The purpose of Phase 1b of the study is to determine the maximum tolerated dose (MTD) of oprozomib in combination with melphalan and prednisone (OMP).

The purpose of Phase 2 of the study is to estimate the overall response rate (ORR) and complete response rate (CRR) of the OMP combination.

Key Inclusion Criteria:

1. Newly diagnosed symptomatic multiple myeloma patients who are transplant ineligible with measureable disease as indicated by one or more of the following:

   1. Serum M-protein ≥ 500 mg/dL
   2. Urine M-protein ≥ 200 mg/24 hour
   3. Serum Free Light Chain: Involved free light chain (FLC) level ≥ 10 mg/dL, provided serum FLC ratio is abnormal

2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

3. Creatinine clearance (CrCl) ≥ 30 mL/min, either measured or calculated using the formula of Cockcroft and Gault [(140 - age) × mass (kg) / (72 × serum creatinine mg/dL)]. Multiply result by 0.85 if female.

Key Exclusion Criteria:

1. Any prior systemic antimyeloma therapy except oral steroids (dexamethasone up to a total dose of 160 mg or equivalent within 14 days prior to the first dose of study treatment is allowed). Use of topical or inhaled steroids is acceptable.
2. Congestive heart failure (New York Hearth Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to first dose
3. Known or suspected HIV, active Hepatitis A, B C or virus infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests [bilirubin, AST] will be allowed).
4. Significant neuropathy (Grade 2 with pain or higher) at the time of first dose.
5. Plasma cell leukemia.
6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
7. Known amyloidosis