|The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
Early results of a phase 1 study of patients with relapsed/refractory multiple myeloma suggest that the benefits of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy may be enhanced when combined with an inhibitor of an enzyme that cleaves BCMA from the tumor cell surface. These findings were presented at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition held in Orlando, Florida.1
Although results of previous studies of BCMA-directed CAR-T therapy in multiple myeloma have been promising, available evidence suggests that many of the patients undergoing this type of treatment will ultimately experience disease relapse. The presence of myeloma cell populations with decreased expression of BCMA has been suggested as a putative mechanism of resistance to this approach.
BCMA levels on myeloma cells can be reduced by γ-secretase, a multisubunit protease that releases BCMA, as well as over 100 other membrane-bound proteins, from cell surfaces through cleavage at the transmembrane domain. The action of γ-secretase also increases levels of soluble BCMA. As a consequence, fewer myeloma cell targets are available for BCMA-directed CAR-T therapy. In addition, the soluble form of BCMA is also believed to interfere with CAR-T cell recognition of tumor cells. Recent preclinical studies of small-molecule inhibitors of γ-secretase have shown decreased levels of soluble BCMA, as well as improved surrogates of BCMA-directed CAR-T therapy function, when BCMA cleavage is blocked.2
In this phase I study (ClinicalTrials.gov Identifier: NCT03502577) of patients with relapsed/refractory multiple myeloma, a “run-in” of 3 doses of an oral γ-secretase inhibitor, JSMD194, were administered over 5 days followed by infusion of anti-BCMA CAR-T cells, and administration of oral JSMD194 three times weekly for a total of 3 weeks starting with the CAR-T cell infusion.
Of the 8 patients enrolled in the study, the median patient age was 64.5 years, and high-risk disease features were present in three-quarters of the study population. Of the 7 patients who received study treatment, 2 patients had undergone prior treatment with anti-BCMA CAR-T therapy but were refractory to this approach.
Of the 6 patients evaluable for efficacy, 83.3% and 16.7% achieved a very good partial response and a partial response respectively, for an overall response rate of 100%.
At a median follow-up of 5 months, no patients had experienced disease relapse.
Regarding safety, cytokine release syndrome (CRS) occurred in 100% of patients treated with the study drug. Most of these adverse events were grade 1 or 2 although there was 1 patient death at day 33 that was attributed to CRS and concurrent fungal infection. Neurotoxicity was reported in 70% of patients and the same percentage of patients experienced Grade 3 or higher neutropenic fever.
In their concluding comments, the study authors noted that “longer follow-up is required to determine if the durability of response is improved” with this approach.
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- Cowan AJ, Pont M, Sather BD, et al. Efficacy and safety of fully human BCMA CAR T cells in combination with a gamma secretase inhibitor to increase BCMA surface expression in patients with relapsed or refractory multiple myeloma. Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2019; Orlando, FL. Abstract 204.
- Pont MJ, Hill T, Cole GO, et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood. 2019;134:1585-1597.