Response and Safety of Selinexor with VRD Regimen in Newly Diagnosed Multiple Myeloma (NDMM) with Extramedullary Disease (EMD): A Prospective, Open-Label, Multicenter, Phase 2 Study

INTRODUCTION: Extramedullary disease (EMD) is a rare but increasingly recognized complication in newly diagnosed multiple myeloma (NDMM) patients, associated with a poorer prognosis and drug resistance. However, data on treatment outcomes for EMD are primarily based on retrospective studies, necessitating prospective studies with well-defined EMD to assess treatment efficacy and safety accurately. In this context, we present the preliminary findings from a prospective phase 2 study evaluating the safety and efficacy of selinexor in combination with VRd as a first-line treatment for NDMM patients with EMD(NCT05900882). METHODS: The study enrolled NDMM patients under the age of 75 who had measurable extramedullary disease (defined as paraosseous or extramedullary plasmacytoma ≥2cm. Patients received selinexor (60 mg QW) in combination with VRd (SVRD) regimen as induction therapy for 4 cycles (28 days of each cycle). Following the induction phase, patients underwent two cycles of VRd consolidation therapy after autologous stem cell transplantation (ASCT), while those who did not undergo ASCT received another 4 cycles of SVRD consolidation therapy. All pts received bortezomib plus lenalidomide for maintenance for at least 24 months. The primary endpoint of the study was the best response rate during induction therapy, and secondary endpoints included complete response (CR) rate, duration of response (DOR), safety, and survival outcomes. RESULTS: Between Oct 17, 2022 and May 12, 2023, a total of 10 NDMM pts with EMD were enrolled and received treatment at The First Affiliated Hospital of Nanjing Medical University. The median age was 62 years (range 48-70). Among them, 7 patients (70%) had RISS stage II/III disease, 7 patients (70%) were classified as high risk based on the mSMART stratification, and 3 patients (30%) had extra-osseous extramedullary plasmacytomas (EMP) as per Table 1. By the data cut-off date of July 15, 2023, at a median follow-up of 5.5 months (range 2.2-9.3 months), 5 pts completed 4 cycles of SVRd inductive treatment, 2 pts underwent ASCT, 1 pts discontinued the clinical trial due to progressive disease, and 3 pts were now receiving consolidation therapy ( Figure 1). Among the 10 evaluable pts for best serological response, 4 pts (40%) achieved serological CR/sCR, and 6 pts (60%) achieved VGPR. The depth of remission improved with the continuous treatment. Extramedullary disease evaluation in 9 patients showed complete disappearance of extramedullary lesions in 3 patients (30%), partial response in 5 patients (50%), and stable disease in 1 patient (10%). 8 (80%) pts experienced any grade AE. Grade 3 or 4 AEs were reported in 2 pts (9 events in total), with the most common being leukopenia (3), neutropenia (3) and thrombocytopenia (3). Non-hematological AEs were mainly grade 1-2, except for 1 pt with grade 3 anorexia. No pts required dose reductions or discontinuations due to AEs. CONCLUSIONS: The combination of selinexor with VRd regimen demonstrated early, deep, and durable responses in NDMM patients with extramedullary disease, both in serological and extramedullary responses, with a manageable safety profile. These results suggest that this therapeutic intervention holds promise as an effective and well-tolerated treatment option for multiple myeloma patients with EMD. Further studies are warranted to validate these findings and establish the long-term benefits of this combination therapy.