Safety and efficacy of first-line selinexor plus bortezomib, lenalidomide and dexamethasone (XVRd) in high risk newly diagnosed multiple myeloma: A multi-center, single-arm, phase ib/II trial

Abstract

Abstract Background: Patients newly diagnosed with multiple myeloma (NDMM) harboring high-risk (HR) factors typically have a poor prognosis. According to the mSMART 3.0 criteria, high-risk factors for MM include del(17p), t (4; 14), t (14; 16), del 17p, p53 mutation, gain/amp 1q, R-ISS stage 3, High Plasma Cell S-phase and GEP for high-risk signature. HRMM often presents with aggressiveness, with characteristics of early relapse or primary refractoriness, and there is no unified treatment standard yet. XPO1 protein overexpression in MM leads to nuclear export of tumor suppressor proteins (TSPs) and glucocorticoid receptors (GR), facilitating oncogene translation. Selinexor, a selective XPO1 inhibitor, exerts anti-myeloma effects. A subgroup analysis of the phase 3 BOSTON trial demonstrated significant benefit of selinexor-bortezomib-dexamethasone (SVd) regimen in patients with relapsed/refractory MM (RRMM) with del(17p), t(4;14), t(14;16), or amp(1q21). This trial evaluates the safety and efficacy of selinexor in combination with bortezomib, lenalidomide and dexamethasone (VRd) as a first-line treatment for NDMM patients with HR factors (NCT05422027). This report prviodes updated data on efficacy and safety. Methods:Phase Ib objectives included determining the recommended phase II dose (RP2D) throught safety/tolerability assessment. Dose expansion at the RP2D were designed to evaluate efficacy, including complete response (CR) rate, overall response rate (ORR), very good partial response (VGPR) rate, minimal residual disease (MRD) negativity rate, safety and tolerability. Patients received the XVRd regimen as induction therapy for 4-6 cycles (21 days per cycle). Following induction, patients undergoing autologous stem cell transplantation (ASCT) received 2-4 cycles of XVRd consolidation; whlie non-ASCT patients received total 12 cycles of XVRd consolidatio . All patients received XR as maintenance therapy until disease progression, death, intolerance or other discontinuation reasons. Results: Between July 2022 and August 2025, 21 NDMM patients were enrolled, with a median age of 55.0 years (range:40-67). Of those, 6 (28.6%) patients were ISS stage 3. All patients had HR cytogenetic, with 85.7% exhibiting 1q21 gain/amp, 9.5% exhibiting P53 deficiency, 9.5% exhibiting t(4;14) variant，9.5% exhibiting ³ 2 HR cytogenetic abnormalities. The distribution of free light chain (FLC) was 66.7% κ-type and the 33.3% λ-type FLC. Extramedullary diseases (EMD) were present in 14.3% of patients. In the phase Ib study, the following selinexor dosages were administered: 40 mg qw (n=4) and 60 mg qw (n=3). No dose-limiting toxicities (DLTs) occurred. Common grade 3/4 treatment-related adverse events (TRAE) included thrombocytopenia (57.1%), neutropenia (57.1%), anemia (14.3%), peripheral neuropathy (14.3%). All TRAEs were manageable with supportive care and dose modifications. The maximum tolerated dose (MTD) and RP2D were established as selinexor 60 mg qw. By August 2025, 16 patients were evaluable for response. The ORR was 100%, with CR/sCR, ³VGPR, and partial response (PR) rates of 50.0%, 81.3%, and 18.8%, respectively. The 12-month PFS rate was 80.8%, whlie the 12-month OS rate was 100%. As of the follow-up deadline, the MRD negativity rate (NGF, 10-5) was 75% after post-induction. Among all 21 patients, the incidence of grade 3/4 TRAEs was 57.9%, including neutropenia (31.6%), thrombocytopenia (31.6%), peripheral neuropathy (15.8%), anemia (5.3%), and leukopenia (5.3%). Conclusions:The combination ofselinexor (60 mg qw) with VRd demonstrates encouraging efficacy and a manageable safety profile in patients with HR NDMM. Ongoing efforts to expand enrollment and extend follow-up are aiming at confirming long-term outcomes.