CAR T-Cell Therapy Targeting BCMA and CD38 Induces Positive Responses in Multiple Myeloma

Patients with a difficult-to-treat form of multiple myeloma who were treated with a novel, bispecific anti-BCMA/anti-CD38 chimeric antigen receptor (CAR) T-cell therapy experienced promising responses and a manageable safety profile, according to results of a study that were presented at the 61st Annual American Society of Hematology Annual Meeting and Exposition.

“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,” Yu Hu, MD, PhD, of Union Hospital at Huazhong University of Science and Technology in Wuhan, China, said during a press release.

Among patients with multiple myeloma, roughly 10% will develop tumors in their organs or soft tissue known as extramedullary tumors. Patients who develop these often have poor responses to available therapies, experience a decrease in their quality of life, and have poor prognoses. According to Hu, patients treated in the study demonstrated that the novel dual-targeting CAR T-cell therapy may effectively eliminate extramedullary tumors.

“This new CAR T cell [therapy] may have effects on the suppressor B cell. That means you can overcome the immunosuppression of the tumor environment,” Hu said.

In total, 22 patients with a median age of 59 years (range, 49-72), half of whom were male, were treated in the dose-climbing phase I trial. All patients had multiple myeloma that had returned or not responded to at least 3 prior therapies. Nine patients (41%) had extramedullary tumors. Myeloma cells in the bone marrow were observed at a median of 9.7% (0.50%-56.1%) by flow cytometry. Seventy-three percent of patients had cytogenetic abnormalities such as 1q21 amp (54.6%) and deletion of chromosome 13q (40.9%).

All patients were treated with a 3-day chemotherapy regimen of fludarabine at 25 mg/m²and cyclophosphamide 250 mg/m²to “make room” in the immune system for engineered CAR T cells before infusion with the product. Patients were infused with CAR T cells at 0.5 × 10⁶/kg to 4.0 × 10⁶/kg with at least 2 patients treated at every dose level.

The objective response rate was 90.1%, with 12 patients achieving a stringent complete response (sCR) as their best response, meaning that no plasma cells were detected in the bone marrow. Seven patients (31.8%) had a partial response (PR), meaning that the level of M-protein in the blood or urine was reduced but still detectable, with 2 achieving a very good partial response (VGPR). One patient had a minor response. Eighteen patients (81.8%) reached bone marrow minimal residual disease—negative status.

At the cutoff date of October 31, 2019, 19 patients were still alive with 10 still in sCR, 1 with VGPR, 4 with PRs. Three patients experienced relapse and 1 patient had progressive disease.

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

Cytokine release syndrome (CRS) was observed in 20 out of 22 patients (90.9%), with 11 having grade 1 CRS and 4 with grade 2. Severe CRS grade ≥3 occurred in 5 (22.7%) and only 6 patients overall required treatment. No neurotoxicity was observed. Hepatotoxicity was seen in 3 patients (13.6%) and 1 patient experienced nephrotoxicity.

The peak time of CAR T cells in peripheral blood occurred from day 7 to day 15 after infusions in patients who achieved sCR and from day 14 to day 30 in patients without sCR. The longest duration of CAR T cells in the peripheral blood was >450 days. BM38 CAR was tested by quantitative polymerase chain reaction (qPCR) in the peripheral blood.

Eight out of 9 patients achieved complete or partial response of extramedullary disease, meaning these tumors were undetectable by CT scan.

“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,” Hu said.

Investigators plan to continue follow up on these patients for 2 years. A phase II trial is being planned in both China and the United States to test the treatment’s efficacy in a larger number of patients.

Reference:

Mei H, Hu Y, Li C, et al. A bispecific CAR-T cell therapy targeting BCMA and CD38 for relapsed/refractory multiple myeloma: updated results from a phase 1 dose-climbing trial. Presented at: 61st Annual American Society of Hematology Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 930. https://bit.ly/38imXXG.