Bispecific CAR-T Cell Therapy Shows Promise Treating RRMM

The initial results are positive for a new therapy for relapsed/refractory multiple myeloma (RRMM).

A team of investigators, led by Heng Mei, MD, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, constructed a dual-target BM38 CAR incorporating anti-CD38 and anti-BCMA single-chain variable fragment in tandem, along with 4-1BB signaling CD3 zeta domains.

The investigators also conducted the first in-human clinical trial in patients with RRMM to evaluate the safety. Efficacy, and duration of BM38 T cells.

The study, the American Society of Hematology (ASH) 2019 annual meeting, included patients with RRMM, who had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunodulatory agent.

In the new dose-climbing trial, patients were subjected to a lymphodepleting regimen with Cy(250 mg/m², d-5 to d-3) and Flu(25 mg/m², d-5 to d-3) daily prior to the CAR-T infusion (d0).

In previous clinical trials, anti-B cell maturation antigen (BCMA) chimeric antigen receptor(CAR) T cell therapy has shown promise.

The investigators assessed the efficacy of the treatment with the International Uniform Response Criteria for Multiple Myeloma and graded toxicity with CTCAE 5.0.

The dose gradients of infused CAR-T cells were 0.5, 1.0, 2.0, 3.0 and 4.0×106 cells/kg and at least 2 patients were involved at every dose level.

As of July 31, 2019, 16 patients, 10 (62.5%) had genetic abnormalities and 5 (31.25%) with extramedullary lesions, had received BM38 CAR-T cells in the 5 dose-climbing cohorts. At a median follow-up of 36 weeks, no dose-limiting toxicity, and no grade ≥ 3 neurotoxicity’s were observed.

Cytokine release syndrome (CRS), generally grade 1-2, was reported in 10 (62.5%) patients, while 4 patients had grade ≥ 3 CRS that resolved by tocilizumab and supportive treatment.

Nearly all the patients were observed with hematological toxicities relieved in the first month after infusion, while14 (87.5%) patients achieved an overall response with 8 (50%) sCR, 2 (12.5%) VGPR, and 4( 25.00%) PR and 14 (87.5%) reached bone marrow minimal residual disease-negative status. The longest duration of sCR was over 51 weeks and 5 (62.5%) of patients had still maintained sCR, while an additional 2 patients transformed to VGPR and 1 to PR.

The median duration of progression-free survival(PFS) had not been reached, but PFS rates at 9 months was 75%.

“More encouragingly, 5 (100%)extramedullary lesions were eliminated,” the authors wrote. “Up to the observed day, the BM38 CAR-T cells still exist in the patients’ peripheral blood by flow cytometry(FCM) and quantitative polymerase chain reaction(q-PCR).”

The peak time of CAR-T cells proliferation of sCR patient was about the 2^nd week after infusion, which was earlier than other patients.

4.0 × 10⁶ CAR T cells (patient 11, 12, and 15) were selected for the optimal dose with superior response and acceptable toxicities and expansion cohort would be conducted.

“Our study demonstrates an improved efficacy with the bivalent BM38 CAR-T therapy for RRMM with a high ORR, especially a higher rate and a longer duration of sCR and effective elimination for extramedullary lesions,” the authors wrote. “No neurotoxicity was observed. CRS and other toxicities were manageable. These initial data provide strong evidence to support the further development of the dual-target CAR-T therapy for RRMM.”