This phase 3 randomized, open-label multicenter trial will compare the efficacy, safety and the impact on health-related quality of life (HR-QoL) of SPd versus EloPd in pomalidomide-naïve patients with MM who have received 1 to 4 prior anti-MM regimens and been treated with an immunomodulatory imide drug (IMiD), proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody (mAb).

Inclusion Criteria:

1. Relapsed or refractory MM with measurable disease per IMWG guidelines as defined by at least 1 of the following:

   1. Serum M-protein ≥0.5 g/dL (≥5 g/L) by serum protein electrophoresis (SPEP) or, for immunoglobulin (Ig) A or D myeloma, by quantitative serum IgA or IgD levels ≥ 0.5 g/dL.
   2. Urinary M-protein excretion ≥200 mg/24 hours
   3. Serum free light chain (FLC) ≥100 mg/L, provided that the FLC ratio is abnormal (normal FLC ratio: 0.26 to 1.65)

2. Received at least 1 and no more than 4 prior anti-MM lines of therapy. Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as 1 line of therapy.

3. Prior therapy that includes ≥ consecutive cycles of lenalidomide and a proteasome inhibitor given alone or in combination

4. Prior therapy with an anti-CD38 mAb as part of their immedicate last treatment prior to study entry (Before protocol version2.0, patient with any prior therapy with an anti-CD38 mAb were eligible for the study).

5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

6. Resolution of any clinically significant non-hematological toxicities (if any) from previous treatments to Grade ≤1 by Cycle 1 Day 1 (C1D1). Patients with Grade 2 non-hematological toxicities may be included.

7. Adequate hepatic function within 28 days prior to C1D1:

   1. Total bilirubin <2 × upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of <3 × ULN)
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 × ULN

8. Adequate renal function within 28 days prior to C1D1 (estimated creatinine clearance [CrCl] of ≥15 mL/min (not requiring dialysis), calculated using the formula of Cockcroft and Gault or measured by 24-hour urine collection).

9. Adequate hematopoietic function within 7 days prior to C1D1 defined as absolute neutrophil count ≥1.5 x 109/L , hemoglobin ≥8.5 g/dL, and platelet count ≥100 x 109/L (patients for whom <50% of bone marrow nucleated cells are plasma cells) or ≥75 x 109/L (patients for whom ≥50% of bone marrow nucleated cells are plasma cells).

   1. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (e.g., eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.

   2. Patients must have:

      • At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and
      • At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment.

   However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.

10. Patients with active hepatitis B virus (HBV) are eligible if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 IU/mL. Patients with evidence of non-active HBV should be discussed with the Medical Monitor and should be monitored or receive prophylaxis at the discretion of the Investigator and study site institutional guidelines

11. Patients with a history of hepatitis C virus (HCV) are eligible if they have received adequate curative anti-HCV treatment and HCV viral load is below the limit of quantification.

12. Patients with a history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T cell counts ≥350 cells/µL, negative viral load, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year and should be on established antiretroviral therapy (ART) for at least 4 weeks.

13. Female patients of childbearing potential must have a negative serum pregnancy test within 10 to 14 days and a second test within 24 hours prior to the first dose of study treatment. Female patients of childbearing potential and fertile male patients who are sexually active must use highly effective methods of contraception throughout the study and for 3 months following the last dose of study treatment.

14. Age ≥18 years at the time of signing informed consent.

15. Written informed consent signed in accordance with federal, local, and institutional guidelines.

16. Patients must be able and willing to take enteric-coated aspirin according to clinical practice, or if history of prior thrombotic disease, must be fully anticoagulated with warfarin (international normalized ratio [INR] 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism (PE) at the Investigator's discretion. For patient on warfarin, INR should be repeated as clinically indicated. Use of alternative anticoagulants, such as direct oral anticoagulants, may be considered per Investigator discretion.

Exclusion Criteria:

1. Smoldering MM.

2. Plasma cell leukemia.

3. Documented active systemic amyloid light chain amyloidosis.

4. Any history of central nervous system MM.

5. Prior treatment with:

   1. A selective inhibitor of nuclear export (SINE) compound, including selinexor
   2. Pomalidomide and/or elotuzumab.

6. Any concurrent medical condition or disease that is likely to interfere with study procedures.

7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.

8. Known intolerance, hypersensitivity, or contraindication to any of the study treatments.

9. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy including investigational therapies and high dose dexamethasone (i.e., 40 mg daily for 4 days per week) ≤2 weeks prior to C1D1. Patients on long-term glucocorticoids during Screening do not require a washout period but must be able to tolerate the specified dexamethasone dose in this study.

10. Prior autologous stem cell transplantation <60 days or allogeneic stem cell transplantation <4 months prior to C1D1.

11. Major surgery within 4 weeks prior to C1D1.

12. Active graft versus host disease after allogeneic stem cell transplantation.

13. Pregnant or breastfeeding females.

14. In the opinion of the Investigator, patients who are below their ideal body weight and would be unduly impacted by changes in their weight.

15. Clinically significant cardiac disease, including:

    1. Myocardial infarction within 6 months before C1D1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    2. Uncontrolled cardiac arrhythmia (CTCAE v. 5.0 Grade 2 or higher) or clinically significant electrocardiogram (ECG) abnormalities.
    3. Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.

16. Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment.

17. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.

18. Contraindication to any of the required concomitant drugs or supportive treatments.

19. Patients unwilling or unable to comply with the protocol.