Adaptive bridging and holding therapy frequently reduces tumor burden and is associated with reduced toxicity after CAR-T cell therapy in multiple myeloma: A single-center real-world experience.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment of relapsed/refractory multiple myeloma (RRMM) but is associated with substantial toxicity. The association between pre-infusion disease control and post-infusion toxicity remains underexplored, and no treatment standards exist for bridging therapy in RRMM. OBJECTIVE: To characterize the holding and bridging regimens used in clinical practice, evaluate their effectiveness in achieving pre-infusion disease response, and assess the association between the depth of pre-infusion response and the incidence of post-infusion toxicity. STUDY DESIGN: In this single-center retrospective analysis, 88 consecutive RRMM patients received idecabtagene vicleucel (n=22) or ciltacabtagene autoleucel (n=66). Pre-infusion response was assessed using International Myeloma Working Group criteria. The primary endpoint was a composite of any ≥Grade 2 toxicity across six categories: cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, early and late immune effector cell-associated hematotoxicity, and infection, evaluated using log-link regression to estimate risk ratios (RR). RESULTS: Among the 88 patients included in the analysis, the median number of prior lines of therapy was 4. Holding and bridging therapy were administered in 80 (90.9%) and 87 (98.9%) patients, respectively. Twenty-four different therapeutic regimens were administered. Among the 79 patients who received both holding and bridging therapy, 32 (40.5%) changed regimens after apheresis due to insufficient response. Overall, 60/88 patients (68.2%) achieved ≥ partial response before infusion. Patients achieving ≥ very good partial response (VGPR) had a composite ≥Grade 2 toxicity rate of 8/35 (22.9%) compared with 25/53 (47.2%) in those with <VGPR (RR 0.48, 95% CI 0.25-0.95; p=0.035); this association persisted in the adjusted model including all 88 patients (adjusted RR 0.50, 95% CI 0.26-0.98; p=0.042). One case of CAR-T induced Guillain-Barré syndrome and seven cranial nerve palsies were observed, no parkinsonism occurred. Non-relapse mortality was 2/88 (2.3%). Alkylator-based holding therapy did not lead to an increased number of out-of-specification product. CONCLUSION: Deeper pre-infusion response was associated with significantly lower toxicity after BCMA-directed CAR-T therapy, identifying pre-infusion disease control as a potentially modifiable determinant of toxicity. Intensified holding and bridging strategies were feasible and effective in reducing disease burden in highly pretreated patients, supporting prospective validation of response-adapted bridging to improve the safety of CAR-T therapy in RRMM.