A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma

J Hematol Oncol. 2021 Oct 9;14(1):161. doi: 10.1186/s13045-021-01170-7.


Background: BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations.

Methods: We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial.

Results: BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1-2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10-4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months.

Conclusion: Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM.

Trial registration: Chictr.org.cn ChiCTR1800018143.

Keywords: BCMA; Bispecific CAR; CD38; Chimeric antigen receptor-T cells; Multiple myeloma.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / antagonists & inhibitors
  • ADP-ribosyl Cyclase 1 / immunology*
  • Adult
  • Aged
  • Animals
  • B-Cell Maturation Antigen / antagonists & inhibitors
  • B-Cell Maturation Antigen / immunology*
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy, Adoptive / adverse effects
  • Immunotherapy, Adoptive / methods*
  • Male
  • Mice
  • Middle Aged
  • Molecular Docking Simulation
  • Multiple Myeloma / immunology
  • Multiple Myeloma / therapy*
  • Neoplasm Recurrence, Local / immunology
  • Neoplasm Recurrence, Local / therapy
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / therapeutic use*


  • B-Cell Maturation Antigen
  • Receptors, Chimeric Antigen
  • ADP-ribosyl Cyclase 1

Associated data

  • ChiCTR/ChiCTR1800018143