In a single-institution, phase I, first-in-human trial reported in The Lancet Oncology, Cowan et al found that the combination of the γ-secretase inhibitor (GSI) crenigacestat and B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy was tolerable and produced a high response rate in patients with relapsed or refractory multiple myeloma.
“GSIs increase BCMA density on malignant plasma cells and enhance antitumor activity of BCMA CAR T cells in preclinical models,” the investigators said.
Study Details
In the trial, 18 patients who had undergone previous autologous stem cell transplantation or who had persistent disease after more than four cycles of induction therapy received treatment at Fred Hutchinson Cancer Center between July 2018 and April 2021. Patients received three doses of crenigacestat at 25 mg over 48 hours during a treatment run-in to permit assessment of the effect of the GSI on BCMA surface density on bone marrow plasma cells. Patients then received BCMA CAR T cells infused at doses of 50, 150, 300, and 450 × 10⁶ CAR T cells combined with crenigacestat at 25 mg three times a week for up to nine doses.
Key Findings
Median follow-up was 36 months (95% confidence interval [CI] = 26 months to not reached). No phase II dose of the combination was established.
The most common nonhematologic grade ≥ 3 adverse events were hypophosphatemia (in 78% of patients), fatigue (61%), hypocalcemia (50%), and hypertension (39%); grade ≥ 3 infections occurred in 22%. Cytokine-release syndrome of any grade occurred in 94% of patients and was grade 3 or 4 in 11%. Immune effector cell–associated neurotoxicity syndrome (ICANS) of any grade occurred in 39% and was grade 3 or 4 in 11%. Two treatment-related deaths occurred, both outside the 28-day reporting period: one from disseminated herpes simplex virus infection and one from cytokine-release syndrome and ICANS.
Among 17 patients with an increase in BCMA antibody binding capacity measured on bone marrow plasma cells before and after crenigacestat run-in, antibody binding capacity increased from a median of 663 receptors per cell to 9,583 receptors per cell—a median increase of 12.2 times (interquartile range = 9.8–30.5).
Among all 18 patients, response (partial or better) was achieved in 16 (89%), including complete response or better in 55% and stringent complete response in 44%. Median duration of response was 14.4 months (95% CI = 5.9 months to not reached). Among 11 patients who had not received prior BCMA-targeted therapy, response was observed in 11 (100%), with complete response or better in 91% and stringent complete response in 73%. Among seven patients who had received prior BCMA-targeted therapy, response was achieved in five (71%)—all partial or very good partial responses.
The investigators concluded: “Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials.”
Damian J. Green, MD, of the Clinical Research Division, Fred Hutch Cancer Center, Seattle, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by Juno Therapeutics (a Bristol Myers Squibb company) and the National Institutes of Health. For full disclosures of the study authors, visit thelancet.com.
