Efficacy of BCMA T-Cell Engagers (TCE) Vs. Chimeric Antigen Receptor T-Cell Therapy (CAR-T) Following BCMA-Directed Therapies, Relapsed/Refractory Multiple Myeloma: The Chicken or the Egg Dilemma
Authors: Snyder Jordan , Ahmed Nausheen , Mahmoudjafari Zahra , Abdallah Al-Ola , McGuirk Joseph P. , Mushtaq Muhammad Umair , Habib Alma , Khan Abdullah Mohammad , Laharwal Mehak M , Mewawalla Prerna , McKenna Marshall , Tiger Yun Kyoung , Shaikh Hira , Vegel Andrew , Struble Emily , Lochner Jonathan , Strouse Christopher , Green Kimberly M , Davis James A , Hashmi Hamza , Atrash Shebli , Friend Reed , Paul Barry 
Published: December 2024

Introduction: The landscape of multiple myeloma (MM) has changed significantly since the approval of B-cell maturation antigen (BCMA)-directed therapies (BDT). Currently, four different BDTs are approved by the FDA in the US: 2 T-cell engagers (TCE) - teclistamab and elranatamab, and 2 chimeric antigen receptor T-cell (CAR-T) therapies - Idecabtagene viceleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Several others are in various stages of development. Consequently, there are concerns about the most effective way to sequence multiple BDTs. Our study aims to evaluate the efficacy of BCMA TCE in comparison to BCMA CAR-T post-BDT in relapsed/refractory MM (RRMM) in a real-world patient population.

Methods: A retrospective review was conducted at 7 centers in the US in collaboration with US Myeloma Innovations Research Collaborative (USMIRC). The review involved 95 patients (pts) with RRMM who had received either BCMA TCE or BCMA CAR-T following prior BDT. The prior BDT could have been standard of care or investigational products, including CAR-T, antibody-drug conjugate (ADC), TCE, or monoclonal antibodies (mAb). Overall response rate (ORR), complete response (CR), very good partial response (VGPR) was evaluated using the International Myeloma Working Group (IMWG) criteria. Using R Core Team (2024) software, a descriptive analysis was performed. Continuous variables were summarized and reported the mean (minimum, maximum) and median (interquartile range [IQR]). Dichotomized factors were summarized by total numbers and frequency. Fisher's exact was used to analyze contingency tables. Wilcoxon rank-sum test was used to compare two independent samples.

Results: Among the 95 RRMM pts who previously received treatment with a BDT, 44% received a BCMA CAR-T as the second BDT (42 pts, with 32 receiving ide-cel and 10 cilta-cel) and 56% received BCMA TCE as the second BDT (53 pts, 52 receiving teclistamab and 1 receiving elranatamab). The median age was 66 years (range: 42-83) for both groups, with 60% vs. 58% having IgG isotype in the BCMA CAR-T vs BCMA TCE, respectively. Twenty six percent vs. 28% had stage 3 disease per the revised international staging system (R-ISS), and 43% vs. 57% had high-risk cytogenetics in the BCMA CAR-T vs. TCE groups, respectively. Furthermore, 43% vs. 42% had extramedullary disease and 86% vs. 92% had triple refractory disease. The median lines of therapies (LOT) were 8 (6-12) vs. 7 (6-9) in the BCMA CAR-T vs. BCMA TCE cohorts. The most common prior BDT in the BCMA CAR-T cohort was ADC at 64%, followed by TCE at 29%. In the BCMA TCE cohort, the most common prior BDT was CAR-T at 75%, followed by ADC at 23%.

At a median follow-up of 21 months (IQR: 5-not reached [NR]), the ORR with a second BDT was notably higher in the BCMA CAR-T group compared to the BCMA TCE group, at 79% versus 51% (p&lt;0.001), while responses of ≥ VGPR were seen in 64% vs 47% (p&lt;0.001) of patients treated with BCMA CAR-T and BCMA TCE, respectively. Additionally, the median PFS was 6 months (95% CI: 5-14) for BCMA CAR-T and 2 months (95% CI: 1-8) for BCMA TCE (p=0.057). The median OS was 30 months (95% CI: 30-NR) for BCMA CAR-T and 12 months (95% CI: 7-NR) for BCMA TCE (p=0.008). Disease progression was the most common cause of death in both groups, accounting for 16 (33%) vs. 18 (29%) deaths in patients receiving BCMA CAR-T and TCE, respectively. Non-relapse mortality occurred in 4 (8%) vs. 8 (15%) deaths in the BCMA CAR-T and BCMA TCE groups, respectively (p &gt; 0.05).

Conclusion: Subsequent therapy after initial BDT treatment is a crucial consideration, particularly with the approval of numerous BDTs for RRMM. Our study showed significant efficacy with BCMA CAR-T and BCM TCE. However, improved depth of response, as well as longer PFS and OS was seen in the BCMA CAR-T cohort compared to BCMA TCE cohort. Considering the recent approval of BCMA CAR-T for early relapse MM, the ability to safely and effectively use subsequent BDTs is an important consideration for choosing therapy and should be evaluated in prospective trials.