Overview

The purpose of this study is to assess the efficacy, antitumor activity, safety and tolerability of selinexor plus low-dose dexamethasone in participants with penta-refractory multiple myeloma or selinexor and bortezomib plus low-dose dexamethasone in participants with triple-class refractory multiple myeloma.

Eligibility

Inclusion Criteria:

• Age greater than or equal to (\>=)18 years at the time of signing informed consent.
• Written informed consent in accordance with federal, local, and institutional guidelines.
• Measurable MM based on IMWG guidelines as defined by at least one of the following:
  1. Serum M-protein \>= 0.5 gram per deciliter (g/dL) by serum protein electrophoresis (SPEP) or, for Immunoglobulin (Ig) A myeloma, by quantitative IgA.
  2. Urinary M-protein excretion \>= 200 mg/24 hours.
  3. Free light chain (FLC) \>= 100 milligram per liter (mg/L), provided that the FLC ratio is abnormal.
• Only for arms Sd-40 BIW, Sd-100 QW and Sd-80 BIW prior to protocol version (PV) 5.0: Participants must have relapsed or refractory multiple myeloma (RRMM) and have previously received at least 4 anti-MM prior therapies and have MM that is refractory to previous treatment with at least 2 proteasome inhibitors (PIs), at least 2 immunomodulatory agent (IMiDs), and 1 anti-cluster of differentiation (CD38) monoclonal antibody. Refractory is defined as lesser than or equal to (\<=) 25 percent (%) response to therapy, or progression during therapy or progression within 60 days after completion of therapy.
• Only for Arms Sd-40 BIW and Sd-100 QW as of PV 5.0: Participants must have RR MM and have been previously treated with \>=3 anti-MM therapies (with exposure to at least 2 PI drugs, at least 2 IMiDs, and 1 anti-CD38 monoclonal antibody), and be refractory to at least 1 drug of each class (PI/IMiD/anti-CD38). Refractory is defined as \<=25% response to therapy or progression during therapy or progression within 60 days after completion of therapy.
• Only for arm SVd: Participants must have previously received 1 to 5 anti-MM prior therapies and have MM that is refractory to previous treatment with at least 1 PI, at least 1 IMiD, and 1 anti- CD38 monoclonal antibody.
• Eastern Cooperative Oncology Group (ECOG) performance status of \<= 2.
• Female participants of childbearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male participants must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for 7 months for female and 4 months for male following the discontinuation of study treatment.

Exclusion Criteria:

• Active plasma cell leukemia.
• Documented systemic amyloid light chain amyloidosis.
• Active central nervous system MM.
• Only for SVd arm: Greater than Grade 2 peripheral neuropathy or Grade \>= 2 peripheral neuropathy with pain at baseline, regardless of whether or not the participant is currently receiving medication.
• Radiation, chemotherapy, immunotherapy, or any other anticancer therapy (including investigational therapies) \<= 2 weeks prior to Cycle 1 Day 1 (C1D1). (Steroids are permitted up to 1 pulse of 40 mg per day for 4 days in the 2 weeks prior to C1D1).
• Active graft vs. host disease (after allogeneic stem cell transplantation) at C1D1.
• Ongoing clinically significant non-hematological toxicities from prior treatments that are Grade greater than (\>) 2 at C1D1.
• Inadequate hepatic function defined as total bilirubin \>= 2x upper limit of normal (ULN) (\>= 3x ULN for participants with Gilbert's syndrome), aspartate transaminase (AST) \>= 2.5x ULN, and alanine transaminase (ALT) \>= 2.5x ULN.
• Inadequate renal function defined as estimated creatinine clearance of lesser than (\<) 20 milliliter per minute (mL/min), calculated using the formula of Cockroft and Gault.
• Inadequate hematopoietic function defined as the following:
  1. Absolute neutrophil count (ANC) \< 1000/cubic millimeter (mm\^3)
  2. Platelet count \< 75,000/mm\^3
  3. Hemoglobin (Hb) level \< 8.5 g/dL
• Life expectancy of \< 4 months, based on the opinion of the Investigator.
• Major surgery within 4 weeks prior to C1D1.
• Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to first dose.
• Active gastrointestinal dysfunction interfering with the ability to swallow tablets, or any gastrointestinal dysfunction that could interfere with absorption of the study treatment.
• Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus RNA or hepatitis B virus surface antigen.
• Female participants who are pregnant or lactating.
• Known intolerance, hypersensitivity, or contraindication to glucocorticoid therapy at C1D1.
• Concurrent therapy with approved or investigational anticancer therapeutic including topical therapies.
• Prior exposure to a SINE compound, including selinexor.
• Serious, active psychiatric or active medical conditions which, in the opinion of the Investigator or the Sponsor, could interfere with the participation in the study.
• Contraindication to any of the required concomitant drugs or supportive treatments.