagnostic threshold for post-CAR-T ferritin in IEC-HS in RRMM has not been previously established. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium to identify the optimal post-CAR-T ferritin threshold to distinguish RRMM patients (pts) with and without a diagnosis of IEC-HS. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold based on Youden's Index. The performance of the threshold was evaluated overall and stratified by CAR-T product (cilta-cel, ide-cel). Additional analyses included the temporal relationship of peak ferritin and IEC-HS diagnosis, the evaluation of IEC-HS criteria according to ferritin levels, comparison of IEC-HS criteria co-occurrence, and comprehensive baseline characteristic comparisons across ferritin strata. Results: Of 1502 RRMM CAR-T recipients (ide-cel, n=712; cilta-cel, n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. A post-CAR-T ferritin threshold of 7470 ng/mL was identified as optimal for distinguishing pts with and without IEC-HS (AUC 0.938). Sensitivity (0.904) and specificity (0.934) were both very high, indicating high discriminatory ability. Stratified ROC analyses showed near-identical optimal thresholds for cilta-cel (7450 ng/mL; sensitivity 0.885, specificity 0.936, AUC 0.94) and ide-cel (7470 ng/mL; sensitivity 0.952, specificity 0.933, AUC 0.95), indicating minimal impact of CAR-T product on ferritin's prognostic utility. Baseline pt characteristics (N=1,413) differed significantly by ferritin threshold. Pts above the ferritin threshold of 7470 (N=154) were younger (median 64 vs 67 years; p=0.004), more frequently male (65% vs 56%; p=0.043), had higher baseline ferritin (1,300 vs 187; p<0.001), higher ECOG at apheresis (p=0.001), more likely penta-refractory (p=0.016), had higher baseline bone marrow plasma cell burden (p<0.001), and had higher R-ISS scores (p<0.001). Evaluation of IEC-HS criteria (Hines et al, TCT 2023) demonstrated significantly higher rates of laboratory and clinical criteria, including hepatic transaminase elevation (43% vs 15%), hypofibrinogenemia (53% vs 0%), cytopenias (95% vs 81%), hypertriglyceridemia (43% vs 8%), ICANS (52% vs 23%), renal insufficiency (20% vs 0%), and soluble IL-2 receptor elevations (47% vs 4%), in pts with ferritin >7500 ng/mL compared to those with lower ferritin. Heatmap visualization revealed distinct patterns of co-occurring criteria in high- and low-ferritin groups. Assessment of the timing of peak ferritin and IEC-HS diagnosis among IEC-HS cases revealed a median difference of 0 days (IQR: -1, 0), suggesting simultaneous occurrence. Median time to max ferritin was 9 days (IQR 8,12) in IEC-HS pts compared to 8 days (IQR 5,10) in non-IEC-HS pts (Wilcoxon p<0.05). Conclusions: In this analysis of over 1500 patients, a post-CAR-T ferritin level of 7500 ng/mL robustly identifies RRMM pts with IEC-HS following either cilta-cel or ide-cel. Pts exceeding this threshold demonstrate marked enrichment in IEC-HS diagnostic criteria and significant differences in baseline characteristics, warranting further study of the role of ferritin in IEC-HS diagnosis and early intervention.

