7511 Background: Chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engager (BiTE) antibodies for relapsed and refractory multiple myeloma (MM) are increasingly used earlier in the disease course but the optimal sequencing remains unclear. It has been hypothesized that CAR T before BiTE would lead to less T-cell exhaustion and better outcomes than BiTE before CAR T. Methods: A multicenter retrospective cohort study using the TriNetX Global Collaborative Network from 2021-2025 to evaluate outcomes among MM pts who received both CAR-T (idecel or ciltacel) and a BiTE (teclistamab, talquetamab, or elranatamab). Cohorts by treatment sequence: CAR-T followed by BiTE (CAR-T→BiTE) or BiTE followed by CAR-T (BiTE→CAR-T). Primary outcome: 5-yr mortality from the initiation of first advanced immunotherapy. Secondary outcomes: incidence of CRS, ICANS, infection, sepsis, ICU admission, and 1-yr mortality following each therapy. Propensity score matching included demographic variables, comorbidities, prior myeloma therapies (including prior SCTx) and baseline laboratory values. Results: 389 pts were included (244 CAR-T→BiTE; 145 BiTE→CAR-T); in the CAR T 1st group, 72% received ide-cel and 28% had cilta-cel, whereas in the BiTE 1st group 86% went on to receive cilta-cel as the CAR T product. Median overall survival was reached in the BiTE-first cohort (3.59 years) but not in the CAR-T–first cohort. Five-year survival was significantly higher with CAR-T–first sequencing (57.1% vs 25.5%; log-rank p = 0.045). In adjusted Cox regression, CAR-T–first sequencing was independently associated with lower 5-year mortality (hazard ratio 0.57, 95% CI 0.34–0.95). In unmatched analyses stratified by the specific BiTE (anti-BCMA vs anti-GPRC5D) used, overall survival did not differ significantly within each treatment sequence (all log-rank p > 0.05). In propensity score–matched analyses (112 patients per group), CAR-T–first pts experienced higher ICANS (all grades, 22% vs 10.7%) after first therapy but lower ICU admission (52% vs 70%), and significantly lower CRS (37% vs 56%, all grades) following second therapy. Rates of infection, sepsis, and 1-yr mortality were similar between groups. Conclusions: Among patients with MM who received both CAR-T and BiTE therapies, CAR-T–first sequencing was associated with significantly improved long-term survival in spite of a much higher percentage receiving the less effective CAR T product. The additional finding of a lack of survival differences by specific BiTE used also suggests that treatment order, rather than product selection, may be the primary determinant of long-term outcomes. These findings support consideration of earlier CAR-T deployment when feasible and underscore the importance of sequencing strategy in the evolving landscape of MM immunotherapy.
O’Brien et al. (Thu,) studied this question.