Combination Study of Pomalidomide, Marizomib, and Low-Dose Dexamethasone in Relapsed and Refractory Multiple Myeloma

Inclusion Criteria Subjects must meet the following criteria to be eligible for study participation: 1. At least 18 years at the time of signing the informed consent form. 2. Able to understand and voluntarily sign an informed consent form prior to any study-related assessments/procedures. 3. Able to adhere to the study visit schedule and other protocol requirements. 4. Documented diagnosis of multiple myeloma and measurable disease by serum or urine protein electrophoresis (SPEP or UPEP): SPEP ≥0.5 g/dL, UPEP ≥200 mg/24 hours, or involved serum free light chain (FLC) level ≥10 mg/dL provided the serum FLC ratio is abnormal. 5. Previously received 1 or more lines of anti-myeloma therapy that must have included both lenalidomide and bortezomib (either separately or in combination). 6. Documented disease progression during or within 60 days after their most recent line of anti myeloma therapy. 7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2. 8. All study participants in the USA must be registered into the mandatory POMALYST REMS™ (Risk Evaluation \& Mitigation Strategy) program, and be willing and able to comply with the requirements of the POMALYST REMS™ program. 9. All study participants in the USA who are females of child-bearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the POMALYST REMS™ program. 10. All study participants outside the USA must agree to comply with the POMALYST® PPRMP requirements. 11. All subjects must be able and agree to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin). 12. For females of child bearing potential (FCBP): Agree to use 2 reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact for at least 28 days before starting study treatment, while participating in the study (including dose interruptions), and for at least 28 days after study treatment discontinuation; must follow pregnancy testing requirements as outlined in the POMALYST REMS™ program or the PPRMP. 13. For all females: Agree to abstain from breastfeeding during study participation and for at least 28 days after study treatment discontinuation. 14. For all males: Agree to use a latex or synthetic condom during any sexual contact with FCBP while participating in the study and for at least 28 days following discontinuation from study treatment, even if he has undergone a successful vasectomy. 15. For all males: Agree to refrain from donating semen or sperm while on study and for at least 28 days after discontinuation from study treatment. 16. Refrain from donating blood while on study treatment and for at least 28 days after discontinuation from study treatment. 17. Agree not to share medication. Exclusion Criteria Subjects with any of the following will be excluded from participation in the study: 1. Peripheral neuropathy Grade ≥2. 2. Non-secretory multiple myeloma. 3. Any of the following laboratory abnormalities: * ANC \<1,000/µL; * Platelet count \<50,000/µL for subjects in whom \<50% of bone marrow nucleated cells are plasma cells; or a platelet count \<30,000/µL for subjects in whom ≥50% of bone marrow nucleated cells are plasma cells; * Creatinine clearance (CrCL) \<45 mL/min as measured directly or as calculated according to Cockcroft Gault formula; * Corrected serum calcium \>13.5 mg/dL (\>3.4 mmol/L); * Hemoglobin \<8 g/dL (\<4.9 mmol/L; prior red blood cell \[RBC\] transfusion or recombinant human erythropoietin use is permitted before study entry); * Serum aspartate aminotransferase (AST) \>3.0 x upper limit of normal (ULN); * Serum alanine aminotransferase (ALT) \>3.0 x ULN; * Serum total bilirubin \>1.5 x ULN (\>3.0 x ULN for subjects with known Gilbert's disease). 4. Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥5 years. Subjects may be entered earlier than 5 years if they have received curative treatment for the following: * Basal cell carcinoma of the skin; * Squamous cell carcinoma of the skin; * Carcinoma in situ of the cervix; * Carcinoma in situ of the breast; Or if they have: o Incidental histologic finding of prostate cancer (T1a or T1b using the TNM \[tumor, nodes, metastasis\] clinical staging system) or non metastatic prostate cancer that is in complete remission or does not require treatment. 5. Previous therapy with POM and/or MRZ. 6. History of allergic reaction or hypersensitivity to thalidomide, lenalidomide, bortezomib, carfilzomib, boron, mannitol, or DEX. 7. Grade ≥3 rash during prior thalidomide or lenalidomide therapy. 8. Gastrointestinal disease that may significantly alter the absorption of POM. 9. History of the following: * Congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; * Myocardial infarction within 12 months prior to starting study treatment; * Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris. 10. Any of the following within 14 days prior to initiation of study treatment: * Plasmapheresis; * Major surgery (kyphoplasty is not considered major surgery); * Radiation therapy; * Anti-myeloma drug therapy. 11. Received any investigational agents within 28 days or 5 half-lives (whichever is longer) prior to initiation of study treatment. 12. Conditions requiring chronic steroid or immunosuppressive treatment (eg, rheumatoid arthritis, multiple sclerosis, or lupus), which likely need additional steroid or immunosuppressive treatments in addition to the study treatment. 13. Subjects may not receive corticosteroids (\>10 mg/day of prednisone or equivalent) within 3 weeks prior to enrollment (use of steroidal inhalation aerosol for asthma is permitted). 14. Unable or unwilling to undergo antithrombotic prophylactic treatment. 15. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, as determined by the Investigator. 16. Pregnant and/or breastfeeding females. 17. Known seropositive for or active viral infection with human immunodeficiency virus (HIV). 18. Known seropositive for or active viral infection with hepatitis B virus (HBV), with the following exceptions: * negative are eligible. * Subjects who had hepatitis B but have received an antiviral treatment and show non-detectable viral DNA for 6 months are eligible. * Subjects who are seropositive because of hepatitis B virus vaccine are eligible. 19. Known seropositive for or active viral infection with hepatitis C virus (HCV), with the following exception: Subjects who had hepatitis C but have received an antiviral treatment and show no detectable viral ribonucleic acid (RNA) for 6 months are eligible.