Two-Target Chimeric Antigen Receptor-T cells in Relapsed or Refractory Multiple Myeloma

A recent phase I trial, co-led by Heng Mei and Chenggong Li, evaluated the use of chimeric antigen receptor-T cells (CAR-Ts) targeting both B-cell maturation antigen (BCMA) and CD38 proteins in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) and deemed them to be “feasible, safe, and significantly effective.” Their findings were published in the Journal of Hematology & Oncology.

According to the authors, this was the first trial to demonstrate the potential value of humanized bispecific BM38 CAR-Ts in RRMM. The report stated that the treatment “showed significant in vivo persistence, deep and durable responses and effective elimination of [extramedullary disease (EMD)].”

The antitumor activity of the BM38 CAR-Ts was tested in vitro and in vivo in 23 patients with RRMM. Researchers judged the primary endpoint, safety, via the severity, frequency, and duration of adverse events. Overall response rate (ORR) was presented as a key secondary endpoint. Cytokine release syndrome (CRS) and other observed toxicities were graded.

BM38 CAR-Ts showed stronger in vitro anti-cancer cell effects than single-target CAR-Ts. During the trial, CRS—mostly grade I to II—occurred in 20 patients (87%). At nine months, 20 patients (87%) had attained a clinical response and minimal residual disease-negativity, and 12 (52%) has achieved a stringent complete response. Extramedullary plasmacytoma was reduced or eliminated in the majority of patients. The participants’ median progression-free survival was 17.2 months. Notably, two relapsed patients maintained BCMA and CD38 expression on MM cells. BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months, and 62.2% at 12 months.

Given their preliminary findings, the study’s collaborators proposed that bispecific BM38 CAR-Ts may have stronger anti-tumor effects than BCMA– or CD38–specific CAR-Ts while also mitigating some limitations of single-target immunotherapy, such as primary resistance and relapse. The authors called for multicenter clinical trials to validate their findings, and further suggested the effects of CD38-targeted single-chain variable fragment (scFv) as a direction for future research.