BMS-986393 Shows First-In-Class Potential in Relapsed/Refractory Multiple Myeloma

A single infusion of treatment with the autologous GPRC5D-targeted CAR T-cell therapy BMS-986393 led to high responses that deepened over time in patients with relapsed/refractory multiple myeloma who received between 1 and 3 prior lines of therapy, according to data from the phase 1 CC-95266-MM-001 trial (NCT04674813) that were presented at the 21st International Myeloma Society Annual Meeting.¹

At a median follow-up of 5.3 months (range, 2.0-9.3), the objective response rate (ORR) in evaluable patients (n = 24) was 96%, which included a stringent complete response rate (sCR) of 37.5%, CR rate of 4.2%, very good partial response rate of 33.3%, and partial response rate of 20.8%. The median time to response was 1.0 month (range, 0.9-2.9), and the median duration of response was not reached. Moreover, 87% (n = 20/23) of responses were ongoing; the remaining 3 patients experienced disease progression.

“A single infusion of BMS-986393, a potential first-in-class GPRC5D-targeted autologous CAR T-cell therapy, is safe and demonstrates promising preliminary efficacy in patients with relapsed/refractory multiple myeloma and 1 to 3 prior treatment regimens,” lead study author Myo Htut, MD, associate professor in the Division of Myeloma, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California, said in a presentation of the data.

Early refractory multiple myeloma is relatively common despite the use of new treatment options and refined sequencing strategies. Ongoing trials are focused on identifying novel therapeutic agents that can fill this unmet need. BMS-986393 is a potential first-in-class autologous CAR T-cell therapy directed toward GPRC5D, an orphan receptor found predominantly on plasma cells.

The bispecific T-cell–engager talquetamab-tgvs (Talvey) is presently the only GPRC5D-directed agent that has FDA approval, having received an indication in August 2023 for the treatment of adult patients with relapsed or refractory multiple myeloma following at least 4 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.³

Previously reported data from the phase 1 trial of BMS-986393 indicated that a single infusion was “safe and efficacious” in patients with heavily pretreated disease, regardless of prior BCMA-directed therapy. At a median follow-up of 4.9 months (range, 2.0-9.3), the ORR when given at the recommended phase 2 dose (RP2D) of 150 x 10⁶ CAR T cells was 91% (n = 21/23) and the CR rate was 48%.²

The study enrolled patients with relapsed/refractory multiple myeloma that progressed within 12 months of the latest regimen per International Myeloma Working Group criteria. Patients received between 1 and 3 prior anti-myeloma regimens, including a PI and IMiD, in addition to having undergone autologous stem cell transplant. They also had an ECOG performance status of 0 or 1. Prior BCMA-directed therapy, including CAR T-cell therapy, was allowed.¹

Per the study design, patients underwent apheresis, CAR T-cell manufacturing, and lymphodepletion on days –5, –4, and –3 from infusion with daily fludarabine 30 mg/m² plus cyclophosphamide 300 mg/m². Following a single infusion of BMS-986393 at the RP2D, patients entered post-treatment follow-up for 24 months. Bridging therapy during manufacturing was allowed for disease control.

The primary objective was safety at the RP2D. Secondary objectives included evaluations of antitumor and pharmacokinetic (PK) activity. Safety was evaluated in all patients who received the therapy and efficacy was assessed in those who also had measurable disease at the latest disease assessment prior to infusion and had at least 1 post-infusion disease-response assessment.

As of March 18, 2024, 31 patients had received treatment with BMS-986393, with a 100% manufacturing success rate. Htut stated that the baseline characteristics of the cohort reflected a “difficult-to-treat population,” noting that 29% of patients had extramedullary plasmacytoma, 68% required bridging therapy, and 55% had triple-class refractory disease. Moreover, the median time since initial diagnosis was 46 months (range, 6-132).

Regarding safety, Htut stated that the profile was manageable with a low incidence of high-grade treatment-emergent adverse effects (TEAEs). Any-grade and grade 3/4 TEAEs, respectively, included neutropenia (any grade, 71%; grade 3/4, 68%), anemia (39%; 23%), thrombocytopenia (52%; 23%), cytokine release syndrome (CRS; 81%; 0%), hyperglycemia (35%; 3%), hypocalcemia (35%; 0%), constipation (32%; 0%), infections and infestations (32%; 0%), dysgeusia (29%; 0%), fatigue (26%; 0%), nail disorder (26%; 0%), dry mouth (23%; 0%), and nausea (23%; 0%).

CRS events were all grade 1/2 and transient. The median time to first event was 3 days (range, 1-4) after infusion, and the median duration was 3.5 days (range, 1-7). No patients had macrophage activation syndrome or hemophagocytic lymphohistiocytosis. Infections occurred in 32% (n = 10) of patients and all were grade 1/2.

On-target, off-tumor treatment-related AEs (TRAEs) were also infrequent, of low grade, and manageable, according to Htut. TRAEs occurred in 94% (n = 29) of patients, 42% (n = 13) of which were grade 3/4. Immune effector cell–associated neurotoxicity syndrome occurred in 10% (n = 3) of patients and all cases were grade 1/2 and resolved. The median onset was 5 days (range, 4-6) after infusion, and the median duration was 2 days. Only 1 case of other select neurotoxicity––grade 2 ataxia––occurred. Other select on-target TRAEs included dysgeusia (any grade, 29%) and dysphagia (any grade, 6%) and involved the skin (any grade, 10%). Weight loss was reported in 1 patient, and this was deemed possibly related to study therapy. Of the 20 on-target/off-tumor skin, nail, or dysgeusia that occurred, the median time to resolution was 48 days (range, 4-93).

PK and pharmacodynamic analyses also illustrated high persistence following infusion and deep tumor clearance. PK analyses showed evidence of rapid and robust cellular expansion that reached a peak transgene level (Tmax) 14 days after infusion. Additionally, the peak transgene level (C_max) was similar to that seen in patients with heavily pretreated disease.^1,2 Moreover, longitudinal assessment of serum BCMA levels suggested that BMS-986393 produced deep tumor clearance, with the nadir reached within 2 to 3 months of infusion.¹

In addition to CC-95266-MM-001, BMS-986393 is under evaluation as monotherapy in a pivotal phase 2 study (NCT06297226) in quadruple-exposed patients and in combination with other agents in a phase 1 trial (NCT06121843) in patients with relapsed/refractory disease.

Disclosures: Dr Htut had no disclosures to report.

References

1. Htut M, Nadeem O, Berdeja JG, et al. Safety and preliminary efficacy of BMS-986393, a GPRC5D CAR T cell therapy, in patients (pts) with relapsed/refractory (RR) multiple myeloma (MM) and 1–3 prior regimens: results from a phase 1 study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-08.
2. Bal S, Htut O, Nadeem O, et al. BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): updated results from a phase 1 study. Blood. 2023;142(suppl 1):219. doi:10.1182/blood-2023-181857
3. FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma. FDA. August 9, 2023. Accessed September 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myelom