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GPRC5D-Directed CAR T-Cell Therapy BMS-986393 Shows Potential for R/R MM

July 17, 2023

Mid-July 2023

Leah Lawrence

Leah Lawrence is a freelance health writer and editor based in Delaware.

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

  1. 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.
  2. Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387(13):1196-1206.

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