A new CAR T product going after a new target, GPRC5D, showed initial safety and utility even in patients who had received prior BCMA CAR T treatment, according to a recent presentation at the American Society of Hematology (ASH) meeting. 

CAR T cell therapies targeting B cell maturation antigen (BCMA) have resulted in unprecedented depth and duration of response in myeloma, because the BCMA protein levels are present  in your blood every day, allowing a measurement with a quick blood test to determine if you are responding to treatment or not. This is why for the last couple of years a lot of research and resources have been put into the CAR T cell therapies targeting B cell maturation antigen.

But when BCMA therapies stop working or BCMA levels drop and can no loner be detected, what's next? New targets are needed. 

When finding a new target, it's important that the treatment kills the abnormal cells while preserving normal cells. One such “additional target” is a receptor called GPRC5D, which is expressed in myeloma cells with limited expression in other tissues. 

At the ASH meeting, Susan Bal, MD presentated data on MCARH109, a GPRC5D-directed CAR T cell therapy, which demonstrated promising initial safety and efficacy in patients with myeloma warranting further study of this CAR T target. 

In the presentation titled: NCT04674813: a phase 1, first in-human, multicenter, open-label, dose-finding study evaluating BMS-986393 (CC 95266),  Dr. Bal shared the Phase I clinical trial data for patients who had received more than  ≥ 3 prior lines of therapy containing a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 therapy, and a stem cell transplant.

Patients followed the same pattern for other CAR T therapies of receiving bridging therapy if needed, then lymphodepleting chemotherapy (fludarabine 30 mg/m2 + cyclophosphamide 300 mg/m2 daily for 3 days) followed by a single infusion of BMS-986393. 

Primary objectives are to determine the safety, tolerability, and maximum tolerated dose (MTD) and/or recommended phase 2 dose of BMS-986393.

In this study, 21 patients enrolled and 17 patients received BMS-986393 at doses of 25 (n = 5), 75 (n = 9), and 150 (n = 3) × 106 CAR T cells. Among treated patients, 8 (47%) had high-risk cytogenetics; Seven (41%)  received prior BCMA-targeted therapies, including 6 (35%) with BCMA-directed CAR T cell therapy. Four (24%) had penta-refractory myeloma.

Grade 3/4 treatment-emergent adverse events related to BMS-986393 (TRAEs or side effects) were reported in 11/17 (65%) patients; of these, the most frequent were neutropenia, or low neutrophil counts (41%) and thrombocytopenia, or low platelet counts (35%).

Responses were reported in 12 of 14 patients evaluable for initial (1 month) clinical response (overall response rate, 86%), including in 4/6 and 3/5 pts treated with prior BCMA-directed and BCMA-directed CAR T cell therapies, respectively. Median duration of response has not been reached for any dose level, with a median follow-up of 4 months.

As we can see, at all tested dose leves, the studied drug (BMS-986393) was safe, the first hurdle for phase I studies. For the most important side effects on this kind of therapy (cytokine release syndrome and neurotoxicity), cytokine release syndrome was reported in 11 patients from the 21, but fortunately never beyond grade 1 (the lowest grade of side effect.). Neurotoxicity was infrequent (reported in only 2 patients), and when present, it was short-lived. 

Learn more about cytokine release syndrome here

The best overall response ranged from 80% to 100%, those at the two highest dose levels.

Depending if the patient had prior BCMA treatment or not, the overall response rate was 100% if the patient had no prior BCMA and 77% if the patient did. 

In conclusion, at all tested dose levels, BMS-986393 demonstrated a favorable safety profile: cytokine release syndrome was mostly grade 1-2, neurotoxicity was infrequent, and when present, was low grade and reversible. The dose-escalation is ongoing and the maximum tolerated dose has not been reached. This drug shows durable responses and promising efficacy at all tested dose levels, including MRD negative complete responses and in BCMA-exposed patients.

These preliminary data support GPRC5D-directed CAR-T Therapy with BMS-986393 as a new treatment in relapsed/refractory myeloma, irrespective of prior BCMA-directed therapy. 

For more information about the inclusion/exclusion criteria, click here.