Response and Safety of Selinexor with VRD Regimen in Newly Diagnosed Multiple Myeloma (NDMM) with Extramedullary Disease (EMD)

INTRODUCTION:

Extramedullary disease (EMD) is a rare but increasingly recognized complication in newly diagnosed multiple myeloma (NDMM) patients, associated with poorer prognosis and drug resistance. Nonetheless, data on treatment outcomes for EMD are primarily derived from retrospective studies, highlighting the need for prospective studies with well-defined EMD to accurately assess treatment efficacy and safety. 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 75 years old who exhibited measurable extramedullary disease (defined as plasma cell infiltration of an anatomical sites distant from bone marrow or measurable paraosseous or extramedullary soft tissue-related plasmacytoma ≥2cm. Pts 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, pts 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 July 20, 2024, a total of 20 NDMM pts with EMD were enrolled and received treatment at The First Affiliated Hospital of Nanjing Medical University and Nanjing First Hospital. The median age was 58 years (range 43-70). Among them, 15 patients (75.0%) had ISS stage II/III disease. FISH was not available in 4 patients. According to the mSMART stratification,9 patients (45%) were classified as high risk including 4(20%) double-hit. 19 patients (95.0%) had EM-B(extramedullary bone-related plasmacytoma). 5 patients (25%) had EM-S (soft tissue-related plasmacytoma). 4 patients (20%) had both EM-B and EM-S. By the data cut-off, at a median treatment time of 11 months (range 0.8-20 months), 13 pts completed 4 cycles of SVRd inductive treatment, 7 pts underwent ASCT, 2 pts underwent CART, 2 pts had progressive disease during induction therapy. 1 pts had progressive disease after ASCT.

Among the 19 evaluable pts for best serological response, 8 pts (42.1%)achieved serological CR/sCR, and 9 pts (47.4%) achieved VGPR. The depth of remission improved with the continuous treatment. Continuous extramedullary disease evaluation in 17 patients showed complete disappearance of extramedullary lesions in 10 patients (58.8%), PR in 5 patients (29.4%), and SD in 2 patient (11.8%).

18 (90%) pts experienced any grade AE. Grade 3 or 4 AEs were reported in 5 pts (6 events in total), with the most common being thrombocytopenia (4/20), neutropenia(1/20) and pneumonia(1/20). Non-hematological AEs were mainly grade 1-2. 5 pts were required dose reductions to 40 mg.

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.

No relevant conflicts of interest to declare.

Selinexor was granted accelerated approval by the FDA for use in combination with the steroid dexamethasone [Xd] for the treatment of adult patients with relapsed and/or refractory myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. The approval of the Xd regimen was based on data from Part 2 of the STORM phase IIb clinical trial.