A novel conditioning regimen combining selinexor with melphalan  Improves Survival in Patients with multiple myeloma:a prospective study

Abstract Background: High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) remains the standard consolidation therapy for multiple myeloma (MM). Previous attempts to optimize conditioning regimens have not yielded superior outcomes. Selinexor, a selective inhibitor of exportin-1 (XPO-1), has demonstrated synergistic antitumor effects with melphalan in preclinical models. Aims: To evaluate the efficacy and safety of a selinexor-melphalan conditioning regimen. Methods: Based on the recommended phase 2 dose (RP2D) established by Nishihori et al., the initial regimen administered selinexor 60 mg on days -4 and -1 combined with melphalan 100 mg/m² on days -3 and -2. Due to severe vomiting (leading to Mallory-Weiss syndrome) in the first patient, the protocol was amended to selinexor 60 mg on days -11 and -4 and melphalan 100 mg/m² (70 mg/m² for creatinine clearance <60 mL/min) on days -3 and -2. The study was approved by the institutional ethics committee, with written informed consent obtained from all participants. Results: From January 2022 to May 2025, 32 MM patients (median age 59 years, range 33-69; male:female 16:16) achieving ≥partial response(PR) post-induction were enrolled. Baseline characteristics included renal dysfunction (CrCl <60 mL/min, n=5), immunoglobulin subtypes (IgG=16, IgA=9, IgD=2, light chain=5) and high-risk features:R-ISS stage III(n=7, 22%),del(17p)(n=1, 3%),TP53 mutation(n=1, 3%), t(4;14)(n=1, 3%)and 1q21 gain/amplification(n=14, 44%).Six patients (19%) had extramedullary disease. All received proteasome inhibitor-based induction, with 28% receiving daratumumab-based salvage therapy.Pre-transplant disease status: stringent complete response (sCR, n=10), complete response (CR, n=6), very good partial response (VGPR, n=8), and PR(n=8).Following stem cell infusion (median CD34+ dose 2.50 ×10⁶/kg [1.65-5.54]), neutrophil and platelet engraftment occurred at median 10 days (range 9-16) and 14 days (range 9-30), respectively. Post-transplant, 13/29 evaluable patients (45%) achieved deeper responses (6 PR→≥CR, 1 PR→VGPR, 6 VGPR→≥CR, 2 CR→sCR), and 9/16 (56%) with pre-transplant residual disease achieved minimal residual disease(MRD)-negative.Except for the initial case exhibiting severe vomiting, no grade 4-5 hematological adverse events(CTCAE v5.0) or transplant-related deaths were observed.With a median follow-up of 19 months (range3-42; data cutoff August 3, 2025),the estimated 1-year progression-free survival (PFS) and overall survival (OS) rates by Kaplan-Meier analysis were 90.9% (95%CI: 78.9-100) and 93.8% (95%CI: 83.3-100), respectively. Three biochemical relapses and three clinical relapses occurred, with two deaths due to disease progression. Conclusion: The selinexor-melphalan conditioning regimen demonstrates promising efficacy, enhancing depth of response and survival outcomes with manageable toxicity. These findings warrant validation in larger randomized trials.