A single infusion of BMS-986393, an autologous GPRC5D-targeted CAR T-cell therapy, has shown promising results in patients with relapsed/refractory multiple myeloma. Data from the phase 1 CC-95266-MM-001 trial, presented at the 21st International Myeloma Society Annual Meeting, indicate high and deepening responses in patients who had received between one and three prior lines of therapy. This potential first-in-class therapy offers a new avenue for patients with limited treatment options.
High Response Rates Observed
The trial data revealed an objective response rate (ORR) of 96% in evaluable patients (n = 24) at a median follow-up of 5.3 months (range, 2.0-9.3). This included a stringent complete response rate (sCR) of 37.5%, a complete response (CR) rate of 4.2%, a very good partial response rate (VGPR) of 33.3%, and a partial response rate (PR) of 20.8%. The median time to response was rapid, at just 1.0 month (range, 0.9-2.9), and the median duration of response was not reached, with 87% of responses ongoing.
Myo Htut, MD, from City of Hope, highlighted the significance of these findings, stating that BMS-986393 is safe and demonstrates promising preliminary efficacy in this patient population.
Addressing Unmet Needs in Multiple Myeloma
Early refractory multiple myeloma remains a significant challenge, even with the advent of new treatment options. BMS-986393, targeting GPRC5D, a receptor predominantly found on plasma cells, represents a novel approach. While talquetamab-tgvs (Talvey) is currently the only FDA-approved GPRC5D-directed agent, it is indicated for patients with at least four prior lines of therapy, underscoring the need for effective treatments in earlier lines.
Trial Design and Patient Characteristics
The phase 1 trial enrolled patients with relapsed/refractory multiple myeloma who had progressed within 12 months of their last regimen. These patients had received between one and three prior anti-myeloma regimens, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), and had undergone autologous stem cell transplant. The treatment protocol involved apheresis, CAR T-cell manufacturing, and lymphodepletion with fludarabine and cyclophosphamide, followed by a single infusion of BMS-986393 at the recommended phase 2 dose (RP2D).
As of March 18, 2024, 31 patients had been treated with BMS-986393, with a 100% manufacturing success rate. The patient cohort was characterized as difficult-to-treat, with a significant proportion having extramedullary plasmacytoma (29%), requiring bridging therapy (68%), and having triple-class refractory disease (55%).
Manageable Safety Profile
The safety profile of BMS-986393 was deemed manageable, with a low incidence of high-grade treatment-emergent adverse events (TEAEs). Common TEAEs included neutropenia (71% any grade, 68% grade 3/4), anemia (39% any grade, 23% grade 3/4), and thrombocytopenia (52% any grade, 23% grade 3/4). Cytokine release syndrome (CRS) occurred in 81% of patients, but all cases were grade 1/2 and transient.
On-target, off-tumor treatment-related AEs (TRAEs) were also infrequent and generally low grade. Immune effector cell–associated neurotoxicity syndrome occurred in 10% of patients, with all cases resolving.
Pharmacokinetics and Tumor Clearance
Pharmacokinetic analyses demonstrated rapid and robust cellular expansion, with peak transgene levels reached 14 days post-infusion. Longitudinal assessment of serum BCMA levels indicated deep tumor clearance within 2 to 3 months of infusion.
Ongoing and Future Studies
BMS-986393 is currently being evaluated in a pivotal phase 2 study (NCT06297226) as a monotherapy in quadruple-exposed patients and in a phase 1 trial (NCT06121843) in combination with other agents for relapsed/refractory disease. These ongoing studies aim to further define the role of BMS-986393 in the treatment landscape of multiple myeloma.
