Bridging Therapy's effects on clinical outcomes after commercial BCMA CAR T-cell therapy used in the standard of care treatment of relapsed and refractory multiple myeloma

Abstract

Abstract Background: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has revolutionized treatment of relapsed/refractory multiple myeloma (RRMM), prolonging survival and extending treatment-free intervals to patients with aggressive, high-risk disease. However, virtually all patients eventually experience relapse following CAR T therapy. CAR T treatment requires bridging therapy during the manufacturing period, which can extend up to 3 months. Some have postulated that bridging may affect outcomes due to its effects on T-cell health and on disease status. Optimizing the bridging strategy presents an opportunity to improve outcomes. Methods: We performed a retrospective chart review of 69 patients who received CAR T therapy for RRMM at our institution between December 2022 and November 2024. Patients were categorized by bridging regimen: Selinexor-based, bispecific T-cell engager, cytotoxic chemotherapy (VD-PACE or VAD), biological myeloma therapeutics (proteasome inhibitors, anti-CD138 agents, immunomodulatory agents), or no bridging therapy. All patients who received cytotoxic chemotherapy began bridging after apheresis. Responses were assessed using International Myeloma Working Group criteria. Statistical analysis was performed using JMP Pro 18. Results: At time of evaluation, there were 69 eligible patients, 35 were female and 34 were male. 68% were white, and 29% were black. More than half of the patients had high risk disease (56% high, 1.5% intermediate, and 42% standard risk). Patients received an average of 6.5 lines of treatment prior to CAR T-cell therapy. 56 patients received bridging therapy. Bridging regimens included: Selinexor-based (20%), bispecific T-cell engager (9%), cytotoxic chemotherapy (10%), and biological myeloma therapeutics (41%). Ultimately, 56 received Carvkyti, and 13 received Abecma. Median follow-up was 273 days. At CAR T infusion, patients receiving bispecific T-cell engager bridging achieved deeper responses compared to other groups (p<0.01), but were less likely to achieve a complete response (CR) or very good partial response (VGPR) as their best overall response (p=0.03). Those bridged with cytotoxic chemotherapy were less likely to achieve deep responses as their best overall response (p=0.01), and at 3 months post-infusion, these patients were more likely to have progressive disease (PD) and less likely to achieve CR (p=0.03). This pattern persisted at 12 months (p<0.001). It is possible that this reflects the state of the patients' disease and poorer T-cell health as these patients had a trend toward having received more lines of therapy prior to CAR T that narrowly missed significance (p=0.06). Conversely, patients receiving Selinexor-based bridging had a trend towards having better responses at time of CAR T-cell re-infusion that narrowly missed statistical significance (p=0.06), but this relationship was not maintained at 3 or 12 months, or with best overall response (p>0.05 in all analyses). Patients who received biological myeloma therapeutic bridging regimens were less likely to have PD at 12 months (p=0.03). Notably, response at CAR T infusion did not correlate with responses at 3 or 12 months, best overall response, or minimal residual disease (p>0.05 in all analyses). Regarding toxicity, patients bridged with cytotoxic chemotherapy more frequently required growth factor support in the 3 months post-CAR T infusion (p=0.04). Patients with PD at bridging completion had higher rates of Cytokine Release Syndrome compared to those achieving ≥VGPR (p=0.02). No similar relationship was observed for Immune Effector Cell-Associated Neurotoxicity Syndrome due to low overall prevalence in the study population (n=9).Conclusion: This analysis demonstrates that choice of bridging therapy significantly impacts outcomes in RRMM patients receiving CAR T therapy. Cytotoxic chemotherapy bridging was associated with inferior responses and increased supportive care needs, while bispecific T-cell engager therapy achieved superior pre-infusion responses but showed concerning long-term outcomes. Our study suggests Selinexor may be a preferrable bridging agent for patients who are ineligible for bridging with biological myeloma therapeutics. Although limited by small sample sizes in some bridging categories, these findings may inform clinical decision-making and support the design of prospective trials optimizing bridging strategies for CAR T therapy.