GPRC5D-Targeted CAR T-Cell Therapy CT071 for the Treatment of Refractory/Relapsed Multiple Myeloma

Introduction

Despite significant progress in the therapeutic landscape for relapsed or refractory multiple myeloma (RRMM), the disease remains incurable. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a promising target, even for those who are refractory to B-cell maturation antigen (BCMA) CAR T cell therapies. CT071 is a fully human GPRC5D-targeting autologous CAR T cell product manufactured using an expedited CARcelerate^TM platform which shortens the manufacturing process to around 30 hours resulting in shorter vein-to-vein time.

Aims

In this first-in-human, single-arm, open-label exploratory clinical trial, we evaluated the safety, pharmacokinetics, and preliminary efficacy of CT071 in patients with RRMM (NCT05838131).

Methods

Patients with RRMM who had previously received ≥ 3 prior lines of therapy (LOT) or patients who experienced progression or lack of response having been treated with a proteasome inhibitor and an immunomodulatory agent or those who were double class-refractory, all with ECOG score of 0-2 were enrolled. CT071 was administered as a single infusion at doses of 1.0×10⁵ or 3.0×10⁵ CAR-positive T cells/ kg using i3+3 design for dose-escalation and expansion.

Results

As of June 21, 2024, a total of 17 patients had been dosed with CT071, including 8 patients at 1.0×10⁵ cells/kg and 9 patients at 3.0×10⁵ cells/kg with a median follow-up of 6.0 months (range 1.0 to 11.2). The median age for the cohort was 63.0 years (range 37 to 72) and 64.7% were male. Twelve (70.6%) subjects had high-risk cytogenetics, 4 (23.5%) had extramedullary disease (EMD), and 16 (94.1 %) were at R-ISS stage II or III. The median prior LOT was 5 (range: 1, 12); 16 (94.1%) patients were double-class refractory, 11 (64.7%) were triple-class refractory, 4 (23.5%) were penta-drug refractory, 9 (52.9%) had prior autologous stem cell transplant, and 4 (23.5%) had prior CAR T therapies targeting BCMA or BCMA/CD19. Only 1 patient required bridging therapy before administration of CT071.

A total of 11 patients (64.7%) experienced cytokine release syndrome (CRS), all at Grade 1 (n=8) or 2 (n=3). The median duration of CRS was 3 days (range 2 to 8), and all recovered. No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. No dose limiting toxicity (DLT) occurred. The most common Grade 3 or 4 AEs were hematological toxicities, including lymphopenia (100%), leukopenia (88.2%), neutropenia (76.5%), thrombocytopenia (52.9%), and anemia (47.1%). Onychomadesis occurred in 4 patients (23.5%) and skin rash occurred in 1 patient (5.9%), all Grade 1.

The overall response rate (ORR) was 94.1% (16/17), and the stringent complete response (sCR) rate was 52.9% (9/17). Notably, 7 patients achieved complete response or better at week 4. One patient with stable disease (SD) demonstrated ongoing tumor shrinkage of a large EMD (125 mm×99 mm at baseline) with 38.2% decrease at week 26, along with 93.0% decrease in serum M protein from baseline. All 4 patients with previous exposure to BCMA or BCMA/CD19 CAR T achieved responses (2 sCR and 2 partial response). Fifteen out of 17 patients achieved MRD negativity at 10⁻⁶ threshold.

Conclusion

Preliminary results from this study of CT071 demonstrate a promising safety profile with compelling clinical response in RRMM patients including those with prior BCMA or BCMA/CD19 CAR T exposure.