GPRC5D-CAR T-cell Therapy Shows Continued Benefit in R/R Multiple Myeloma

The GPRC5D-targeted chimeric antigen receptor (CAR) T-cell therapy OriCAR-017 (Oricell Therapeutics) was well-tolerated with promising efficacy in patients with relapsed/refractory multiple myeloma (R/R MM), according to new data published in The Lancet Haematology.¹

The data reported were from the phase 1, first-in-human, single-arm, POLARIS trial (NCT05016778) conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Participants treated with OriCAR-017 had no serious adverse events (AEs), treatment-related deaths, or neurotoxicity. All patients responded to treatment, with a 60% complete response (CR) rate and 40% very good partial response rate.

"Advances in the treatment of R/R MM, including the introduction of immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies as well as stem cell transplantation, have prolonged survival in R/R MM patients, the disease remains a clinically incurable plasma cell neoplasm [sic]," He Huang, MD, PhD, Distinguished Professor and Associate Dean, Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, said in a statement.² "Nevertheless, almost all R/R MM patients eventually experience 1 or more relapses, with poorer survival outcomes for those with high-risk cytogenetic characteristics or refractory diseases. Data from our study showed that with extraordinary clinical efficacy, OriCAR-017 has been proved to be a novel, safe and effective therapy for patients with R/RMM, especially for those who experienced a relapse after receiving BCMA-targeted therapy. We are looking forward to continuously conducting follow-up clinical studies of OriCAR-017 in concert with Oricell."

First authors Mingming Zhang, PhD, Guoqing Wei, PhD, and Linghui Zhou, MSc, from Zhejiang University School of Medicine, and colleagues enrolled 13 participants aged 18-75 years old with GPRC5D+ R/R MM, an ECOG performance status of 0–2, and at least 4 prior lines of treatment in the POLARIS study. Participants received a single intravenous dose of 1 × 10⁶ CAR T cells per kg (n = 3), 3 × 10⁶ CAR T cells per kg (n = 3), or 6 × 10⁶ CAR T cells per kg (n = 3) in the dose-escalation phase. In the expansion phase, 1 additional participant received the recommended phase 2 dose of 3 x 10⁶ CAR T cells per kg. Recruitment to the expansion phase terminated early due to the COVID-19 pandemic in May 2022. One participant was excluded due to GPRC5D negativity and another 2 discontinued after apheresis due to rapid disease progression. The 10 participants for whom data are available were 50% male and 100% Chinese. Half of patients (n = 5) had previously received BCMA-targeted CAR T-cell therapy. 

READ MORE: GPRC5D-Targeted CAR T-Cell Therapy Shows Promising Efficacy After BCMA Therapy in R/R MM

No maximum-tolerated dose was identified. Common AEs of at least grade 3 included neutropenia (100%), thrombocytopenia (90%), leukopenia (90%), and anemia (70%). All patients experienced cytokine release syndrome (grade 1, 90%; grade 2, 10%). Two patients discontinued treatment due to disease progression.

The median follow-up was 238 days (interquartile range, 182–307). Two patients progressed after reaching stringent CR (at 5 and 9 months after infusion). One patient had a GPRC5D-positive relapse and another had GPRC5D-negative relapse. The remaining 8 patients who remained in remission all had minimal residual disease-negativity with no deaths. The median progression-free survival time was not reached, but estimated progression-free survival at 9 months for all patients was 87.5% (95% CI, 38.7–98.1).

“The results of the study by Zhang and colleagues, along with the clinical trial of MCARH109 (NCT04555551), suggest that targeting GPRC5D with CAR T cells is a feasible therapeutic approach for MM and warrants further investigation. Activity in patients with previous exposure to BCMA-directed therapies is especially promising,” Nico Gagelmann, MD, University of Hamburg, and Jennifer Brudno, MD, associate research physician, Center for Cancer Research, National Cancer Institute, wrote in a recent editorial on the potential of GPRC5D-CAR T-cell therapy.³ “The extent to which on-target toxic effects will prove to be a barrier to use of CAR T cells directed against this new antigen target is yet to be seen. The results of these early phase trials are limited and larger, multicenter, and ideally multinational studies are necessary to evaluate this strategy in a diverse group of patients.”

REFERENCES

1. 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. Lancet Haematol. February2023: 10(2): e107–116. doi: 10.1016/S2352-3026(22)00372-6
2. Oricell Publishes Data from POLARIS Clinical Study Evaluating OriCA-017 in the Treatment of RRMM in The Lancet Haematology. News release. Oricell Therapeutics. January 30, 2023.https://www.prnewswire.com/news-releases/oricell-publishes-data-from-polaris-clinical-study-evaluating-oricar-017-in-the-treatment-of-rrmm-in-the-lancet-haematology-301734082.html
3. Gagelmann N, Brudno J. GPRC5D-targeting chimeric antigen receptors: a new treatment for multiple myeloma? Lancet Haematol. February 2023: 10(2): e82-83. doi: 10.1016/S2352-3026(22)00385-4