Sequential BCMA and GPRC5D CAR-T cell therapy combined with an optimizing bridging regimen for Relapsed/Refractory multiple myeloma with bulky/extensive extramedullary disease: A synergistic integration approach

Abstract

Abstract Background: Relapsed/refractory multiple myeloma (RRMM) with bulky/extensive extramedullary disease (EMD) represents a major clinical challenge, characterized by a poor prognosis, an immunosuppressive tumor microenvironment (TME), and a high risk of antigen escape after single-antigen targeted therapies. We developed a optimizing, multi-pronged strategy to overcome these barriers. This approach utilizes a comprehensive bridging regimen of DCEP chemotherapy plus low-dose radiotherapy (LDRT) to debulk disease and prime the TME, followed by sequential infusions of two distinct CAR T-cell products targeting BCMA and GPRC5D to mitigate antigen-loss relapse. We hypothesized that LDRT would synergistically enhance local tumor control and antigen presentation without adding significant toxicity, while the DCEP chemotherapy would provide systemic disease control, and the sequential dual-antigen targeting would provide deep and durable responses. Methods: In this single-arm, investigator-initiated trial, we enrolled RRMM patients with bulky EMD who had received ≥3 prior lines of therapy. The bridging regimen consisted of one cycle of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) and LDRT (7.5 Gy in 5 fractions) to a dominant EMD lesion. Following lymphodepletion with fludarabine(25-30mg/m2)/cyclophosphamide(250-300mg/m2), patients received a sequential infusion of anti-BCMA CAR T-cell (1-2×106/kg) on Day 0, followed by anti-GPRC5D CAR T-cell (1-2×106/kg) on Day 1. The primary endpoints were safety and overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and CAR-T kinetics. Results: As of the data cut-off, 8 patients with multiple bulky EMD lesions were treated. The cohort was heavily pretreated (median 5 prior lines) and carried high-risk features: 70% (6/8) had high-risk cytogenetics, one patient was post-allogeneic HSCT, and two were dialysis-dependent. With a median follow-up of 8.5 months (range, 3-15), the combination therapy demonstrated profound efficacy. The ORR was 87.5% (7/8), with a stringent complete response (sCR) rate of 62.5% (5/8). 87.5% (7/8) responders achieved a complete metabolic response of their EMD lesions(Figure 1). The survival outcomes are promising, though immature: the median DOR and PFS have not been reached. The estimated 6-month PFS rate is 87.5%. At the time of analysis, all patients were alive, resulting in an OS rate of 100%. The treatment was well-tolerated. The bridging regimen with DCEP and LDRT did not result in unexpected toxicities. Cytokine release syndrome (CRS) occurred in 87.5% (7/8) of patients, 5/8 in Grade 1 and 1/4 in Grade 2, no ≥Grade 3 CRS . No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Grade ≥3 hematologic toxicities were transient and manageable. The infection rate was 62.5% (5/8) within the first 90 days and 37.5% (3/8) during long-term follow-up, all successfully managed. CAR-T expansion kinetics showed a robust and sustained in vivo proliferation profile . Conclusion: This study demonstrates that an optimizing strategy combining a DCEP+LDRT bridging regimen with sequential infusion of BCMA and GPRC5D CAR T-cells is a highly effective and safe approach for RRMM patients with bulky/extensive EMD. The LDRT component was well-tolerated and appeared to synergize with systemic therapy to overcome the hostile TME of EMD sites. The best objective response rates and promising early survival data in this ultra-high-risk population, coupled with a very favorable safety profile, suggest this multi-modal approach could establish a new therapeutic benchmark for patients with the most challenging forms of myeloma.