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    Cellular and T cell engager Immunotherapy

    (OA-71) Concurrent Administration of BCMA and GPRC5D Chimeric Antigen Receptor (CAR) T Cells for the Treatment of Relapsed or Refractory Multiple Myeloma: Results from the Phase I TANDEMM Clinical Trial

    Thursday, September 18, 2025
    16:40 - 16:50 East Coast USA Time
    Location: Room 701
    Introduction: Therapies targeting B cell maturation antigen (BCMA) and G protein coupled receptor class C, group 5, member D (GPRC5D) represent a major advance in the management of multiple myeloma. However, relapses are common and multi-antigen targeting has been proposed as a potential approach to achieve durable responses.

    Methods:

    We conducted a phase I, dose escalation trial of concurrent infusion of BCMA and GPRC5D CAR T cells, MCARH125 and MCARH109 in patients with relapsed or refractory myeloma. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell infusion at one of 3 dose levels (DL): DL 0, 150 X 106 cells of MCARH125 alone; DL 1, 50 X106 cells of MCARH109 and 150 X 106 cells of MCARH125; DL 2, 150 X106 cells of MCARH109 and 150 X 106 cells of MCARH125. The primary objective was to assess safety of MCARH125  alone or in combination with MCARH109, while the secondary objective was to assess anti-myeloma efficacy. Translational studies included assessing the antigen expression by immunohistochemistry and flow cytometry, T cell phenotyping by multi-omic profiling, and expansion of both CART products by quantitative polymerase chain reaction (qPCR).

    Results:

    19 patients with multiple myeloma and at least 3 prior lines of treatments were enrolled, and 15 patients were treated across the 3 doses levels. No patients in DL 0 and 67% of patients in DLs 1/2 had prior BCMA treatment. All patients (100%) had cytokine release syndrome with 1 (17%) patient at DL 0 and 2 (22%) patients at DLs 1/2 having grade 2 CRS; there were no grade 3 or higher CRS. One patient each at DL 0 and DL 2 had grade 3 immune effector cell associated hemophagocytic syndrome and this was considered a dose limiting toxicity (DLT). There were no instances of non-ICANS neurologic toxicities which have been reported with both BCMA and GPRC5D-directed therapies. Among the 15 treated patients, 13 (87%) patients achieved an objective response. This included all 6 (100%) patients at DL 0, and 7 (78%) of 9 patients treated at DLs 1/2. The median PFS for DL 0 and DL 1/2 were 20.1 months (95% CI: 17.5 to NR months) and 18.2 months (95% CI: 6.4 to NR). Down-regulation of one or both antigens was an important factor in patients with relapsed or refractory disease after treatment. Pre-infusion products among responders were enriched for CD8+ T cell memory populations by single cell RNA and ATAC sequencing. We also show that expansion of one CAR population can limit expansion of the second population, as dual-CAR treated patients (DLs 1/2) had significantly less BCMA-CAR expansion than BCMA-CAR alone treated patients (DL 0), despite equivalent BCMA CAR T cell doses at infusion.

    Conclusions: In this proof-of-concept trial, we demonstrate feasibility, safety, and efficacy of concurrently targeting two myeloma specific antigens BCMA and GPRC5D by co-administering two different CAR T products manufactured from a single apheresis.