A recent study published in the Journal of Clinical Oncology (JCO) has spotlighted a novel CAR-T cell therapy, MCARH109, targeting GPRC5D, offering new hope for patients with relapsed/refractory multiple myeloma (RRMM). While BCMA-targeted CAR-T therapies have shown promise, many patients eventually relapse, creating a critical need for alternative therapeutic targets.
Study Overview
The phase I, open-label, dose-escalation study followed a 3+3 design and assessed four dose levels of MCARH109 (25×10⁶, 50×10⁶, 150×10⁶, and 450×10⁶ CAR-T cells) in 19 RRMM patients, including those with high-risk cytogenetics and prior exposure to BCMA-directed treatments.
Safety and Toxicity
Seventeen patients received MCARH109 between October 2020 and November 2021. At the highest dose (450×10⁶), two patients experienced grade 3 neurotoxicity with cerebellar symptoms. Common GPRC5D-related, non-tumor toxicities included nail changes (65%), skin rashes (18%), and taste disturbances (18%), most of which were mild and reversible.
Efficacy and Response
Out of 17 treated patients:
- 71% (12 patients) achieved a partial response (PR) or better
- 7 patients reached stringent complete response (sCR)
- 3 patients achieved very good partial response (VGPR)
- 2 patients had a partial response (PR)
- 8 out of 12 responders became minimal residual disease (MRD) negative
The median duration of response (DOR) was 8.6 months, with 42% maintaining responses for over a year. Notably, two patients remained in continuous sCR at 32 and 41 months.
Survival Outcomes
The median overall survival (OS) was not reached, with a three-year estimated OS of 59%.
Effect in BCMA-Treated Patients
Among 10 patients previously treated with BCMA-targeted therapies, 70% responded to MCARH109. Specifically, 6 out of 8 patients who had received BCMA CAR-T therapy achieved a response, including 3 sCRs.
Antigen Escape and GPRC5D Expression
Among 10 relapsed responders, 60% showed potential loss of GPRC5D expression, suggesting antigen escape as a resistance mechanism. Some displayed reduced GPRC5D expression without complete loss, highlighting the need for multi-target strategies.
Immune Correlates
High-dimensional spectral flow cytometry revealed that responders exhibited significantly enriched CD8⁺CD45RO⁺CCR7⁻ effector memory T cells (TEM) (3.2-fold increase) and a trend toward increased CD8⁺CD45RA⁺CCR7⁻ TEMRA cells. Both subsets displayed high levels of HLA-DR and 2B4. Overall, CD8⁺ T cells in responders expressed higher HLA-DR levels compared to non-responders, providing potential biomarkers for predicting CAR-T therapy response.
Conclusions and Future Directions
MCARH109 demonstrated encouraging safety and efficacy, with a maximum tolerated dose of 150×10⁶ CAR-T cells. Though responses were durable in some cases, antigen escape was more common compared to BCMA-targeted therapies, emphasizing the potential of dual-targeted strategies.
Future large-scale trials are warranted to confirm these findings, better understand resistance mechanisms, and explore additional biomarkers for response prediction. This research represents a significant step toward more personalized, effective treatments for RRMM patients.
