Selinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis

Patients with relapsed/refractory multiple myeloma (RRMM) who are penta-drug refractory, defined as resistant to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, face a dismal prognosis, particularly when progression occurs after exposure to novel T-cell redirecting therapies. Selinexor, an oral inhibitor of exportin-1, offers a distinct mechanism of action and may retain efficacy in this difficult-to-treat setting. We conducted a retrospective analysis at six German tertiary centers between 2023 and 2025 to evaluate the efficacy and safety of selinexor in combination with bortezomib and dexamethasone (SVd) in patients with penta-refractory MM who had relapsed after exposure to both BCMA- and GPRC5D-targeted therapies. 18 patients were identified, with a median of seven prior lines of therapy and a median time from diagnosis of 9.5 years. High-risk cytogenetic abnormalities were present in seven cases (including del17p in six cases). The overall response rate (ORR) was 61%, comprising one complete response, five very good partial responses (VGPR), and five partial responses (PR). The median progression-free survival (PFS) was 4.3 months (follow-up not reached). Among the nine patients (50%) with extramedullary disease (EMD), three achieved complete and one near-complete EMD resolution. Two patients who had relapsed after CAR-T cell treatment with idecabtagene vicleucel achieved PR and VGPR and were successfully transitioned to a second CAR T-cell treatment with ciltacabtagene autoleucel. Hematologic toxicities under SVd were manageable; no treatment-related deaths occurred. SVd demonstrates meaningful activity in patients with penta-refractory MM and prior failure of BCMA/GPRC5D-targeted immunotherapies. The ORR of 61% and a 78% disease control rate with median PFS of 4.3 months support evaluation of SVd in this highly refractory setting after failure of targeted immunotherapeutic approaches against both BCMA and GPRC5D.