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 <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.

Disclosures

Waldschmidt:Sanofi: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; Stemline Menarini: Consultancy; Pharmamar: Honoraria; GSK: Honoraria; Pfizer: Honoraria; Beigene: Honoraria; Janssen: Consultancy. Vucinic:Gilead/Kite, Janssen, BMS Celgene, Novartis: Consultancy, Honoraria; Amgen: Honoraria, Other: Travel grant. Wäsch:Amgen,BMS/Celgene, Janssen, Kite/Gilead, Novartis, Pfier, Sanofi: Consultancy; Janssen, Sanofi: Research Funding; Abbvie,Amgen, BMS/Celgene, Janssen, Kite/Gilead, Pfizer, Sanofi: Honoraria. Nogai:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Jannsen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Keiner: Current holder of stock options in a privately-held company; Amgen: Other: travel grants; Beigene: Other: travel grants. Alsdorf:Janssen: Consultancy, Honoraria, Other: Travel costs, accommodations, expenses, assistance in medical writing; Immatics: Consultancy, Other: Travel costs, accommodations, expenses, assistance in medical writing; GSK: Honoraria; Astellas: Honoraria; AstraZeneca: Honoraria; Biontech: Other: Travel costs, accommodations, expenses, assistance in medical writing, Research Funding; Affimed: Research Funding. Shumilov:BMS: Consultancy, Honoraria; Incyte: Honoraria; Oncopeptides: Consultancy, Honoraria, Other: Travel and congress support; Sanofi-Aventis: Consultancy, Honoraria, Other: Congress support; Stemline: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and congress support; Gilead: Consultancy, Honoraria, Other: Travel and congress support; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mueller:Kite/Gilead; Astrazeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Miltenyi, BMS, Janssen, Novartis: Consultancy, Honoraria, Speakers Bureau; ArgoBio, CRISPRTherapeutics: Consultancy; Sobi, Abbvie, Beigene: Honoraria, Speakers Bureau. Teipel:University Hospital Carl Gustav Carus Dresden, Germany: Current Employment; Janssen, BMS, Amgen: Consultancy; Janssen: Research Funding; Janssen, BMS, Takeda, GSK, Gilead, Sanofi, Amgen, Stemline, Oncopeptides, AbbVie: Honoraria. Gagelmann:J&J: Honoraria, Other: Travel support; BMS: Honoraria. Engelhardt:Janssen, BMS, Sanofi, Takeda, Pfizer: Consultancy; Janssen: Research Funding; Janssen, BMS, Sanofi, Pfizer: Honoraria. Krönke:Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Speakers Bureau; Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Honoraria; Janssen, Takeda, Abbvie, Jazz Pharmaceuticals, Sanofi, Astra Zeneca, Pfizer: Consultancy; Charité - Universitätsmedizin Berlin: Current Employment. Hudecek:Janssen: Honoraria, Other: Scientific advisory board; Cellgene/BMS: Honoraria, Other: Scientific advisory board; Novartis: Honoraria. Kortüm:GSK: Honoraria; Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Skyline Dx: Research Funding; Pfizer: Honoraria; Menarini Stemline: Honoraria. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Einsele:BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Topp:Autolus Therapeutics: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy; Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Universitatsklinikum Wurzburg: Current Employment. Rasche:Janssen: Honoraria; Skyline Dx: Research Funding; Pfizer: Honoraria; GSK: Honoraria; Amgen: Honoraria; BMS: Honoraria. Merz:Amgen, BMS, Celgene, Gilead, Jannsen, Stemline, SpringWorks and Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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2024
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