GPRC5D-targeted chimeric antigen receptor (CAR) T-cell therapy BMS-986393 produced deep and durable responses in patients with relapsed or refractory multiple myeloma (R/R MM), regardless of prior B-cell maturation antigen (BCMA)–therapy exposure. GPRC5D – G protein-coupled receptor, class C, group 5, member D – has been identified as an immunotherapeutic target in MM.
Susan Bal, MD, of the University of Alabama at Birmingham, presented results of a phase I study detailing the safety and efficacy of BMS-986393 at the European Hematology Association (EHA) 2023 Congress on June 10.
“Efficacy was promising at all dose levels tested, and the safety profile was in line with other CAR T-cell therapies,” Dr. Bal said. “These results support the potential of BMS-986393 as a treatment for patients with R/R MM, and further clinical development is underway.”
The dose-escalation, first-in-human study of BMS-986393 enrolled patients with R/RMM who had three or more prior lines of therapy. Patients received BMS-986393 at doses of 25 (six patients), 75 (nine patients), 150 (12 patients), 300 (six patients), and 450 (three patients) x 106 CAR T cells. During the dose expansion portion, 12 additional patients received 150 x 106 CAR T cells; 11 patients received 300 x 106 CAR T cells; and eight patients received 450 x 106 CAR T cells.
The majority (83.6%) of patients had grade 3-4 treatment-emergent adverse events, most commonly neutropenia (59.7%), anemia (31.3%), and thrombocytopenia (29.9%). Risk for high-grade infection was only about 15%, Dr. Bal noted. No deaths from infection occurred.
Cytokine release syndrome (CRS) of any grade occurred in 86.6% of patients. One patient had grade 5 CRS related to the study drug, and this occurred at the highest dose level.
On-target, off-tumor adverse events included any-grade skin adverse events (20.9%), dysgeusia (17.9%), nail events (9.0%), and dysphagia (1.5%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-type neurotoxicity was infrequent, with a total incidence of 10.4%. Non-ICANS neurotoxicity appeared to be dose related, was mostly low grade, and showed signs of reversibility in some patients, Dr. Bal said.
The overall response (OR) rate was 86.5% in the 52 efficacy evaluable patients. The complete response (CR) rate was 38.5%, with responses occurring at all dose levels. In patients with prior BCMA-directed therapy exposure (25 patients), including CAR T cells, the OR rate was 76.0% with CR occurring in 36.0% of the patients.
All six patients who were efficacy and measurable residual disease (MRD) evaluable and had CR or better were MRD-negative at month three.
Data published in the New England Journal of Medicine in late 2022 by Sham Mailankody, MBBS, and colleagues provided encouraging initial proof-of-concept data for a GPRC5D-targeted CAR T-cell therapy that was manufactured at Memorial Sloan Kettering Cancer Center in New York.2 A total of 17 patients were enrolled.
BMS-986393 is a very similar construct with some modified manufacturing processes, Dr. Bal noted.
“The results presented for BMS-986393 build upon and validate the initial proof of concept for GPRC5D-targeted CAR-T in a multicenter trial in 67 patients with a BMS manufactured product,” Dr. Bal said.
Any conflicts of interest declared by the authors can be found in the original article.
References
- Bal S, Berdeja J, Htut M, et al. MS-986393 (CC-95266), a G protein–coupled receptor class C group5 member D (GPRC5D)–targeted CAR T-cell therapy for relapsed/refractory multiple myeloma (RRMM): results from a phase 1 study. Abstract S193. Presented at the European Hematology Association (EHA) 2023 Congress; June 10, 2023; Frankfurt, Germany.
- Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387(13):1196-1206.
