Dual-Targeted CAR T-Cell Therapy Leads to Very High Response Rates in Relapsed or Refractory Multiple Myeloma

JHOP - February 2020 Vol 10, No 1 - ASH Highlights, CAR T-Cell Therapy, Multiple Myeloma

The investigational dual-­targeted CD38 chimeric antigen receptor (CAR) T-cell therapy achieved an objective response in more than 90% of patients with relapsed or refractory multiple myeloma who had received ≥3 previous therapies and whose disease had spread outside of the bone marrow. Furthermore, the therapy cleared extramedullary lesions in almost all patients with these lesions, according to results presented at ASH 2019.

This novel CAR T-cell therapy is the first to target the B-cell maturation antigen (BCMA), a protein on the surface of myeloma cells, as well as CD38 in multiple myeloma. This study focused on one of a growing number of bispecific T-cell engagers (better known as BiTE).

“This is the first clinical trial of anti-BCMA and CD38 dual-targeted CAR T-cell therapy in refractory multiple myeloma. Our study demonstrates improved efficacy and manageable safety and shows that this product can effectively achieve elimination of extramedullary tumors,” said Yu Hu, MD, PhD, Institute of Hematology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China, who presented the study results. “Although these data are preliminary, they are encouraging for patients with multiple myeloma who have not responded to other therapies,” he added.

Approximately 10% of patients with multiple myeloma will have extramedullary tumors in their organs or soft tissue. Patients with such tumors often have poor response to available therapies, a poor prognosis, and a decline in quality of life.

Exciting Preliminary Results

Dr Hu reported the preliminary results of 22 patients with multiple myeloma in the dose-escalation phase 1 clinical trial whose disease was unresponsive or relapsed after receiving ≥3 therapies. The median patient age was 59 years (range, 49-72 years), and 50% of the patients were male. Overall, 9 (41%) patients had extramedullary tumors.

The median percentage of myeloma cells in the bone marrow was 9.7% (range, 0.50%-56.1%) by flow cytometry. A total of 73% of the patients had cytogenetic abnormalities, including chromosome 1q21 amplification (54.6%) or deletion of chromosome 13q (40.9%).

All patients received treatment with a 3-day lymphodepleting regimen of chemotherapy with fludarabine at 25 mg/m2 and 250 mg/m2 cyclophosphamide before infusion of the novel BM38 CAR T-cell therapy at a planned dose of 0.5 × 106/kg to 4.0 × 106/kg CAR T-cells, with at least 2 patients receiving treatment at every dose level.

The objective response rate was 90.1%, with 54.5% of patients achieving a stringent complete response as the best response (ie, plasma cells were cleared from the bone marrow). Overall, 7 (31.8%) patients had a partial response, defined as a reduced level of M-protein in the blood or urine that was still detectable, with 2 patients achieving a very good partial response (VGPR). One patient had a minor response. A total of 18 (81.8%) patients reached bone marrow minimal residual disease–negative status.

High Response Rate in Extramedullary Disease

Of the 9 patients with extramedullary disease, 8 achieved a complete or partial response of extramedullary disease, rendering these tumors undetectable by computed tomography scan.

At the cutoff date of October 31, 2019, 19 of the 22 patients were still alive, with 10 still in stringent complete response, 1 with VGPR, and 4 with a partial response. A total of 3 patients had a relapse, and 1 patient had progressive disease.

The median progression-free survival (PFS) had not been reached, and the 9-month PFS rate was 78.9%. For the 17 patients still in remission at 7 months after treatment, the median duration of response was 28.8 weeks.

Cytokine release syndrome (CRS) was observed in 20 (90.9%) patients. Grade ≥3 severe CRS was reported in 5 (22.7%) patients, and 6 patients required treatment for CRS. No neurotoxicity was observed. Hepatotoxicity occurred in 3 (13.6%) patients, and 1 patient had nephrotoxicity.

“With this dual-targeted CAR T-cell therapy, we have demonstrated a high response rate, especially a higher rate and longer duration of stringent complete response, compared with other therapies, as well as effective elimination of extramedullary lesions, with no serious neurologic adverse effects and manageable levels of other adverse effects,” Dr Hu stated.

Continuing Studies

A 2-year follow-up of patients enrolled in the dose-escalation phase 1 trial will be conducted. In addition, a phase 2 clinical trial will be initiated in China and in the United States with a larger number of patients with multiple myeloma.

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