GPRC5D-Targeted CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma

Phase 1 POLARIS Trial 

Per phase 1 results from the first-in-human, single-center, single-arm POLARIS trial, GPRC5D-targeted CAR-T cell therapy (OriCAR-017) is a promising treatment modality for patients with relapsed/refractory (R/R) multiple myeloma (MM).

Patients eligible for this study included those aged 18 to 75 years who were diagnosed with R/R MM. Additionally, participants had to have an ECOG performance status of 0-2, a GPRC5D expression in bone marrow plasma cells greater than 20% or were positive for GPRC5D by immunohistochemistry, and received at least 3 previous lines of treatment which included proteasome inhibitors, immunomodulatory drugs, and chemotherapy.

Between June 9, 2021, and Feb 28, 2022, 13 patients were recruited for inclusion into the study. One patient was excluded because of GPRC5D negativity and 2 patients were discontinued after apheresis due to rapid progression. 

Patients were consecutively assigned to receive a single dose of intravenous OriCAR-017 at 1 × 10⁶ CAR-T cells per kg, 3 × 10⁶ CAR-T cells per kg, or 6 × 10⁶ CAR-T cells per kg in the dose-escalation phase. In the expansion phase of this trial, patients received the recommended phase 2 dose. Primary endpoints included safety, maximum tolerated dose, and recommended phase 2 dose. When recording safety and activity analyses, data did include all patients who received OriCAR-017.

9 patients were assigned to the dose-escalation phase. 3 received 1 × 10⁶ CAR-T cells per kg, three received 3 × 10⁶ CAR-T cells per kg, and three received 6 × 10⁶ CAR-T cells per kg. The maximum tolerated dose was not recorded, as no dose-limiting toxic effects were observed throughout treatment. Regarding safety and preliminary activity, the recommended phase 2 dose was set at 3 × 10⁶ CAR-T cells per kg. This was received by 1 additional patient in the dose expansion phase. 5 patients, or 50% of the cohort, were previously treated with BCMA-targeted CAR-T cell therapy. The median follow-up was 238 days (IQR 182-307). 

While there were no serious adverse events and no treatment-related deaths, the most common grade 3 or worse adverse events were hematological, including neutropenia (ten [100%] of ten patients), thrombocytopenia (nine [90%]), leukopenia (nine [90%]), and anemia (seven [70%]). All patients experienced cytokine release syndrome (nine [90%] grade 1 and one [10%] grade 2). Additionally, no neurological toxic effects were reported. All 10 patients had an overall response; 6 (60%) had a stringent complete response and 4 (40%) had a very good partial response. 2 patients discontinued treatment due to disease progression (one GPRC5D-positive patient in the middle-dose group and one GPRC5D-negative patient in the low-dose group).

Mingming Zhang, PhD, Institute of Hematology, Zhejiang University, China, and colleagues concluded, “The results of this study suggest that GPRC5D is an active target for immunotherapy in multiple myeloma. GPRC5D-targeted CAR T-cell therapy is a promising treatment modality for patients with relapsed or refractory multiple myeloma and deserves further testing.”

Source:

Zhang M, Wei G, Zhou L, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): A first-in-human, single-centre, single-arm, phase 1 trial. The Lancet Haematology. February 2023. doi: 10.1016/S2352-3026(22)00372-6