Prior Exposure to BCMA-Directed Therapy Is Associated with Inferior Outcomes after BCMA CAR-T in Multiple Myeloma – a Single Institution Experience

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Introduction Chimeric antigen receptor (CAR)-T therapy, bispecific T-cell engager antibodies (BiTE), and antibody-drug conjugates (ADC) represent revolutionary advances in the treatment of relapsed/refractory (R/R) multiple myeloma (MM). Results from CARTITUTE-2 Cohort C showed reasonable efficacy of BCMA CAR-T after prior exposure to BCMA-targeting agents (BCMA-exposed MM), although the response rates were lower compared to BCMA-directed therapy naïve patients (BCMA-naïve MM) in CARTITUDE-1 (Cohen et al., 2023). We aimed to compare the outcomes of BCMA CAR-T in BCMA-exposed vs BCMA-naïve MM in a real-world setting. Methods We performed a retrospective chart review of MM patients who received BCMA CAR-T at UPMC between 2021-2024. Patients with at least 6 months of follow-up post-CAR-T were included in the analysis. Baseline demographics, MM disease risk, and clinical outcomes were compared between the patients who received BCMA-directed therapy (belantamab mafodotin or teclistamab; BCMA-exposed group) and those who did not (BCMA-naïve group). Results Among 59 patients, 8 (13.5%) had received treatment with either belantamab mafodotin (n=7) or teclistamab (n=1) before CAR-T infusion Baseline patient characteristics , including age, sex, cytogenetic risk, and median number of prior lines of therapy, were comparable between both cohorts. 45 (76%) received cilia-cel, and 14 (24%) received ide-cel. The rates and grades of CRS and ICANS were not statistically different between the two groups. Significantly better best responses (CR or VGPR, 86%) were observed in BCMA-naïve group compared to 38% in BCMA-exposed group (p=0.001). Overall survival (OS) and event-free survival (EFS) were significantly higher in BCMA-naïve group compared to BCMA-exposed one, with median OS 611 vs. 281 days (p= 0.01), median EFS 385 days vs. 53 days (p=0.005), respectively (Figure A-B). BCMA-naïve group also survived longer after relapse or disease progression compared to the BCMA-exposed group (median post-progression survival, 353 days vs. 105 days, p=0.04). Among BCMA-naïve patients who relapsed or progressed after CAR-T, significantly longer survival was observed in ones who received BCMA-directed therapy as a first salvage treatment compared to other therapy (median post-progression survival, 535 days vs. 150 days, p=0.03; Figure C). Conclusion We observed inferior outcomes with BCMA CAR-T in patients with prior exposure to BCMA-targeted therapy compared to BCMA-naïve patients. Our data also showed that BCMA-naïve patients could be salvaged by BCMA-directed therapy when they progressed after CAR-T. Although the sample size is limited, our data may support BCMA CAR-T before patients are exposed to other BCMA-directed therapies. Further studies are needed to establish the optimal sequencing strategy, including GPRC5D targeted therapy .

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