Selinexor and Backbone Treatments of Multiple Myeloma Patients

Inclusion Criteria:

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

2. Age greater than or equal to (≥) 18 years at the time of informed consent.

3. Histologically confirmed diagnosis with measurable disease for relapsed/refractorymyeloma.

4. Symptomatic MM, based on IMWG guidelines.

5. Patients must have measurable disease as defined by at least one of the following:

6. Serum M-protein ≥ 0.5 gram per deciliter (g/dL) by serum proteinelectrophoresis (SPEP) or, for immunoglobulin A (IgA) myeloma, by quantitativeIgA

7. Urinary M-protein excretion at least 200 mg/24 hours

8. Serum free light chain (FLC) ≥ 100 milligram per liter (mg/L), provided thatFLC ratio is abnormal

9. If SPEP is felt to be unreliable for routine M-protein measurement (example,for IgA MM), then quantitative immunoglobulin (Ig) levels by nephelometry orturbidometry are acceptable

10. Any non-hematological toxicities (except for peripheral neuropathy as described inexclusion criterion #22) that patients had from treatments in previous clinicalstudies must have resolved to less than or equal (≤) Grade 2 by C1D1.

11. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.

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

• For SPd, SRd, and SPEd: Total bilirubin < 2* upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirecthyperbilirubinemia] who must have a total bilirubin of ≤ 3* ULN) and bothaspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5* ULN

• For SVd, SPVd, SDd, SNd, SBd and SDPd: Total bilirubin of < 1.5* ULN (exceptpatients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] whomust have a total bilirubin of ≤ 3* ULN) and both AST and ALT < 2.0* ULN

• For SKd and SMd: Total bilirubin < 2x ULN (except patients with Gilbert'ssyndrome [hereditary indirect hyperbilirubinemia] who must have a totalbilirubin of ≤ 3x ULN) and both AST and ALT < 3.0x ULN

9. Adequate renal function within 28 days prior to C1D1. For Arms 1-11, estimatedcreatinine clearance (CrCl) calculated using the formula of Cockroft and Gault (1976).

• ≥ 20 milliliter per minute (mL/min) for SVd, SDd, and SKd arms

• ≥ 30 mL/min for SNd, SBd, and SMd arms

• ≥ 45 mL/min for SPd, SPVd, SPEd and SDPd arms

• > 60 mL/min for SRd arm

10. Adequate hematopoietic function within 28 days prior to C1D1: absolute neutrophilcount (ANC) ≥ 1,000/mm^3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet count ≥ 100,000/mm^3.

• SPVd (Arm 4) and SKd (Arm 6) only: platelet count ≥150,000.

• SMd (Arm 12) only: platelet count ≥75,000 for subjects in whom <50% of bonemarrow nucleated cells are plasma cells; or platelet count <50,000 for subjectsin whom ≥50% of bone marrow nucleated cells are plasma cells.

11. Female patients of childbearing potential must have a negative serum pregnancy testat Screening. Female patients of childbearing potential and fertile male patientsmust use highly effective methods of contraception throughout the study and for 90days following the last dose of study treatment. For Arm 12 (SMd), all studysubjects must agree and adhere to all testing and contraception requirements asspecified in the mezigdomide Global Pregnancy Prevention Plan (PPP) SPd (Arm 1) Only.

12. Relapsed or refractory MM with:

13. Documented evidence of progressive disease (PD) after achieving at least stabledisease (SD) for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)

14. ≤ 25 percent (%) response (i.e., patients never achieved ≥ MR) or PD during orwithin 60 days from the end of the most recent MM regimen (i.e., refractory MM)

15. Previously undergone ≥ 2 cycles of lenalidomide and a PI (in separatetherapeutic regimens [not for maintenance] or in combination)

16. In the expansion arm at RP2D, patients must not be pomalidomide refractory SVd (Arm 2) Only:

17. Relapsed or refractory MM with:

18. Documented evidence of relapse after ≥ 1 previous line of therapy

19. Not refractory to bortezomib in their most recent line of therapy SRd in RRMM (Arm 3) Only:

20. Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowedas long as patient's MM was not refractory to prior lenalidomide; patients whose MMwas refractory to lenalidomide maintenance regimens will be allowed in this cohort). SPVd (Arm 4) Only:

21. Patients who received 1- 3 prior lines of therapy, including ≥ 2 cycles oflenalidomide and have demonstrated disease progression on their last therapy (mayinclude prior bortezomib, as long as the patient's MM was not refractory tobortezomib therapy), but patients must be pomalidomide-naïve in the Dose Expansionat RP2D (Cohort 4.3 ONLY). SDd (Arm 5) Only:

22. Patients who received ≥ 3 prior lines of therapy, including a PI and animmunomodulatory agent (IMiD), or patients with MM refractory to both a PI and anIMiD.

23. Patients must not have received prior anti-cluster of differentiation 38 (anti-CD38)monoclonal antibodies (Cohort 5.3 ONLY - Dose Expansion at RP2D). SKd (Arm 6) Only:

24. Patients may have received prior PIs; however, their MM must NOT be refractory tocarfilzomib. SRd in NDMM (Arm 7) Only:

25. Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria (calcium elevation, renal failure, anemia, lytic bone lesions) or myeloma-definingevents and need systemic therapy. No prior systemic therapy for NDMM is permittedother than pulse dose dexamethasone (maximum dose of 160 mg) or corticosteroidequivalent. SNd (Arm 8) Only:

26. Patients must have MM that relapsed after 1 - 3 prior lines of therapy (may notinclude those with MM refractory to bortezomib or carfilzomib but patients must beixazomib-naïve). SPEd (Arm 9) Only:

27. Patients who received ≥ 2 prior therapies, including lenalidomide and a proteasomeinhibitor (in separate or the same regimens), but patients must bepomalidomide-naive and elotuzumab-naive in the Dose Expansion at RP2D (Cohort 9.3ONLY). SBd (Arm 10) Only:

28. Patients who have MM that was refractory to an IMiD, a proteasome inhibitor, andrefractory or intolerant (or both) to an anti-CD38 monoclonal antibody. Patientsmust be belantamab mafodotin-naive in the Dose Expansion cohort at RP2D (Cohort 10.3ONLY). SDPd (Arm 11) Only:

29. Patients who received 1-3 prior therapies, including lenalidomide and a proteasomeinhibitor (in separate or the same regimen), but patients must be pomalidomide-naiveand daratumumab-naive in the Dose Expansion cohort at RP2D (Cohort 11.3 ONLY). SMd (Arm 12) only:

30. Patients with RRMM who have received at least 2 prior lines of therapy, including anIMiD, a PI, and an anti-CD38 monoclonal antibody. Patients must have either failed aT-cell redirecting treatment (eg, CAR-T or bispecific antibody) or otherwise cannotreceive such therapy due to either medical or logistic reasons.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:

1. Smoldering MM.

2. MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), andquantitative immunoglobulin levels cannot be used instead.

3. Documented active systemic amyloid light chain amyloidosis.

4. Active plasma cell leukemia.

5. Red Blood Cell (RBC) and platelet transfusions and blood growth factors within 14days of C1D1 (Arms 1-11 only). Red blood cells and platelet transfusions and bloodgrowth factors within 7 days of C1D1 (Arm 12).

6. Platelet transfusion or G-CSF within 7 days or pegfilgastrim within 14 days prior tothe complete blood count (CBC) used to determine eligibility.

7. Radiation, chemotherapy, or immunotherapy or any other tumor-directed therapy ≤ 2weeks prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patientson long-term glucocorticoids during Screening do not require a washout period. Spotradiation is permitted at any time for treatment of fractures or to preventfractures as well as for pain management.

8. Patients with history of spinal cord compression with residual paraplegia (DoseEscalation Phase only).

9. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1.

10. Prior autologous stem cell transplantation < 1 month, or allogeneic stem celltransplantation < 3 months prior to C1D1.

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

12. Life expectancy < 3 months.

13. Major surgery within 4 weeks prior to C1D1.

14. Active, unstable cardiovascular function:

15. Symptomatic ischemia, or

16. Uncontrolled clinically-significant conduction abnormalities (e.g., patientswith ventricular tachycardia on antiarrhythmics are excluded; patients with 1stdegree atrioventricular (AV) block or asymptomatic left anterior fascicularblock/right bundle branch block (LAFB/RBBB) will not be excluded), or

17. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3,or

18. Myocardial infarction (MI) within 3 months prior to C1D1

19. Ejection fraction (EF) < 50% at Screening (Arms 1-11 only, screeningechocardiogram not required for Arm 12, SMd)

20. Uncontrolled active hypertension (Arms 1-11 only).

21. Uncontrolled active infection requiring parenteral antibiotics, antivirals, orantifungals within one week prior to first dose.

22. Known active hepatitis A, B or C.

23. Known human immunodeficiency virus (HIV) infection or HIV seropositivity.

24. Any active gastrointestinal dysfunction that prevents the patient from swallowingtablets or interferes with absorption of study treatment.

25. Currently pregnant or breastfeeding.

26. A serious active psychiatric or active medical condition which, in the opinion ofthe Investigator, could interfere with treatment.

27. Hypersensitivity to any of the treatments for the arm in which the patient isenrolled.

28. SVd Arm (Arm 2), SPVd (Arm 4), and SNd Arm (Arm 8) only: Prior history of neuropathyGrade > 2, or Grade ≥ 2 neuropathy with pain at Screening (within 28 days prior toC1D1).

29. Patients who are eligible for the selinexor PK Run-in only: Treatment with moderateor strong inhibitors/inducers of CYP3A within 7 days prior to Day 1 of the PK Run-inperiod.

30. Patients who are eligible for the selinexor PK Run-in only: Not able to receive astrong CYP3A4 inhibitor due to concomitant medications.

31. SKd arm only: HBs Ag + plus HBc Ab + even though no active hepatitis B virus (HBV)hepatitis. If HBs Ag - plus HBc Ab +, treating physician needs to contact themedical monitor.

32. Prior exposure to a selective inhibitor of nuclear export (SINE) compound, includingselinexor. SBd (Arm 10): Only:

33. Current corneal epithelial disease except mild punctate keratopathy. SMd (Arm 12 only):

34. History of allogeneic stem cell or solid organ transplant at any time.

35. History of anaphylaxis or hypersensitivity to thalidomide, lenalidomide,pomalidomide (including ≥Grade 3 rash during prior thalidomide, lenalidomide, orpomalidomide therapy), carfilzomib or dexamethasone, any CELMoD agents, or theexcipients contained in the formulations, or subject has any contraindications perlocal prescribing information.

36. Subject is unable or unwilling to agree to refrain from donating blood while onstudy intervention, during dose interruptions, and for at least 28 days followingthe last dose of study intervention.

37. Subject is unable or unwilling to undergo protocol required thromboembolismprophylaxis.

38. Use of strong CYP3A4 modulator or proton-pump inhibitors (eg, omeprazole,lansoprazole), within 2 weeks of starting study intervention.

39. Active concomitant malignancies or history of another malignancy within 3 yearsprior to C1D1 except for adequately treated early-stage basal cell or squamous cellcarcinoma of skin, adequately treated carcinoma in situ of breast or cervix, ororgan confined prostate cancer.

40. History of chronic hepatitis B with detectable viral load.

41. Subject is unable or unwilling to receive protocol-required dual antiemeticprophylaxis