Efficacy and safety of selinexor combined with VRD in newly diagnosed multiple myeloma with EMD: a phase 2 trial

Extramedullary disease (EMD) at diagnosis confers a poor prognosis in newly diagnosed multiple myeloma (NDMM). This multicenter, open-label, single-arm, phase 2, investigator-initiated trial evaluated selinexor combined with bortezomib, lenalidomide, and dexamethasone (SVRD) in NDMM with EMD. Between 17 October 2022 and 27 November 2025, 30 patients were enrolled; 29 treated patients formed the modified intention-to-treat (mITT) and safety populations (median age, 60 years). Induction comprised four 28-day SVRD cycles with protocol-specified consolidation/maintenance and optional autologous stem cell transplantation (ASCT). The primary end point was best overall response rate (ORR) during induction according to International Myeloma Working Group criteria. Patients without a postbaseline assessment were imputed as nonresponders. In the mITT cohort, the ORR was 89.7% (stringent complete response [CR], 58.6%; CR, 3.4%; very good partial response, 10.3%; partial response, 17.2%). Imaging documented EMD regression in 89.7% of patients (complete resolution, 79.3%; partial resolution, 10.3%). The 12-month progression-free survival and overall survival rates were 87.9% and 96.3%, respectively (medians not reached; median follow-up, 18 months). High-risk cytogenetics were present in 31.0% of patients, and 27.6% met the ultra-high-risk (double-hit) criteria. Grade ≥3 treatment-emergent adverse events occurred in 37.3% of patients, most commonly thrombocytopenia (24.1%), neutropenia (6.9%), and pneumonia (10.3%); no treatment-related deaths occurred. SVRD produced deep hematologic responses and high EMD clearance with manageable toxicity, thereby enabling ASCT in 51.7% of participants. These findings support SVRD as a rational frontline option for EMD-positive NDMM and justify randomized studies to confirm durability and to benchmark it against contemporary quadruplets and cellular therapies. This trial was registered at www.ClinicalTrials.gov as NCT05900882.