Abstract Introduction: IEC-HS is an emerging and potentially life-threatening complication in multiple myeloma (MM) patients (pts) treated with CAR-T therapies. We conducted a retrospective, multi-institutional analysis to define the features and outcomes of IEC-HS after ide-cel or cilta-cel in the real-world setting. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium for patients with relapsed/refractory MM (RRMM) who received commercial cilta-cel or ide-cel. IEC-HS was defined by each center based on diagnostic criteria (Hines et al, TCT 2023). Kaplan-Meier and multivariable Cox models were used for time-to-event outcomes while logistic regression was used for categorical outcomes. Results: Of 1502 RRMM pts who received either ide-cel (n=712) or cilta-cel (n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. Product-specific incidences were 2.9% for ide-cel and 6.7% for cilta-cel. The median time from CAR-T infusion to IEC-HS onset was 9.5 days (range 2-37 days). IEC-HS-related clinical findings (Hines et al, 2024) included cytopenias (95%), elevated soluble IL-2R levels (79%), fever (76%), elevated LDH (71%, median 1,800 U/L), hypofibrinogenemia (70%), hypertriglyceridemia (65%), ICANS (63%), hepatic transaminase elevation (56%), pulmonary involvement (46%), renal insufficiency (29%), hyperbilirubinemia (22%), and hemophagocytosis in bone marrow (6%). The median interval from peak CRS to IEC-HS onset was 4 days (IQR 1–6). Some variables, such as splenomegaly and coagulopathy, were not systematically collected. Nearly all pts received pharmacologic intervention: corticosteroids (94%, n=59), anakinra (76%, n=48), tocilizumab (71%, n=45), emapalumab (13%, n=8), ruxolitinib (16%, n=10), or etoposide (3%, n=2). Only one pt (2%) did not receive any IEC-HS therapy. Among those evaluable for outcomes, 58% (n=35) improved, 12% (n=7) developed further CAR-T-related complications (e.g., recurrent IEC-HS, delayed neurotoxicity), and 30% (n=18) had no therapeutic response and died. Compared to non-IEC-HS pts (n=1,428), those with IEC-HS were younger (median age 63 vs 66), male (61% vs 57%), and more frequently received cilta-cel (72% vs 52%, all p<0.01). They had higher rates of triple-class (81%) and penta-refractory (43%) disease, greater pre-treatment bone marrow plasma cell burden (40% vs 6%), and higher baseline ferritin (1058 vs 208 ng/mL). Prior autologous SCT was less common, and advanced R-ISS stage was more prevalent. IEC-HS was associated with dramatically worse PFS and OS: with cilta-cel, median PFS was 6.5 months (mo) with IEC-HS (vs 33.1 without); for ide-cel, 8.9 vs 11.4 mo. Median OS for cilta-cel IEC-HS pts was 9.6 mo (not reached in non-IEC-HS pts); for ide-cel IEC-HS, 19.6 mo (vs 40.8 mo). Multivariable analysis confirmed IEC-HS as an independent predictor of shorter PFS (HR 1.88, 95% CI 1.29–2.74, p=0.0011) and OS (HR 2.30, 95% CI 1.39–3.83, p=0.0013). Notably, IEC-HS was not associated with lower response rates – either best CR (63.9% vs 64.0%, p=0.71) or ORR (91.8% vs 90.9%, p=0.97). Cilta-cel pts had a higher probability of achieving a deep (CR) response, regardless of IEC-HS status. Grade > 3 CRS occurred in 14% (n=3/21) of ide-cel and 15% (n=8/52) of cilta-cel IEC-HS pts, versus 2% (n=12/691) and 2% (n=13/737) in non-IEC-HS pts, respectively. Any-grade ICANS was observed in 67% (n=14/21) of ide-cel and 55% (n=29/52) of cilta-cel IEC-HS cases, compared to 26% (n=179/690) and 20% (n=148/738) in non-IEC-HS. Grade ≥3 ICANS occurred in 29% (n=6/21) of ide-cel and 26% (n=14/52) of cilta-cel IEC-HS cases, relative to 4% (n=25/690) and 4% (n=27/738) in pts without IEC-HS. Severe infections were also more common: 71% (n=15/21) of ide-cel and 53% (n=28/52) of cilta-cel IEC-HS pts experienced at least one infection, compared to 31% (n=214/691) and 29% (n=217/737) in non-IEC-HS groups. Conclusions: IEC-HS is an uncommon but severe and early complication after CAR T-cell therapy for RRMM. Despite similar ORRs with or without IEC-HS, IEC-HS was associated with significantly worse PFS and OS for both ide-cel and cilta-cel. These findings support the need for vigilant monitoring and potential preemptive treatment strategies to better manage this syndrome.

