Bridging therapy response and low pre-lymphodepletion plasma cell burden are associated with improved safety and efficacy outcomes of ciltacabtagene autoleucel in multiple myeloma

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Abstract Introduction.Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapy (CAR-T) approved for relapsed/refractory multiple myeloma (RRMM) after ≥1 prior lines of therapy (pLOT). Bridging therapy (BT) is frequently used to control disease while awaiting CAR-T manufacturing, with the potential to reduce the risk of immune-mediated toxicities and enhance efficacy through disease debulking. Emerging data suggest that both BT type and disease burden at the time of lymphodepletion (LD) may influence treatment response and toxicity. In this analysis, we characterize the use of BT and evaluate the impact of pre-LD tumor burden on cilta-cel outcomes in the standard of care (SOC) setting. Methods. We conducted a retrospective study of RRMM patients treated with commercial cilta-cel at Moffitt Cancer Center between May 11, 2022 and November 13, 2024. Patient characteristics, including BT type and response per International Myeloma Working Group criteria, were summarized using descriptive statistics. Efficacy and safety outcomes were evaluated and stratified by biochemical response to BT (≥25% reduction in paraprotein from apheresis to the start of LD vs. paraprotein either increased, no change, or <25% reduction) and by pre-LD plasma cell burden (PCB, <50% vs. ≥50% plasma cells). Results. Among 128 RRMM patients who underwent leukapheresis, 100 (78%) received BT followed by SOC cilta-cel. Most patients were heavily pretreated, with a median of 5 pLOT (range 1-11); only 4 patients had ≤2 pLOT. Several unique BT regimens were used: alkylators (44%), PI-based combinations (21%), IMiD/CD 38 mAb (14%), selinexor or talquetamab (7% each), and others (6%). Patients with <6 vs. ≥6 pLOT were more likely to receive talquetamab BT (p=0.06). No other significant differences in baseline characteristics were observed by BT regimen, likely due to limited sample size and treatment heterogeneity. Of 84 patients with measurable disease, 77/84 (92%) achieved a partial response or better following cilta-cel. Best overall response rate (ORR) was numerically higher in BT responders compared to non-responders (95% vs. 89%, p=0.5). BT responders were more likely to have <50% pre-LD PCB (89% vs. 57%, p=0.001) and less likely to have high-risk cytogenetics at any time prior to CAR-T infusion (41% vs. 83%, p<0.001) which was driven by del17p (10% vs. 46%, p=0.005) and 1q gain abnormality (55% vs. 82%, p=0.03). BT responders also had a lower peak absolute lymphocyte count post-CAR-T infusion (580/µL vs. 1140/µL, p=0.01). Biochemical response rates (≥25% paraprotein reduction) by BT type were highest with talquetamab (83%), followed by PI-based combinations (61%), and alkylators (43%). Patients with biochemical response to BT experienced numerically lower rates of grade ≥3 cytokine release syndrome (CRS, 0% vs. 9%, p=0.13), any grade immune effector cell-associated neurotoxicity syndrome (ICANS, 11% vs. 21%, p=0.2), and grade ≥3 ICANS (3% vs. 11%, p=0.2, respectively). Safety outcomes did not differ significantly by BT type. Patients with low (<50%, N=59) vs. high (≥50%, N=24) pre-LD PCB (data available in 83 patients with measurable disease with ≥ 90 days of follow up) had numerically higher response rates to cilta-cel (ORR: 95% vs. 88%, p=0.3, ≥Complete Response: 63% vs. 58%, p=0.7) and longer progression-free survival (median not reached vs 14 months, p=0.13). Low pre-LD PCB was also associated with a significantly lower rate of grade ≥3 CRS compared to high pre-LD PCB (0% vs. 13%, p=0.02), and a numerically lower rate of any-grade ICANS (14% vs. 21%, p=0.5) and Parkinsonian neurotoxicity [0, (0%) vs. 2 (8%), p=0.08], although no significant differences in grade ≥3 ICANS or other non-ICANS neurotoxicities were observed. Conclusion. Bridging therapies were heterogenous and led to better safety and efficacy after cilta-cel. Talquetamab-based BT was associated with improved cilta-cel responses in heavily pretreated RRMM. Biochemical response to BT and low pre-LD PCB (<50%) were associated with higher responses and lower rates of CRS and neurotoxicity. Reevaluating the role of bridging therapy is critical for optimizing clinical management extending beyond its traditional use as a temporizing measure. Larger cohorts with longer follow-up are needed to better assess the effectiveness of specific BT regimens and their impact on long-term outcomes with SOC cilta-cel.

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