Bortezomib, Selinexor, and Dexamethasone in Patients With Multiple Myeloma

Inclusion Criteria:

1. Histologically confirmed MM with measurable disease per IMWG guidelines as definedby at least 1 of the following:

2. Serum M-protein ≥ 0.5 g/dL (> 5 g/L) by serum protein electrophoresis (SPEP) orfor immunoglobulin (Ig) A myeloma, by quantitative serum IgA levels; or

3. Urinary M-protein excretion at least 200 mg/24 hours; or

4. Serum free light chain (FLC) ≥ 100 mg/L, provided that the serum FLC ratio isabnormal (normal FLC ratio: 0.26 to 1.65).

5. Had at least 1 prior anti-MM regimen and no more than 3 prior anti-MM regimens.Induction therapy followed by stem cell transplant and consolidation/maintenancetherapy will be considered as 1 anti-MM regimen.

6. Documented evidence of progressive MM (based on the Investigator's determinationaccording to the modified IMWG response criteria) on or after their most recentregimen.

7. Prior treatment with bortezomib or other Proteasome Inhibitor (PI) is allowed,provided all of the following criteria are met:

8. Best response achieved with prior bortezomib at any time was ≥ PR and with thelast PI (PI therapy (alone or in combination) was ≥ PR, AND

9. Participant did not discontinue bortezomib due to ≥ Grade 3 related toxicity,AND

10. Must have had at least a 6-month PI-treatment-free interval prior to Cycle 1Day 1 (C1D1) of study treatment.

11. Must have an ECOG Status score of 0, 1, or 2.

12. Written informed consent in accordance with federal, local, and institutionalguidelines.

13. Age ≥18 years.

14. Resolution of any clinically significant non-hematological toxicities (if any) fromprevious treatments to ≤ Grade 1 by C1D1. Patients with chronic, stable Grade 2non-hematological toxicities may be included following approval from the MedicalMonitor.

15. Adequate hepatic function within 28 days prior to C1D1.

16. Total bilirubin <1.5 × upper limit of normal (ULN) (except patients withGilbert's syndrome who must have a total bilirubin of <3 × ULN), and

17. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal to <2 × ULN.

18. Adequate renal function within 28 days prior to C1D1 (estimated creatinine clearance [CrCl] of ≥20 mL/min, calculated using the formula of Cockroft and Gault):

(140-Age) × Mass (kg)/(72 × creatinine mg/dL) Multiply by 0.85 if the patient is female, or if CrCl is ≥20 mL/min as measured by 24-hour urine collection.

11. Adequate hematopoietic function within 7 days prior to C1D1: total white blood cell (WBC) count ≥1500/mm3, absolute neutrophil count ≥1000/mm3, hemoglobin ≥8.5 g/dL andplatelet count ≥75,000/mm3 (patients for whom < 50% of bone marrow nucleated cellsare plasma cells) or ≥50,000/mm3 (patients for whom ≥50% of bone marrow nucleatedcells are plasma cells).

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

13. Patients must have:

• At least a 2-week interval from the last red blood cell (RBC) transfusion priorto the Screening hemoglobin assessment, and

• At least a 1-week interval from the last platelet transfusion prior to theScreening platelet assessment.

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

12. Female patients of childbearing potential must have a negative serum pregnancy testat Screening. Female patients of childbearing potential and fertile male patientswho are sexually active with a female of childbearing potential must use highlyeffective methods of contraception throughout the study and for 3 months followingthe last dose of study treatment.

Exclusion Criteria:

1. Prior exposure to a SINE compound (i.e. an XPO-1 inhibitor), including selinexor.

2. Prior malignancy that required treatment or has shown evidence of recurrence (exceptfor non-melanoma skin cancer or adequately treated cervical carcinoma in situ)during the 5 years prior to randomization. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.

3. Has any concurrent medical condition or disease (e.g., uncontrolled activehypertension, uncontrolled active diabetes, active systemic infection, etc.) that islikely to interfere with study procedures.

4. Uncontrolled active infection requiring parenteral antibiotics, antivirals, orantifungals within 1 week prior to C1D1. Patients on prophylactic antibiotics orwith a controlled infection within 1 week prior to C1D1 are acceptable.

5. Active plasma cell leukemia.

6. Documented systemic light chain amyloidosis.

7. MM involving the central nervous system.

8. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skinchanges (POEMS) syndrome.

9. Spinal cord compression.

10. Greater than Grade 2 neuropathy or ≥ Grade 2 neuropathy with pain at baseline,regardless of whether or not the patient is currently receiving medication

11. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.

12. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy (includinginvestigational therapies) ≤ 2 weeks prior to C1D1. Localized radiation to a singlesite at least 1 week before C1D1 is permitted. Glucocorticoids within 2 weeks ofC1D1 are permitted. Patients on long-term glucocorticoids during Screening do notrequire a washout period but must be able to tolerate the specified dexamethasonedose in this study.

13. Prior autologous stem cell transplantation < 1 month or allogeneic stem celltransplantation < 4 months prior to C1D1.

14. Active graft versus host disease (after allogeneic stem cell transplantation) atC1D1.

15. Pregnant or breastfeeding females.

16. Body Surface Area < 1.4 m² at baseline, calculated by the Dubois or Mostellermethod.

17. Life expectancy of < 4 months.

18. Major surgery within 4 weeks prior to C1D1.

19. Active, unstable cardiovascular function:

20. Symptomatic ischemia, or

21. Uncontrolled clinically significant conduction abnormalities (e.g., patientswith ventricular tachycardia on anti-arrhythmics are excluded; patients withfirst-degree atrioventricular block or asymptomatic left anterior fascicularblock/right bundle branch block will not be excluded), or

22. Congestive heart failure of New York Heart Association Class ≥ 3 or known leftventricular ejection fraction < 40%, or

23. Myocardial infarction within 3 months prior to C1D1.

24. Known active human immunodeficiency virus (HIV) infection or HIV seropositivity

25. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis Cvirus ribonucleic acid (RNA) or hepatitis B virus surface antigen.

26. Any active gastrointestinal dysfunction interfering with the patient's ability toswallow tablets, or any active gastrointestinal dysfunction that could interferewith absorption of study treatment.

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

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

29. Patients unwilling or unable to comply with the protocol, including providing 24-hour urine samples for urine protein electrophoresis at the required time points.