The following criteria is provided for health care professionals.

Key Inclusion Criteria:

1. Male or female patients 18 years or older
2. Patients must have a diagnosis of MM, based on standard criteria2 as follows:
   1. Major criteria:
      • monoclonal immunoglobulin spike on serum electrophoresis IgG greater than 3.5 g/dL or IgA greater than 2.0 g/dL; kappa or lambda light chain excretion greater than 1 g/day on 24 hour urine protein electrophoresis
      • bone marrow plasmacytosis (greater than 30% plasma cells)
      • plasmacytomas on tissue biopsy
   2. Minor criteria:
      1. bone marrow plasmacytosis (10% to 30% plasma cells)
      2. monoclonal immunoglobulin present but of lesser magnitude than given under major criteria
      3. lytic bone lesions
      4. normal IgM less than 50 mg/dL, IgA less than 100 mg/dL, or IgG less than 600 mg/dL
   3. Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:
      1. any 2 of the major criteria
      2. major criterion 1 plus minor criterion 2, 3, or 4
      3. major criterion 3 plus minor criterion 1 or 3
      4. minor criteria 1, 2, and 3, or 1, 2, and 4 3. Currently has progressive MM that has previously progressed or is currently progressing while receiving or within 8 weeks of receiving bortezomib or carfilzomib as part of a combination treatment. MM patients that demonstrate refractory disease, as defined below, are both eligible for enrollment provided they fulfill the other eligibility criteria:
3. Patients are refractory to a bortezomib or carfilzomib combination regimen, when they progress while currently receiving a bortezomib or carfilzomib combination treatment, or within 8 weeks of its last dose. Prior treatment with four days or less of a total of 400 mg of prednisone (or an equivalent potency of another steroid) for MM will not be considered a regimen 4. Patients that were on bortezomib-containing regimens must have been administered at least 4 doses of a minimum of 1.0 mg/m2 in no more than 28-days cycles. Subjects must have received at least one cycle meeting this definition and have shown PD to be considered eligible 5. Patients that were on carfilzomib-containing regimens must have received at least 6 doses of at least 27 mg/m2 in no more than 28 days per cycle. Subjects must have received at least one cycle meeting this definition and have shown PD to be considered eligible 6. Progressed from one of the specific bortezomib- or carfilzomib-containing regimens as listed on page 44. Although bortezomib- and carfilzomib-containing combination regimens that are otherwise identical except for the PI result in the same ixazomib regimen, they will be enrolled separately so that safety/efficacy can be separately determined, thereby allowing comparisons based on the prior PI that subjects were exposed to as part of the regimen that they failed (carfilzomib vs. bortezomib) 7. Patient may have received a carfilzomib- or bortezomib-containing regimen at any time and may have received other non-proteasome inhibitor-containing intervening treatments

Key Exclusion Criteria:

1. Patient has been diagnosed with:
   1. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M protein) and skin changes (POEMS) syndrome.3
   2. Primary amyloidosis
   3. Plasma cell leukemia
   4. Severe hypercalcemia, i.e., serum calcium = 12 mg/dL (3.0 mmol/L) corrected for albumin
2. Non-hematologic malignancy within the past 5 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
3. Impaired cardiac function or clinically significant cardiac diseases, including myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, clinically significant pericardial disease, severe uncontrolled ventricular arrhythmias, echocardiogram or multigated acquisition scan (MUGA) evidence of left ventricular ejection fraction (LVEF) below institutional normal within 28 days prior to enrollment, electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant
4. Patient has peripheral neuropathy grade 3 or higher or Grade 2 with pain on clinical examination during the screening period
5. Patient has received the following prior therapy:
   1. Chemotherapy within 21 days of enrollment (6 weeks for nitrosoureas)
   2. Corticosteroids (>10 mg/day prednisone or equivalent) within 21 days of enrollment
   3. Immunotherapy or antibody therapy as well as thalidomide, pomalidomide, lenalidomide, arsenic trioxide, carfilzomib, or bortezomib within 21 days before enrollment
6. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent 6. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing