The following criteria is provided for health care professionals.

Inclusion Criteria:

1. Written informed consent in accordance with federal, local, and institutional guidelines.
2. Age ≥ 18 years at the time of informed consent
3. Histologically confirmed diagnosis, measurable disease and evidence of disease progression of MM, as described below.
4. Symptomatic MM, based on IMWG guidelines. Patients must have measurable disease as defined by at least one of the following:
   1. Serum M-protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA myeloma, by quantitative IgA
   2. Urinary M-protein excretion at least 200 mg/24 hours
   3. Serum FLC ≥ 100 mg/L, provided that FLC ratio is abnormal
   4. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement (e.g., for IgA MM), then quantitative Ig levels by nephelometry or turbidometry are acceptable.
5. Any non-hematological toxicities (except for peripheral neuropathy as described in exclusion criterion #24) that patients experienced from treatments in previous clinical studies must have resolved to ≤ Grade 2 by Cycle 1 Day 1.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
7. Adequate hepatic function within 21 days prior to C1 D1:
   • For SPd and SRd: Total bilirubin < 2x ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x ULN) and both AST and ALT < 2.5x ULN)
   • For SVd, SPVd and SDd): Total bilirubin of ≤ 1.5x ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x ULN) and both AST and ALT < 2.0x ULN)
   • For SKd: Total bilirubin < 2x ULN (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3x ULN) and both AST and ALT < 3.0x ULN
8. Adequate renal function within 21 days prior to C1 D1:
   • Estimated creatinine clearance of (calculated using the formula of Cockroft and Gault):
   • ≥ 20 mL/min for SVd, SPVd, and SDd Arms
   • ≥ 45 mL/min for SPd Arm (as requested by the manufacturer)
   • > 50 mL/min for SRd Arm
9. Adequate hematopoietic function within 21 days prior to C1 D1: total white blood cell (WBC) count ≥ 1,500/mm3, ANC ≥ 1000/mm3, hemoglobin (Hb) ≥ 8.0 g/dL, and platelet count ≥ 75,000/mm3. For expansion cohorts only, platelet counts > 50,000/mm3; for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells, platelets or ≥ 30,000/mm3 are acceptable for expansion cohorts. Patients receiving hematopoietic growth factor support, including erythropoietin (EPO), darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophagecolony stimulating factor (GM-CSF), and platelet stimulators (e.g., eltrombopag or romiplostim) may continue to do so. However, patients in the escalation cohorts must be platelet transfusion independent for > 1 week in order to be enrolled in the study.
10. Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at Screening. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose.

    SPd (Arm 1) Only:

11. Relapsed and refractory MM with:

    1. Documented evidence of PD after achieving at least SD for ≥ 1 cycle during a previous MM regimen (i.e., relapsed MM)
    2. ≤ 25% response (i.e., patients never achieved ≥ MR) or PD during or within 60 days from the end of the most recent MM regimen (i.e., refractory MM)
    3. Previously undergone ≥ 2 cycles of lenalidomide and a proteasome inhibitor (in separate therapeutic regimens [not for maintenance] or in combination)
    4. In the expansion arm at RP2D, patients must not be pomalidomide refractory

    SVd (Arm 2) Only:

12. Relapsed or refractory MM with

    1. Documented evidence of relapse after ≥ 1 previous line of therapy
    2. Not refractory to bortezomib in their most recent line of therapy

    SRd in RRMM (Arm 3) Only:

13. Patients who received ≥ 1 prior therapeutic regimen (prior lenalidomide is allowed as long as patient's MM was not refractory to prior lenalidomide; patients whose MM was refractory to lenalidomide maintenance regimens will be allowed in this cohort).

    SPVd (Arm 4) Only:

14. Patients whose MM is relapsing after ≥ 1 prior therapy with progression on their last therapy.

    SDd (Arm 5) Only:

15. Patients who received ≥ 3 prior lines of therapy, including a PI and an IMiD, or patients with MM refractory to both a PI and an IMiD.
16. Patients must not have received prior daratumumab therapy (Cohort 5.3 ONLY - dose expansion at RP2D).

    SKd (Arm 6) Only:

17. Patients may have received prior bortezomib or carfilzomib therapy, however their MM must NOT be refractory to carfilzomib.

    SRd in NDMM (Arm 7) Only:

18. Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria or Myeloma Defining Events and need systemic therapy.
19. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone (maximum dose of 160 mg).

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), and quantitative immunoglobulin levels cannot be used instead
3. Documented active systemic amyloid light chain amyloidosis
4. Active plasma cell leukemia
5. Blood (or blood product) transfusions and blood growth factors within 7 days of C1D1 (only for patients enrolling into the Expansion Phase)
6. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patients on long-term glucocorticoids during Screening do not require a washout period. Prior radiation is permitted for treatment of fractures or to prevent fractures as well as for pain management
7. Patients with history of SCC with residual paraplegia (Dose Escalation Phase only).
8. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1
9. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell transplantation < 3 months prior to C1D1
10. Active graft versus host disease after allogeneic stem cell transplantation
11. Life expectancy < 3 months
12. Major surgery within 4 weeks prior to C1D1
13. Active, unstable cardiovascular function:
    1. Symptomatic ischemia, or
    2. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or
    3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥ 3, or
    4. Myocardial infarction (MI) within 3 months prior to C1D1
    5. Ejection fraction (EF) < 50% at Screening
14. Uncontrolled active hypertension
15. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose
16. Known active hepatitis A, B or C
17. Known HIV infection or HIV seropositivity
18. Any active gastrointestinal dysfunction that prevents the patient from swallowing tablets or interferes with absorption of study treatment
19. Currently pregnant or breastfeeding
20. A serious psychiatric or medical condition which, in the opinion of the Investigator, could interfere with treatment
21. Hypersensitivity to any of the treatments for the Arm in which the patient is enrolled
22. In the SVd (Arm 2) only: Prior history of neuropathy Grade > 2, or Grade 2 neuropathy with pain at screening (within 21 days prior to C1D1)
23. Prior exposure to a SINE compound, including selinexor