Comparing the Combination of Selinexor-Daratumumab-Velcade-Dexamethasone (Dara-SVD) With the Usual Treatment (Dara-RVD) for High-Risk Newly Diagnosed Multiple Myeloma

PRIMARY OBJECTIVE: I. To compare deep response (complete response \[CR\] + stringent CR \[sCR\]) by the end of induction cycle 4 in newly diagnosed high-risk multiple myeloma patients (HR NDxMM), in both study arms. SECONDARY OBJECTIVES: I. To assess the minimal residual disease (MRD)-negativity (10\^-5). II. To assess overall response rate (ORR), very good partial response (VGPR), and partial response (PR). III. To assess progression-free survival (PFS) and duration of response (DOR). CORRELATIVE OBJECTIVE: I. To identify differential gene expression signature that predicts response to selinexor through ribonucleic acid sequencing (RNAseq) and cell-free deoxyribonucleic acid (cfDNA) studies. EXPLORATORY THROMBOEMBOLISM RISK OBJECTIVES: I. To estimate cumulative incidence of venous and arterial thromboembolic events. II. To calculate IMPEDE and SAVED risk scores at baseline and at time of venous thromboembolic event. III. To describe thromboprophylaxis strategies on treatment and venous and arterial thromboembolic events. IV. To estimate incidence of clinically significant (major) bleeding events and assess association with thromboprophylaxis strategy. V. To assess the association of venous and arterial thromboembolic events with PFS and all-cause mortality. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (Dara-SVD): Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, and selinexor orally (PO), bortezomib SC, and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo positron emission tomography (PET), magnetic resonance imaging (MRI), or computed tomography (CT), and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study. ARM II (Dara-RVD): Patients receive daratumumab and hyaluronidase-fihj SC on days 1, 8, 15, \& 22 for cycles 1-2, then days 1 \& 15 for cycles 3-4, lenalidomide PO once daily (QD) on days 1-21 of each cycle, and bortezomib SC and dexamethasone PO on days 1, 8, 15, \& 22 of each cycle. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo PET, MRI, or CT, and bone marrow aspiration and biopsy, and collection of blood and urine samples throughout the study. After completion of study treatment, patients are followed up at 6 months and 1 and 2 years.