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Low Dose GSI, BCMA CAR T-Cell Combo Yields Anti-Tumor Activity in R/R MM
Investigative data were shared at the 2021 Annual American Society of Hematology (ASH) Meeting to report on escalating doses of chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) in relapsed or refractory (R/R) multiple myeloma (MM).
“CAR T-cells targeting BCMA demonstrate rapid and deep responses in patients with multi agent R/R MM. Previously, gamma secretase inhibitors (GSI) show an increase of BCMA surface density on tumor cells and a decrease in soluble BCMA levels,” explained Andrew Cowan, MD, French Hutchinson Cancer Research Center, Washington, and co-researchers.
To be eligible for enrollment, patients were required to have a R/R MM diagnosis with ≥10 percent plasma cells in the bone marrow by CD138 IHC and measurable disease. Patients received GSI (JSMD194) monotherapy consisting of 3 oral doses (25 mg), which was administered 48 hours apart over 5 days to assess the impact of GSI on plasma cell BCMA expression.
After lymphodepletion, BCMA CAR T-cells were infused at a starting dose of 5 x 107 CAR+ cells with a combination of JSMD194 dosed orally at 25 mg thrice weekly for 3 weeks, starting on the day of the CAR infusion.
Overall, 18 patients underwent leukapheresis, with JSMD194, and BCMA CAR T-cell treatment. The median patient age was 65 years, and each had a median of 10 prior lines of therapy. The study found 67 percent of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab. Further, 72 percent had high-risk cytogenetic features and 28 percent had extramedullary disease.
“39 percent of patients had prior BCMA targeted therapy. Other BCMA targeted CAR T-cell products had previously been administered to 22 percent. All patients completed the 5-day run-in with JSMD194. After 3 oral doses of GSI, an increased was observed from a median of 610 to 9563 receptors per cell, a 12-fold median,” continued Dr Cowan and co-authors.
Notably, 5 patients were treated at 5x107 CAR+ cells, 3 were treated at 15x107, 3 were treated at 30x107, and 7 were treated at 45x107 CAR+ cells dose levels. Treatment was identified to be consistent with other BCMA CAR-T therapies, with manageable toxicities.
The overall response rate was 89 percent, with 14 patients achieving ≥ a very good partial response (VGPR) and 8 patients achieving CR (including 5 with partial CR). Deep responses were observed at all dose levels. The median follow-up time was 20 months, the median progression free survival (PFS) rate was 11 months (95% CI, 6 months to not reached).
Reported treatment-emergent adverse events (TEAEs) included cytokine release syndrome (CRS) which was experienced by 95 percent of patients, mostly grade 1-2 (83%).
“We have demonstrated that the GSI with BCMA CAR T-cell combination treatment is safe and tolerable. GSI administration routinely increased BCMA surface density on plasma cells. Further, we observed durable, rapid responses in a heavily pretreated refractory population of MM patients, of whom a significant proportion had prior BCMA targeted and CAR-T therapy. This combination may augment anti-tumor activity, even when very low doses of BCMA CAR T-cells are administered,” concluded Dr Cowan, et al.—Alexa Stoia
Cowan A, Pont M, Sather B, et al. Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase BCMA Surface Expression in Patients with R/R Multiple Myeloma. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 551
