Trial of CAR T-Cell Therapy Targeting GPRC5D Shows Efficacy in Resistant Multiple Myeloma

The first trial investigating a chimeric antigen receptor therapy to target GPRC5D in patients with resistant multiple myeloma reveals remissions in 70.6% of the enrolled patients.

A chimeric antigen receptor (CAR) T-cell therapy targeting the GPRC5D antigen produced impressive results in the first trial examining patients with resistant multiple myeloma (NCT04555551), according to experts at Dana-Farber Cancer Institute.1

Findings showed that with the CAR T-cell therapy, 70.6% of the 17 patients in the trial had remissions. All patients had myeloma that had relapsed or was resistant to previous therapies. Additionally, many responders had relapsed after treatment with a previous generation of CAR T-cell therapies targeting BCMA.

The opening of a new larger trial which aims to target an antigen known as GPRC5D in patients with myeloma will begin due to the positive results of this trial.

“CAR T-cell therapies targeting BCMA, a protein prevalent on immune system B cells, have shown promise in advanced myeloma, but many patients relapse,” said Eric L. Smith, MD, PhD, of Dana-Farber, the co-senior author of the study with Renier Brentjens, MD, PhD, of Roswell Park Comprehensive Cancer Center, in the press release. “We developed CAR T cells targeting an antigen that we identified, called G protein-coupled receptor, class C group 5 member D, or GPRC5D, which were effective in the laboratory against myeloma cells and in animal models of the disease, including those that no longer responded to BCMA-targeting CAR T cells. Our phase 1 study represents the first time this second-generation CAR T-cell therapy has been tested in patients.”

In this phase 1 dose-escalation study, MCARH109, a GPRC5D-targeted CAR T-cell therapy, was administered to patients at 4 dose levels. The study included patients aged 18 years and older with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy.2

Patients were required to have an ECOG performance status of 0 or 1, measurable disease defined as meeting either serum M protein ≥ 0.5 g/dL, involved serum free light chain greater than or equal to 10 mg/dL with an abnormal free light chain ratio, urine M-protein at 200 mg/24 hours or greater, measurable plasmacytomas seen on imaging, or bone marrow plasma cells at 30% or greater as determined by CD138 immunohistochemistry staining.3

Further, patients must have had serum creatinine 1.5mg/dL or greater or a measured creatinine clearance ≥ 50 mL/min, ALT, and AST ≤ 3 X ULN and total bilirubin ≤ 2 mg/dL, adequate pulmonary function, adequate cardiac function, and for patients with prior allogeneic stem cell transplant (ASCT), at least 100 days since ASCT at the time of initial screening.

The primary end point was maximum tolerated dose (MTD), and the secondary end point of the trial was overall response rate.

There were 17 patients enrolled in the phase 1 trial, each who received a median of 6 prior treatments for their myeloma, including ones who had received CAR T-cell therapy targeting BCMA. In the trial, 4 dose levels for the second-generation CAR T-cell therapy were tested.

The MTD was identified as 150×106 CAR T cells and investigators believed the therapy was generally safe as side effects were comparable to those associated with BCMA-directed CAR T-cell therapies.

A total of 15 patients had cytokine release syndrome (CRS) where in all cases but 1, CRS was mild or moderate. However, the 1 patient had been treated with 450×106 CAR T-cell dose, the highest dose level. Also at the highest dose level, 2 patients experienced toxicity possibly associated with the cerebellum of the brain. Additionally, no patients died from adverse events associated with the CAR T-cell therapy.

In post-treatment tests, 12 patients (70.6%) responded to the treatment, revealing a measurable decline in their cancer.Complete responses were seen in 6 patients who at the end of the trial, had an absence of detectable cancer. Two patients continue to show a response to the therapy, more than a year after they were treated.

“CAR T-cell therapy is one of the most promising ways to treat cancer,” said Sham Mailankody, MBBS, first author and principal investigator for the clinical trial at Memorial Sloan Kettering Cancer Center, in the press release. “While the clinical trial is still in early stages, we are encouraged by the results as post-treatment tests are showing that 6 participants had a complete response to the treatment and 12 of the patients are showing a measurable decline in their cancer.”

Now, the multi-center clinical trial of GPRC5D-targeted CAR T-cell therapy for patients with relapsed or treatment-resistant myeloma is currently enrolling patients at Dana-Farber Cancer Institute, as well as at other centers.

1. CAR T-Cell therapy targeting GPRC5D antigen proves effective in first trial in patients with resistant multiple myeloma. News Release. Dana-Farber Cancer Institute. September 28, 2022. October 5, 2022.
2. Mailankody S, Devlin SM, Landa J, et al. GPRC5D-Targeted CAR T Cells for Myeloma. N Engl J Med. 2022;387(13):1196-1206. doi:10.1056/NEJMoa2209900
3. MCARH109 chimeric antigen receptor (CAR) modified T cells for the treatment of multiple myeloma. Updated July 6, 2022. Accessed October 5, 2022.