A Single-Center, Single-Arm, Phase I Clinical Trial of Anti-BCMA/GPRC5D Bispecific CAR T-Cells in Patients with Refractory and Relapsed Multiple Myeloma with Extramedullary Disease

Background: Despite the promising outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating relapsed or refractory multiple myeloma (RRMM), addressing extramedullary disease (EMD) in this context remains a therapeutic challenge. This study aimed to evaluate the safety, efficacy, and activity of anti-BCMA/GPRC5D bispecific CAR T-cells in RRMM patients with EMD.

Methods: A Phase I, single-arm, open-label clinical trial was conducted at the Western Theater Command Hospital of the Chinese People's Liberation Army. Eligible patients were RRMM adults aged 18-75 years with ECOG performance status 0-3 and EMD. Patients received escalating doses of anti-BCMA/GPRC5D bispecific CAR T-cells, starting at 1.0×10⁶ CAR T-cells per kg. The primary endpoints were safety and efficacy, while secondary endpoints encompassed assessment of activity. Safety and activity analyses encompassed all patients who received the CAR T-cell product per protocol. The study protocol was approved by the institutional ethics committee (2024EC1-ky033).

Results: Between July 2023 and May 2024, nine patients with RRMM and EMD were enrolled and underwent leukapheresis. Three patients were subsequently excluded due to rapid disease progression. Six patients received the anti-BCMA/GPRC5D bispecific CAR T-cell infusion. With a median follow-up of 6.5 months (IQR 2–12), the median age was 58 years (IQR 48–67), and the cohort included three males (50%) and three females (50%). Genetic risk factors were present in three patients, undetected in two, and absent in one. The maximum tolerated dose was established as 2.0×10⁶ CAR T-cells per kg. Hematological toxicity, excluding lymphopenia, was the most frequent grade 3 or higher adverse event (100%). Cytokine release syndrome (CRS) occurred in 62.5% of patients, all of which were grade 1 or 2. The overall response rate (ORR) among evaluable patients was 100%, with three patients (50%) achieving complete response (CR), including one with subsequent disease progression. One patient (17%) achieved very good partial response (VGPR), and two (33%) achieved partial response (PR), both of whom subsequently died due to disease progression.

Conclusion: The findings of this Phase I trial suggest that anti-BCMA/GPRC5D bispecific CAR T-cell therapy may represent a promising therapeutic option for patients with refractory and relapsed multiple myeloma complicated by extramedullary disease. Further investigation in larger, controlled trials is warranted to confirm these preliminary observations and refine treatment strategies.