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2007 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

Program: Oral and Poster Abstracts
Session: 655. Multiple Myeloma: Cellular Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Bispecific Antibody Therapy, Clinical Research, Plasma Cell Disorders, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Genomics, Diseases, Therapy sequence, Real-world evidence, Treatment Considerations, Biological therapies, Immunology, Lymphoid Malignancies, Biological Processes, Technology and Procedures, Study Population, Human
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Johannes Waldschmidt, MD1, David Fandrei, MSc2*, Vladan Vucinic, MD3*, Ralph Wäsch4, Axel Nogai, MD5*, Winfried Alsdorf6*, Annamaria Brioli, MD, PhD7,8*, Evgenii Shumilov9*, Fabian Mueller, MD10, Raphael Teipel, MD11*, Nico Gagelmann, MD12*, Monika Engelhardt, MD13, Jan Krönke, MD14, Julia Mersi, MD1*, Michael Hudecek, MD, PhD1*, Martin K. Kortüm15*, Uwe Platzbecker, MD2, Hermann Einsele, MD16, Max S. Topp1*, Leo Rasche, MD17,18* and Maximilian Merz, MD2

1Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
2Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
3Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University of Leipzig, Leipzig, Saxony, Germany
4Department of Internal Medicine I, Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
5Charité Medical University, Berlin, Germany
6University Medical Center Hamburg-Eppendorf, Hamburg, Germany
7Klinik für Innere Medizin C, Universitätsmedizin Greifswald, Greifswald, Germany
8Department of Hematology and Oncology, Medizinische Hochschule Hannover, Hannover, Germany
9Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
10Department of Internal Medicine 5 - Hematology and Oncology, University Hospital of Erlangen, Erlangen, Germany
11Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
12Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
13Department of Hematology, Oncology and Stem Cell Transplantation, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
14Charité - Universitätsmedizin Berlin, Berlin, Germany
15Würzburg University Hospital, Wuerzburg, Germany
16Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
17Mildred-Scheel-Nachwuchszentrum, Wuerzburg, Germany
18Department of Internal Medicine II, University Hospital Wurzburg, Wurzburg, Germany

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; Amgen: Honoraria; BMS: Honoraria; GSK: 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.

*signifies non-member of ASH