Efficacy of Anti-BCMA CAR-T Cell Therapies in Multiple Myeloma Patients with Prior Exposure to Bispecific Antibodies- Results from a Retrospective Multi-Center Registry Analysis
Authors: Waldschmidt Johannes , Fandrei David , Vucinic Vladan , Wäsch Ralph , Nogai Axel , Alsdorf Winfried , Brioli Annamaria , Shumilov Evgenii , Mueller Fabian , Teipel Raphael , Gagelmann Nico , Engelhardt Monika , Krönke Jan , Mersi Julia , Hudecek Michael , Kortüm Martin K. , Platzbecker Uwe , Einsele Hermann , Topp Max S. , Rasche Leo , Merz Maximilian 
Published: December 2024

Background
Over the past years, idecabtagen-vicleucel (ide-cel) and ciltacabtagen-autoleucel (cilta-cel) have emerged as first-in-class anti-BCMA CAR-T cell therapies with unprecedented efficacy in heavily pretreated relapsed/ refractory multiple myeloma (RRMM). While preliminary data suggests that prior exposure to bispecific antibodies (bsAb) negatively affects successful T-cell manufacturing and outcomes after CAR-T, bsAb remain an important bridging option for patients (pts) with penta-class refractory MM who have otherwise exhausted all salvage strategies. In this study, we aimed to dissect the impact of bsAb exposure if used as debulking before vs. bridging after T-cell apheresis in a multicenter real-world cohort of RRMM pts treated with commercial anti-BCMA CAR-T cells.
Methods
Data from n=39 bsAb-exposed MM pts treated at nine different centers in Germany were retrospectively collected and analyzed. Manufacturing failure was noted in 2/39 pts (5.1%). Another individual was excluded due to immature follow-up &lt;4 weeks after CAR-T cell infusion. For the remaining cohort of n=36 pts, survival analyses were conducted using the Kaplan-Meier method. The log-rank test was used for survival comparison among subgroups.
Results
Median age in this study was 63 (range 43-75) years at the time of apheresis. Pts were heavily pretreated with a median of 7 (range 3-13) prior lines of therapy. High-risk cytogenetics, defined as del17p, t(4;14), t(14;16) and/or ampl1q were identified in 19/36 (52.8%) pts, and extramedullary disease was present in 15/36 (41.7%) individuals. The overall response rate was 62.5% and 85.0% in pts treated with ide-cel (n=16, 41.2% very good partial response or better (≥VGPR)) and cilta-cel (n=20, 70.0% ≥VGPR)), respectively. At a median follow-up of 5.1 months after CAR-T infusion, progression-free survival (PFS) across the entire cohort was 9.6 months (0.7-NR) with no significant difference between ide-cel and cilta-cel (p=0.63). Treatment strategies before apheresis showed substantial heterogeneity with talquetamab (n=13) and CD38-antibody based triplets/ quadruplets (n=13) depicting the most frequently used therapies. Disease stabilization at the time of lymphodepletion, but not at apheresis showed a relevant trend for longer duration of response to CAR-T (P=0.091), underlining the critical importance of efficient bridging and disease control before CAR-T infusion. To further dissect the impact of previous bsAb exposure, pts were divided into i) pts without bsAb exposure prior to apheresis (“bridging-only” pts, n=9), pts with ii) teclistamab only (n=7) and iii) talquetamab only (n=15) before apheresis, as well as iv) pts who had received both teclistamab and talquetamab before apheresis (n=5). Shortest median PFS after CAR-T was observed for double-exposed pts (4.4 months), which compared to 9.1 months, 16.3 months and PFS not reached in teclistamab-exposed, talquetamab-exposed and “bridging-only” pts, respectively. To note, we observed that long-term exposure and refractoriness to teclistamab were specifically linked with primary refractoriness to anti-BCMA CAR-Ts. This was illustrated by 2 pts in our cohort who had been treated with teclistamab for ≥3.0 months and were retrospectively confirmed to have carried a biallelic TNFRSF17 loss by whole-genome sequencing before CAR-T infusion. Molecular analyses to retrospectively determine the frequency of GPRC5D and TNFRSF17 alterations in the entire study cohort are currently ongoing and will be presented at the meeting. At last follow-up, 8/39 (20.5%) pts had died from disease progression and 1/39 (2.5%) patient had died from infectious complications.
Conclusions
We here show that bsAb may be beneficial if used as bridging therapy to achieve better disease control before re-infusion of CAR-T. At the same time, our results endorse the notion that bsAb treatment should be avoided prior to T-cell apheresis. In addition, bridging should rather rely on talquetamab than teclistamab to avoid target antigen loss and ensure optimal CAR-T efficacy.