The purpose of this research is to determine whether the combination of selinexor, venetoclax, and dexamethasone therapy can increase anti-cancer effects in patients with translocation 11;14-positive (t(11;14)), relapsed/refractory myeloma (RRMM).

Inclusion Criteria:

1. Patients must have a documented diagnosis of multiple myeloma defined by the International Myeloma Working Group Criteria (IMWG).5 Patients at initial diagnosis must have had a serum M-protein ≥ 3 g/dL and/or bone marrow plasma cells ≥10%, and at least one of the following:

   1. Anemia: Hemoglobin ≤10 g/dL, or
   2. Renal failure: serum creatinine ≥ 2.0 mg/dL, or
   3. Hypercalcemia: Ca ≥10.5 mg/dL, or
   4. Lytic bone lesions on X-ray, CT, or Positron emission tomography/Computed Tomography (PET/CT), or
   5. ≥ 2 focal lesions on spinal magnetic resonance imaging (MRI), or
   6. ≥ 60% bone marrow plasma cells, or Involved/un-involved serum free light chain ratio ≥ 100. Age ≥18 years of age on day of signing informed consent.

2. Patients must have had a bone marrow (BM) biopsy proven plasma cell myeloma harboring the t(11;14) translocation as reported by a Clinical Laboratory Improvement Amendments (CLIA) certified assay (i.e. local fluorescence in situ hybridization (FISH) testing). BM biopsy can be performed at time of enrollment or documented FISH results (i.e. original FISH report) can be used.

3. Must have Relapsed or Relapsed and Refractory Multiple Myeloma. Patients must have documented evidence of having received two prior lines of therapy and be refractory to, not a candidate for (ineligible), or intolerant of at least one immunomodulatory (IMiD), one proteasome inhibitor, and one anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody-based treatments.

4. Documented measurable disease based on the IMWG guidelines within the 4 weeks prior to registration defined by any one of the following criteria:

   1. Serum monoclonal protein ≥ 0.5 g/dl
   2. Urine monoclonal protein >200 mg/24 hour
   3. Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio
   4. Bone marrow plasma cells ≥ 30%
   5. A measurable lesion on PET/CT or MRI ≥ 2 cm

5. Be ≥ 18 years of age on day of signing informed consent

6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of ≤ 3 (Appendix A)

7. Adequate organ function as evidenced by the following laboratory parameters within 4 weeks of C1D1:

   Hematologic:

   1. Absolute neutrophil count (ANC) 1000/microliter (mcL) (granulocyte-colony stimulating factor (G-CSF) allowed)

   2. Platelets ≥ 50,000/mcL (transfusions and stimulators permitted); in patients with >50% bone marrow plasma cells, platelets ≥ 30,000/mcL

   3. Hemoglobin ≥ 8 g/dL (transfusions permitted)

      Non-hematologic:

   4. Serum creatinine ≤ 1.5 X ULN (except if due to myeloma) or calculated creatinine clearance (CrCl)/Estimated glomerular filtration rate (eGFR) (by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), or Cockcroft-Gault) ≥ 15 mL/min/1.73 m2

   5. Serum total bilirubin ≤ 1.5 X ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 X ULN)

   6. Aspartate transaminase (SGOT) and alanine transaminase (SGPT) ≤ 2.5 X ULN

8. Female patients of childbearing potential must have a negative serum pregnancy test at Screening. Female patients of childbearing potential and fertile male patients who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 90 days following the last dose of study treatment.

9. Willing and able to provide written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.

Exclusion Criteria:

1. Has received selinexor or another specific inhibitor of nuclear exporter (SINE) compound previously.
2. Has any concurrent medical condition or disease (eg, uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.
3. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
4. Known intolerance, hypersensitivity, or contraindication to glucocorticoids.
5. Pregnant or breastfeeding females.
6. Active, unstable cardiovascular function, as indicated by the presence of symptomatic ischemia, or Uncontrolled clinically significant conduction abnormalities (eg, patients with ventricular tachycardia on anti-arrhythmics are excluded; patients with first degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block will not be excluded), or Congestive heart failure of New York Heart Association Class ≥3 or known left ventricular ejection fraction <40%, or Myocardial infarction within 3 months prior to C1D1.
7. Subjects with active hepatitis B virus (Hep B) are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 IU/ml prior to first dose of trial treatment. Subjects with untreated hepatitis C virus (HCV) are allowed. Subjects with Human Immunodeficiency Virus (HIV) who have cluster of differentiation 4-positive (CD4+) T-cell counts ≥ 350 cells/µL and no history of AIDS-defining opportunistic infections in the last year are allowed.
8. 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.
9. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (CPGO) (https://www.nccn.org/guidelines/category\_3) for antiemesis and anorexia/cachexia (palliative care).
10. 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.
11. Contraindication to any of the required concomitant drugs or supportive treatments.
12. Patients unwilling or unable to comply with the protocol or known mental or physical illness that would interfere with cooperation with the requirements of the trial or confound the results or interpretation of the results of the trial and, in the opinion of the treating investigator, would make the patient inappropriate for entry into the study.