Extramedullary Multiple Myeloma Responds to Dual-Targeting CAR T-Cell Therapy

Audrey Sternberg

blood cellsD Chimeric antigen receptor (CAR) T-cell therapy targeting both BCMA and CD38 induced an objective response in >90% of patients with multiple myeloma who had received at least 3 prior therapies and whose disease had spread outside of the bone marrow. Yu Hu, MD, PhD, said these results justify further exploration of the dual-targeted therapy in this patient population during a presentation to an audience 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,” said Hu, of Union Hospital at Huazhong University of Science and Technology, as well as Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, both in Wuhan, China.

Among patients with multiple myeloma, roughly 10% will develop tumors in their organs or soft tissue known as extramedullary plasmacytomas. Patients who develop these lesions often have poor responses to available therapies, experience a decrease in their quality of life, and have poor prognoses. According to Hu, the study demonstrated that the novel dual-targeting BM38 CAR T-cell therapy may effectively eliminate extramedullary tumors.

“This new CAR T-cell [therapy] may have effects on the suppressor B cells. 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 was unresponsive to at least 3 prior therapies. Nine patients (41%) had extramedullary tumors. The median percentage of myeloma cells in the bone marrow was 9.7% (range, 0.50%-56.1%) by flow cytometry. Seventy-three percent of patients had cytogenetic abnormalities such as chromosome 1q21 amplification (54.6%) or deletion of chromosome 13q (40.9%).

All patients were treated with a 3-day lymphodepleting regimen of fludarabine at 25 mg/m2 and 250 mg/m2 cyclophosphamide to “make room” in the immune system for the engineered CAR T cells before infusion with the product. Patients were then infused with 0.5 × 106/kg to 4.0 × 10CAR T cells/kg, with at least 2 patients treated at every dose level.

The objective response rate was 90.1%, with 54.5% 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, and 4 with PRs. Three patients had experienced relapse, and 1 patient had progressive disease.

The median progression-free survival (PFS) was not been reached, and the 9-month PFS rate was 78.9%. For the 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 of 22 patients (90.9%), with 11 having grade 1 and 4 having grade 2 CRS. Severe CRS, grade ≥3, occurred in 5 patients (22.7%). Overall, only 6 patients required treatment for CRS. No neurotoxicity was observed. Hepatotoxicity was seen in 3 patients (13.6%), and 1 patient experienced nephrotoxicity.

The peak level of CAR T cells in peripheral blood occurred from 7 to 15 days post infusion in patients who achieved sCR and from day 14 to day 30 in patients without sCR. The longest time that CAR T cells were observed to persist in the peripheral blood was >450 days. BM38 CAR levels in the peripheral blood were tested by quantitative polymerase chain reaction.

Eight of 9 patients achieved complete or partial response of extramedullary disease, meaning that 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 of 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.
Li C, Mei H, Hu Y, 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: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 930. bit.ly/38imXXG.
 
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