Marizomib Central Nervous System (CNS)

Inclusion Criteria:

* Previously diagnosed with MM based on standard IMWG criteria and currently requires treatment.
* Patients in the CNS-involved cohort must have CNS involvement of MM as defined by meningeal myelomatosis and/or radiological evidence of leptomeningeal disease and/or intracranial plasmacytoma involving brain parenchyma.
* Patients in the CNS-involved cohort must have received at least one or more previous lines of therapy including an IMiD and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
* Patients in the RRMM cohort must have received at least two or more previous therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy.
* Patients in the RRMM cohort must have measurable disease defined as at least one of the following:

  * Serum M protein ≥ 0.5 g/dL (≥5 g/L)
  * Urine M protein ≥200 mg/24 hours
  * Serum free light chain (FLC) assay: Involved FLC assay ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65)
* Screening Laboratory evaluations within the following parameters

  * Absolute neutrophil count (ANC) ≥ 1,000 cells/dL (1.0 x 109/L) (Growth factors cannot be used within 14 days before first drug administration)
  * Platelet count ≥ 75,000 cells/dL (75 x 109/L) (without transfusions required during the 14 days prior to initiation of therapy)
  * Hemoglobin ≥ 8.0 g/dl (RBC transfusions are permitted)
  * Total Bilirubin ≤ 1.5 X upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL)
  * AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN
  * Calculated creatinine clearance ≥ 45 mL/min
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* All study participants must be registered into the mandatory POMALYST REMS® program, and be willing and able to comply with the requirements of the POMALYST REMS® program.
* Females of reproductive potential must adhere to the scheduled testing as required in the POMALYST REMS® program.
* Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
* Patients have given voluntary written informed consent before performance of any study-related procedures not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Prior exposure to marizomib. and primary refractoriness to pomalidomide or a pomalidomide combination. Prior pomalidomide exposure is permitted but patients must have shown tolerance (defined as no grade 3 or greater non-hematologic toxicity), as well as responsiveness to pomalidomide-based therapy (defined as MR or better).
* Diagnosed or treated for another malignancy within 3 years prior to enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low risk prostate cancer after curative therapy/watchful waiting.
* Known GI disease or GI procedure that could interfere with the oral absorption of pomalidomide including difficulty swallowing.
* Systemic treatment, within 14 days before the first dose of pomalidomide, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
* Peripheral neuropathy ≥ Grade 3, or Grade 2 with pain on clinical examination during the screening period.
* Any medical or psychiatric illness that in the investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study.
* Current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, Grade 3 thromboembolic event or myocardial infarction within the past 6 months.
* The following therapies within the stated time frames prior to initiation of therapy: previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks; IMiDs, PIs, corticosteroids, other approved therapeutics and monoclonal antibodies (Mabs) within 2 weeks; and investigational therapies within 4 weeks. Please note consideration of the interval for investigational agents from already approved classes of drug in MM (e.g. Cell-Mods, Mabs) can be considered on a case by case basis with the PI. Prior peripheral stem cell transplant within 12 weeks and the use of live vaccines within 30 days.
* Prior allogeneic stem cell transplantation with active graft-versus-host-disease (grade 2 or greater).
* Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy).
* Daily requirement for corticosteroids equivalent to \> 10 mg/day prednisone, except for inhalation corticosteroids, for the RRMM cohort. For patients with CNS involvement who require a higher dose of corticosteroids for control of vasogenic edema (e.g. 16 mg/day dexamethasone), eligibility will be determined on a case-by-case basis after discussion with the PI.
* Any \> Grade 1 adverse reaction unresolved from previous treatments according to the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTC AE v.5.0). The presence of alopecia any grade or peripheral neuropathy ≤ Grade 2 without pain is allowed.
* Concurrent symptomatic amyloidosis or plasma cell leukemia.
* POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes).
* Known active infection requiring parenteral or oral anti-infective treatment within 7 days of start of therapy.
* Known human immunodeficiency virus or active hepatitis C viral infection.
* Active hepatitis B viral infection (defined as HBsAg+).

  * Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-).
  * Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation.
* Pregnant or breast-feeding females.
* Participants who are receiving any other investigational agents.
* History of erythema multiforme or severe hypersensitivity to prior IMiD's®.
* Inability to tolerate thromboprophylaxis.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Known hypersensitivity to thalidomide or lenalidomide or other drugs included in this study.

The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide, lenalidomide, pomalidomide or similar drugs.

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