In a single-institution phase I study reported in The New England Journal of Medicine, Sham Mailankody, MBBS, and colleagues found that chimeric antigen receptor (CAR) T cells targeting G protein–coupled receptor, class C, group 5, member D (GPRC5D) were active in heavily pretreated patients with multiple myeloma, including those who had received prior B-cell maturation antigen (BCMA)-directed therapy.
As stated by the investigators, “BCMA-directed CAR T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. GPRC5D has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.”
Sham Mailankody, MBBS
Study Details
In the trial, 17 evaluable patients enrolled at Memorial Sloan Kettering Cancer Center between September 2020 and June 2021 received GPRC5D-targeted CAR T-cell therapy (MCARH109) as single infusions of 25 (n = 3), 50 (n = 3), 150 (n = 6), and 450 (n = 5) × 106 CAR T cells. Patients had a median number of six prior lines of therapy; all had prior exposure to two proteasome inhibitors, two immunomodulatory drugs, and one anti-CD38 antibody.
Toxicity
The maximum tolerated dose was identified as 150 × 106 CAR T cells. At the 450 × 106 CAR T-cell dose, one patient had grade 4 cytokine-release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), and two patients had grade 3 cerebellar disorder of unclear cause. No cerebellar disorders, ICANS of any grade, or CRS of grade ≥ 3 occurred among the 12 patients receiving doses of 25 to 150 × 106 CAR T cells.
Responses
KEY POINTS
- At the highest tested dose of 450 × 106 CAR T cells, grade 4 CRS and ICANS were observed in one patient and grade 3 cerebellar disorder was seen in two.
- Partial response or better was observed in 71% of all patients and in 57% of patients at doses of 25 to 150 x 106 CAR T cells.
Among all 17 patients, partial response or better was observed in 12 (71%), with very good partial response or better in 10 (59%), and complete response/stringent complete response in 6 (35%). Responses were observed in 7 (70%) of 10 patients who had received prior BCMA therapies, including 6 (75%) of 8 with prior CAR T-cell therapy.
Among the 12 patients receiving doses of 25 to 150 x 106 CAR T cells, partial response or better was observed in 7 (58%), with very good partial response or better in 5 (42%) and complete response/stringent complete response in 3 (25%). Responses were observed in three (50%) of six patients who received prior BCMA therapies, including two (50%) of four with prior CAR T-cell therapy.
Median durations of response were 7.8 months (95% confidence interval [CI] = 5.7 months–not reached) among all patients and 7.8 months (95% CI = 4.6 months–not reached) among those receiving doses of 25 to 150 × 106 CAR T cells. At a median follow-up of 10.1 months (95% CI = 8.5 months–not reached), 6 (50%) of 12 patients in the entire cohort with partial response or better remained progression-free, with 2 patients completing more than 1 year of follow-up after MCARH109 infusion.
The investigators concluded, “The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma.”
Renier J. Brentjens, MD, PhD, of the Department of Medicine, Roswell Park Comprehensive Cancer Center, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Juno Therapeutics/Bristol Myers Squibb. For full disclosures of the study authors, visit nejm.org.
