A Study of Oprozomib, Pomalidomide, and Dexamethasone in Subjects With Primary Refractory or Relapsed and Refractory Multiple Myeloma

1. Multiple myeloma that is primary refractory or relapsed and refractory after at least 2 lines of standard for multiple myeloma including: a. > 2 consecutive cycles of both bortezomib and lenalidomide or thalidomide (alone or in combination) i. Patients who received bortezomib as their last therapy who were not refractory but developed bortezomib intolerance, as defined by the development of Grade 2 peripheral neuropathy with pain or > Grade 3 peripheral neuropathy after ≥ 2 consecutive cycles, are eligible b. Adequate alkylator therapy defined as: i. High-dose melphalan or other alkylating agent as conditioning for autologous or allogeneic stem cell transplant (SCT), or ii. ≥ 6 cycles of induction therapy, or iii. PD after ≥ 2 cycles 2. Disease progression on or within 60 days of completion of the last therapy 3. Measurable disease as indicated by 1 or more of the following: a. Serum M-protein ≥ 500 mg/dL b. Urine M-protein ≥ 200 mg/24 h c. For patients without measurable serum or urine M protein, serum free light chain (SFLC): Involved free light chain (FLC) concentration ≥ 10 mg/dL provided SFLC ratio is abnormal 4. Males and females ≥ 18 years old 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

1. Systemic chemotherapy with approved or investigational anticancer therapeutics, including steroid therapy intended to treat underlying malignancy, within 3 weeks before the first dose or 6 weeks for antibody therapy 2. Dexamethasone at cumulative doses greater than 160 mg or equivalent within 14 days prior to the first dose of study treatment is not allowed. Use of topical or inhaled steroids is acceptable. 3. Radiation therapy within 3 weeks before first dose. Radioimmunotherapy within 8 weeks before first dose. 4. Autologous SCT within 8 weeks and allogeneic SCT within 16 weeks prior to initiation of study treatment. Patients with prior allogeneic SCT should not have evidence of moderate-to-severe graft-versus-host disease (as defined in Filipovich 2005). 5. Known hypersensitivity to any immunomodulatory drugs (IMiDs), including Grade 4 rash 6. Prior treatment of any duration with pomalidomide 7. Known hypersensitivity or intolerance to dexamethasone 8. Prior exposure to oprozomib 9. Congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months before first dose