GPRC5D-Targeted CAR T-Cells Demonstrate Promising Activity in Heavily Pretreated Multiple Myeloma

GPRC5D-targeted CAR T-cell product, MCARH109, was investigated at 4 dose levels in patients with heavily pretreated multiple myeloma including those who had relapsed following B-cell maturation antigen (BCMA) therapy, and was found to demonstrate promising activity, according to data from a phase 1 study (NCT04555551) published in the New England Journal of Medicine.

Investigators identified a maximum tolerated dose of 150x106CAR T cells. The overall response rate (ORR) was 71% (95% CI, 44%-90%) across all dose levels. Additionally, 58% of patients who received the maximum tolerated dose. The ORR was 59% in patients who received prior BCMA therapy.

A total of 17 patients received treatment, with a median age of 60 years. Moreover, patients had a median of 6 previous lines therapy. All patients had previously received 2 proteasome inhibitors, 2 immunomodulatory drugs, and 1 anti-CD38 antibody, and 16 patients havd triple-refractory disease.

A total of 59% of patients received previous treatment with BCMA therapies, and 47% had received previous BCMA CAR T-cell therapy. The median time from last BCMA therapy to MCARH109 infusion was 16.4 months. Of these patients, 90% had an objective response to previous BCMA therapy, with 2 were refractory to BCMA therapy. Every patient was treated with melphalan and underwent autologous stem cell transplant, of whom 3 had previously received transplantation. Eight-two percent were refractory to the last line of therapy, and 94% underwent bridging therapy after leukapheresis. Of these patients, 94% were refractory to their bridging therapy.

After infusion of MCARH109, all patients experienced 1 or more adverse effects (AEs). Grade 1 or 2 cytokine release syndrome (CRS) was observed in 88% of patients except for 1 patient who received 450x106 cells and had a grade 4 event. Additionally, this patient experienced immune effector cell–associated neurotoxicity syndrome (ICANS) or macrophage activation syndrome. To manage CRS, tocilizumab (Actemra) and dexamethasone were given to 53% and 24% of patients, respectively. The patient who experienced grade 4 CRS was given siltuximab (Sylvant) and anakinra (Kineret). Additionally, 2 other patients received the 450x106cells and experienced grade 3 cerebella disorder that may be linked with MCARH109, which would constitute as a dose-limiting toxicity.

Hematologic AEs were most commonly grade 3 or 4. This included grade 3 or higher neutropenia (94%), thrombocytopenia (65%), and anemia (35%). Infections occurred in 18% of patients, 12% of which were grade 3. Of note, there were time-limited, on-target, off tumor toxic effects related to GPRC5D expression including grade 1 nail changes (65%), grade 1 rash (18%), and grade 1 dry mouth (12%). The median from MCARH109 infusions to nail changes was 3.3 months.

A partial response (PR) or better was observed in 71% of patients, 59% of whom had a very good PR or better and 35% had a complete response or stringent complete response. Sixty-seven percent of patients with a PR or better were negative for minimal residual disease in bone marrow. The median duration of response in the overall cohort was 7.8 months (95% CI, 5.7-not reached [NR]), and 7.8 months (95% CI, 4.6-NR) in those who received 25x106 and 150x106CAR T cells. A total of 50% of patients who received MCARH109 at the 25x106 to 150x106dose levels had a PR or better.

At a median follow-up of 10.1 months (95% CI, 8.5-NR), 50% of patients with a PR or better were progression-free. Two of these patients completed more than 1 year of follow-up after MCARH109 infusion.

GPRC5D expression was observed in 88% of patients’ baseline bone marrow or plasmacytoma biopsy. This included 92% of patients with an objective response to MCARH109, and 80% who did not respond. After the initial response, 6 patients progressed, 67% of whom did not have GPRC5D expression at the time of progression and 33% had decreased expression.

Reference

Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387(13):1196-1206. doi:10.1056/NEJMoa2209900