Navigating the Post‐ <scp>BCMA</scp> / <scp>GPRC5D</scp> Landscape: Efficacy of Selinexor, Bortezomib, and Dexamethasone After Sequential Immunotherapy Failure in Penta‐Refractory Multiple Myeloma—A Multicenter 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 after exposure to T-cell-redirecting therapies. Selinexor, an oral exportin-1 inhibitor, offers a distinct mechanism of action and may retain efficacy in this difficult setting. We conducted a retrospective analysis at six German tertiary centers (2023-2025) to evaluate the efficacy and safety of selinexor plus bortezomib and dexamethasone (SVd) in penta-refractory MM after both BCMA- and GPRC5D-targeted therapies. Eighteen patients were identified, with a median of seven prior lines of therapy. High-risk cytogenetic abnormalities were present in seven cases, including del17p in six. The overall response rate (ORR) was 61%, including one complete, five very good partial, and five partial responses, and median progression-free survival (PFS) was 4.3 months. Among 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 partial and very good partial responses and were successfully transitioned to a second CAR T-cell therapy with ciltacabtagene autoleucel. Hematologic toxicities under SVd were manageable, and 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%, disease control in 78% of patients, and median PFS of 4.3 months support further evaluation of SVd in this highly refractory setting after failure of BCMA- and GPRC5D-directed approaches.