Bispecific Antibodies as Bridging to BCMA CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma.

Abstract

Establishing a strategy for sequencing of T cell-redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell-engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen-directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody-based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen-directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10.