GPRC5D-Directed CAR-T Could Be ‘New Treatment Paradigm’ in R/R Multiple Myeloma

BMS-986393, a GPRC5D-directed chimeric antigen receptor (CAR) T-cell therapy had a “favorable” safety profile with “promising” preliminary efficacy in patients with relapsed or refractory (R/R) multiple myeloma, according to a phase I, first-in-human study.

First author Susan Bal, MD, of the University of Alabama at Birmingham, and senior author Jesus Berdeja, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, presented interim results from the dose-escalation portion of the study on BMS-986393 during the 2022 American Society of Hematology Meeting and Exposition.

The dose-escalation portion of the study included patients who received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and, if eligible, a hematopoietic stem cell transplant. Past B-cell maturation agent (BCMA)-directed therapy and CAR T-cell treatment were allowed. The study used a modified toxicity probability interval design with at least three patients per dose level.

Patients underwent screening and leukapheresis with bridging therapy after if needed. They then received lymphodepleting chemotherapy with fludarabine 30 mg/m² plus cyclophosphamide 300 mg/m² daily for three days, followed by a single infusion of BMS-986393. The study’s primary objectives were to determine the safety, tolerability, and maximum tolerated dose and/or recommended phase II dose of BMS-986393.

The researchers enrolled 21 patients by May 24, 2022, with 17 patients receiving doses of BMS-986393 by that time point. Of the 17 patients who received BMS-986393, five received a dose of 25 × 10⁶ CAR T cells, nine received a dose of 75 × 10⁶ CAR T cells, and three received a dose of 150 × 10⁶ CAR T cells. Of the patients who received BMS-986393, 47% had high-risk cytogenetics, 47% had extramedullary plasmacytomas, 41% received prior BCMA-targeted therapies, and 24% had penta-refractory multiple myeloma.

Grade 3 and 4 treatment-emergent adverse events occurred in 65% of patients who received BMS-986393. Neutropenia, which occurred in 41% of patients was the most common event, followed by thrombocytopenia in 35%. Grade 1 treatment-emergent adverse events that were “consistent with on-target, off-tumor activity” impacted the skin in 18% of patients and the nails in 12%, with dysgeusia/dysphagia occurring in 12% of patients, according to the study’s authors.

Cytokine release syndrome occurred in 65% of patients, but was grade 1 or 2 in all cases, with a median duration of two days. Immune effector cell associated neurotoxicity syndrome-type neurotoxicity occurred in 12% of patients but was grade 1 and reversible with steroid treatment in all cases.

“At all tested dose levels, BMS-986393 demonstrated a favorable safety profile; both [cytokine release syndrome] and neurotoxicity were low-grade, and neurotoxicity was infrequent and short-lived. Dose escalation is ongoing; [maximum tolerated dose] has not been exceeded,” the study’s investigators concluded. “Preliminary efficacy appeared promising; antitumor responses were observed, including [patients] with [complete responses] who were [minimal residual disease]-negative at month three. These initial data support GPRC5D-directed CAR T-cell therapy with BMS-986393 as a new treatment paradigm in [relapsed/refractory multiple myeloma].”

Reference

Bal S, Kocoglu MH, Nadeem O et al. Clinical activity of BMS-986393 (CC-95266), a G protein–coupled receptor class C group 5 member D (GPRC5D)–targeted chimeric antigen receptor (CAR) T cell therapy, in patients with relapsed and/or refractory (R/R) multiple myeloma (MM): first results from a phase 1, multicenter, open-label study. Abstract #364. Presented at the 64th ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, Louisiana.