Abstract Introduction: Teclistamab is the first FDA approved BCMA-directed bispecific antibody for the treatment of relapsed and refractory multiple myeloma (RRMM). With BCMA-targeting CAR-T therapies, cytokine release syndrome (CRS) is a risk factor for cardiotoxicity. Teclistamab was associated with fatal cardiovascular adverse events (CVAEs) in a recent US pharmacovigilance database analysis, but this analysis was limited by reporting bias. Therefore, the aim of our study is to conduct a multicenter study to define the real-world incidence of CVAEs in RRMM patients treated with teclistamab. Method We performed a retrospective multi-center cohort study of patients receiving teclistamab at 5 medical centers. Baseline oncologic and cardiovascular characteristics (including vital sign and echocardiographic data) were collected. Baseline cardiovascular disease (CVD) was defined as presence of coronary artery disease, congestive heart failure, severe or symptomatic valvular heart disease, or stroke at baseline. CVAE was collected and categorized based on CTCAE v5.0 by each institution. Major adverse cardiovascular event (MACE) was a composite outcome with any of the following: congestive heart failure, asymptomatic cardiomyopathy (interval LVEF drop >10% to resultant LVEF less than 50%), coronary artery disease requiring intervention, stroke or cardiovascular death. Arrhythmia was a composite outcome with any of the following: atrial tachyarrhythmia, ventricular tachyarrhythmia or bradyarrhythmia. Median follow-up was calculated through reverse Kaplan-Meier method. Multivariable Cox regression analysis was used to define the relation between MACE and survival. Cause of death was categorized as myeloma-related death or non-myeloma-related deaths (i.e. CRS, infection or cardiovascular death). Cause-specific Cox regression was performed to define relationship between MACE and cause of death. Results In a cohort of 219 patients treated with teclistamab with median follow-up of 20.1 months, 7.3% (N=16) developed MACE, 7.3% (N=16) developed arrhythmia and 12.8% (N=28) developing any MACE or arrhythmia. MACE occurred at a median of 4.5 days (IQR 2.25-15.75 days) after teclistamab step-up. The incidence of MACE was 16.4% in patients with baseline CVD versus 2.7% in those without baseline CVD (p<0.001). Patients who developed MACE had inferior ECOG performance status (PS) (PS >=2: 62.5% vs. 27.7%; p=0.008). Additionally, baseline hemoglobin level (9 vs 10g/dL; p=0.072) was numerically lower in MACE, compared to no MACE. There was no difference in age, sex, bone marrow (BM) plasma cell burden, ferritin, C-reactive protein or LDH levels between MACE vs. no MACE group. Patients who developed MACE had lower baseline diastolic blood pressure (67.7 vs 73.8mmHg; p=0.041) and numerically lower LVEF (51.4 vs 59.3%; p=0.059; baseline echocardiogram performed in 86% of all cohort). Patients who developed MACE had similar incidences of CRS (Grade >=2: 25.0 vs 16.7%; p=0.620) and immune effector cell-associated neurotoxicity (ICANS) grade 2 or higher (12.5 vs 7.5%; p=0.812). In multivariable Cox regression analysis, MACE was independently associated with inferior overall survival (HR 2.72; 95% CI 1.41-5.25; p=0.003), after adjusting for baseline CVD, age, high BM burden, extramedullary disease, and plasma cell leukemia. In cause-specific multivariable Cox regression analysis, MACE was independently associated with non-myeloma-related death (HR: 10.77 95% CI 4.39- 26.41; p<0.001) but not with myeloma-related death (1.54; 95% CI 0.64- 3.70; p=0.336). Conclusion In conclusion, in this large, real-world multicenter study, we observed that MACE occurred in over 7% of patients following teclistamab for RRMM, typically within 2 weeks of initiation. MACE was significantly associated with increased non-myeloma-related mortality. In contrast to CAR-T therapy, CRS or ICANS were not associated with MACE, whereas majority of patients who developed MACE had ECOG PS >=2 or baseline cardiovascular disease. More studies are necessary to define mechanisms and strategies to reduce these MACE and improve survival. Patients with baseline cardiovascular disease or poor performance status may benefit from cardiovascular optimization before and during teclistamab therapy.

