Chimeric antigen receptor (CAR) T-cell therapy targeting GPRC5D may be safe and active in patients with heavily pretreated multiple myeloma (MM), according to a phase 1 study published in The New England Journal of Medicine.

GPRC5D is an orphan G protein-coupled receptor known to be expressed in MM cell lines and plasma cells from patients with MM. MCARH109 is a GPRC5D-targeted CAR T-cell therapy.

Researchers conducted a phase 1 study (ClinicalTrials.gov Identifier: NCT04555551) to determine the optimal dose of MCARH109 in patients with relapsed/refractory MM.


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The dose-escalation trial included 17 patients. At baseline, the median age was 60 (range, 38-76) years, and 76% of patients were men. High-risk cytogenetic features were present in 76% of patients, 47% had extramedullary plasmacytoma, and 18% had nonsecretory myeloma.

Patients had received a median of 6 prior lines of therapy (range, 6-14), 82% of patients had disease that was refractory to their last line of therapy, 94% were triple-refractory, and 100% were penta-exposed. All patients had received a prior autologous transplant, and 18% had also received an allogeneic transplant. Previous BCMA and CAR T-cell therapy had been administered to 59% and 47% of patients, respectively.

The patients received MCARH109 at 4 dose levels — 25 x 106, 50 x 106, 150 x 106, and 450 x 106. The maximum tolerated dose (MTD) was 150 x 106. There were 2 patients who had grade 3 cerebellar disorder that was considered to be a dose-limiting toxicity for the 450 x 106 dose. 

The most common adverse event (AE) was cytokine release syndrome (CRS), which occurred in 88% of patients but was mostly grade 1 or 2 in severity. There was 1 patient treated at the 450 x 106 dose who developed grade 4 CRS. This patient also had grade 4 immune effector cell-associated neurotoxicity syndrome (ICANS). There were no other cases of ICANS.

The most common grade 3 or higher AEs were neutropenia (94%), thrombocytopenia (65%), and anemia (35%), but these AEs were suspected to be related to lymphodepleting chemotherapy. 

Overall, 71% of patients achieved a partial response or better, including 58% who received the MTD or lower. Responses were seen in 70% of patients who had received prior BCMA-targeted therapy. 

A complete response or stringent complete response was seen in 35% of patients at all dose levels and 25% of those who received the MTD or lower. Minimal residual disease negativity was observed in 47% of patients in the entire cohort and 50% of those who received the MTD or lower.

At a median follow-up of 10.1 months, 50% of responders (6/12) remained free from progression.

“The results of this study of a GPPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma,” the researchers concluded.

Disclosures: This study was supported by Juno Therapeutics/Bristol Myers Squibb. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. Published online September 28, 2022. doi:10.1056/NEJMoa2209900