Most multiple myeloma patients with relapsed/refractory disease will undergo CAR T-cell therapy targeting B-cell maturation antigen (BCMA), a protein found on multiple myeloma cells. Although the treatment can produce deep, durable responses, many patients subsequently develop BCMA-negative disease and relapse again. “At that point, BCMA-targeted therapies are not effective anymore,” says Ehsan Malek, MD, Director of Multiple Myeloma Translational Research at Roswell Park Comprehensive Cancer Center.

But a phase 2 clinical trial now underway at Roswell Park may offer those patients a treatment option. Dr. Malek is Site Principal Investigator of “Study of BMS-986393, a GPRC5D-Directed CAR T-Cell Therapy in Adult Participants with Relapsed or Refractory Multiple Myeloma (QUINTESSENTIAL)” (NCT06297226), which he and his fellow investigators hope will ultimately fill an unmet need for this patient population. The autologous CAR T-cell strategy utilizes a novel target, GPRC5D, a protein expressed mainly on multiple myeloma cells. 

“GPRC5D is a better target than BCMA, because it leads to less immune compromise,” says Dr. Malek. “Because BCMA is essential for the survival of long-lived plasma cells, targeting it suppresses normal plasma cells to a greater degree than targeting GPRC5D and leads to greater risk of hypogammaglobulinemia, which increases the risk of infection.”

While patients with relapsed/refractory disease sometimes undergo Bispecific T-cell engager (BITE) immunotherapy prior to CAR T-cell therapy, Dr. Malek cautions that it can cause T-cell exhaustion, rendering CAR T-cell therapy less effective in the future. Why? BITEs, he says, are constructed with two prongs — one attached to the target on the myeloma cells and the other to CD3 on the T cells. The prongs bring the patient’s T cells to the myeloma cells and kill them. “If given over the long term, BITEs try to stimulate and bring T cells to myeloma cells persistently, and that leads to T-cell exhaustion.

“CAR T cells manufactured after long-term exposure to BITEs may not have high quality. Optimal management means offering CAR T-cell therapy first.”

At a median follow-up of 8.8 months, a phase 1 clinical trial of this approach produced an overall response rate of 91% and a complete response rate of 48% among patients who received the recommended phase 2 dose, and an overall response rate of 100% in patients who had been treated previously with anti-BCMA therapy. Among evaluable patients, 86% were minimal residual disease-negative.

Sponsored by Juno Therapeutics Inc., the current phase 2, single-arm study expects to enroll 150 patients who have undergone three or more lines of therapy and at least four classes of multiple myeloma treatment, including an immunomodulatory drug, a proteasome inhibitor, an anti-CD38 monoclonal antibody and anti-BCMA therapy.

Phase 1 Clinical Trial Offers Allogeneic CAR T-Cell Therapy

Roswell Park is also the only center in New York State offering a groundbreaking phase 1 allogeneic CAR T-cell clinical trial for patients with relapsed or refractory multiple myeloma, “P-BCMA-ALLO1 Allogeneic CAR T-Cells in the Treatment of Subjects with Multiple Myeloma” (NCT04960579).

While traditional CAR T-cell therapies use a patient’s own T cells, some patients may benefit more from an allogeneic approach, especially if their own T cells are weak or they have had limited success with prior treatments. Designed for patients who have exhausted other possible treatments, the P-BCMA-ALLO1 trial may provide a a hopeful new option.