Abstract Introduction: Bispecific T-cell engagers (TCE) targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab) are important therapeutic options in relapsed/refractory MM (RRMM). However, data on the independent prognostic impact of individual cytogenetic abnormalities and functional high-risk MM on outcomes with TCEs remains limited. Methods We included RRMM patients treated with BCMA TCEs (teclistamab, elranatamab) and talquetamab across 15 centers in the US. Patients where TCEs were used only as bridging therapy to CAR-T were excluded. High-risk cytogenetic abnormalities (HRCA) included del(17p), t(4;14), t(14;16), 1q gain/amplification (1q21+), del(1p) before initiation of TCE. Functional high-risk disease (FHRMM) was defined as PFS <18 months with frontline therapy. Extramedullary disease (EMD) included visceral or soft tissue disease and excluded paraskeletal disease. Progression-free survival (PFS) was estimated from TCE initiation using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictors of PFS in the entire cohort and the subcohorts of BCMA TCEs and talquetamab (Talq). Results We analyzed 943 treatment initiations with TCEs in RRMM, comprising 577 BCMA-directed TCEs [teclistamab (n=436) and elranatamab (n=141)] and 366 talquetamab initiations. The median follow-up from TCE initiation was 13.4 months (95% CI: 12.5–14.2) and median age was 68 years (interquartile range 61-75 years). Two ore more HRCAs were noted in 30% of the cohort (34% in Talq vs. 28% in BCMA TCEs, p=0.04), EMD was present in 21% of patients (26% in Talq vs. 18% in BCMA TCEs, p=0.002), and 45.5% of patients had FHRMM (47% in Talq vs. 45% in BCMA TCE, p=0.54). The median prior lines of therapy was 6 (interquartile range: 5-8), with 92% being triple-class refractory (TCR); 60% received prior BCMA-directed therapy (85% in Talq vs. 45% in BCMA TCE, p<0.0001) and 45% had prior CAR-T in 45% (57% in Talq vs. 37% in BCMA TCE, p<0.001). The best overall response rate (ORR) was 67.1 % for the entire cohort (66.4% for BCMA cohort and 68.2% for Talq), with 32.5% patients achieving a ≥ complete response. The median PFS was 7.7 months (95% CI: 6.7–8.6) for the entire cohort, with a median PFS of 10.1 months (95% CI: 7.5-13.4) for teclistamab and 10.1 months (95% CI: 3.9-NR) for elranatamab. In the more heavily pretreated talq cohort, the median PFS was 6.4 months (95% CI: 5.1-7.5). In a univariate analysis (UVA), several HRCAs were associated with inferior PFS−del(17p) (HR 1.59), t(4;14) (HR 1.43), del(1p) (HR 1.54), and ≥2 HRCAs (HR 1.64), all p<0.01. Apart from HRCAs, adverse disease characteristics included FHRMM (HR 1.20) and EMD (HR 1.46); all p<0.05. Among laboratory markers, hemoglobin <9 g/dL (HR 2.10), platelet count <75 ×10⁹/L (HR 1.96), and elevated ferritin (≥600 ng/mL; HR 2.17) (all p<0.01) were prognostic for PFS. ECOG ≥2 (HR 1.62), prior BCMA-directed therapy (HR 1.56), and prior CAR-T (HR 1.44) (all p<0.001) were also associated with inferior PFS. In a multivariable analysis (MVA), prior BCMA therapy (HR 1.72, p<0.0001), ferritin >600 ng/mL (HR 1.68, p<0.0001), hemoglobin <9 g/dL (HR 1.53, p=0.001), ECOG PS ≥2 (HR 1.52, p=0.0009), del(17p) (HR 1.44, p=0.0034) and FHRMM (HR 1.26, p=0.047), were associated with inferior PFS. Within the talq cohort (n=366), EMD (HR 1.64), del(17p) (HR 1.42), del(1p) (HR 1.54), FHRMM (HR 1.34), ECOG ≥2 (HR 1.56), ferritin >600 (HR 1.88), hemoglobin <9 g/dL (HR 1.6), platelet count <75 ×10⁹/L (HR 1.36) and leukopenia <0.25 x 10⁹/L (HR 1.52) were adverse prognostic markers on UVA. A MVA confirmed the independent impact of ferritin >600 ng/mL (HR: 1.77), ECOG ≥2 (HR 1.61) and functional high-risk status (HR 1.52) on PFS, whereas del(17p) and EMD were trending toward significance. Within the BCMA TCE cohort (n=577), prior BCMA therapy (HR 1.9), ferritin >600 (HR 1.79), ECOG ≥2 (HR 1.55), Hb <9 g/dL (HR 1.54), and del(17p) (HR 1.52) were independently associated with inferior PFS on a MVA.Conclusions: In this large real-world cohort of TCE, outcomes varied by fitness, disease biology, and treatment history. The ECOG PS, elevated ferritin, functional high-risk status and del(17p) were consistently associated with inferior PFS. Prior BCMA exposure was an independent risk factor for inferior PFS in the BCMA TCE cohort, but not with talquetamab.