A Phase 1b Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of Oprozomib in Combination With Pomalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

• Subject has provided informed consent prior to initiation of any study-specific activities/procedures
• Age >= 18 years old at the time of signing the informed consent
• Subject must have a pathologically documented, definitively diagnosed, multiple myeloma relapse, or refractory progressive disease after at least 2 lines of therapy for multiple myeloma. Prior therapeutic treatment or regimens must include a proteasome inhibitor and lenalidomide
• Subject must be willing and able to undergo bone marrow aspirate per protocol

• Measurable disease (assessed within 28 days prior to day 1), as indicated by one or more of the following:
Serum M-protein >= 0.5 g/dL
Urine M-protein >= 200 mg/24 hours
In subjects without detectable serum or urine M-protein: serum Free Light
Chain (sFLC) >= 10 mg/dL (>= 100 mg/L) and an abnormal sFLC ratio
• Eastern Cooperative Oncology Group (ECOG) performance status of <= 2
• Hematological function, as follows, without transfusion support:
Absolute neutrophil count >= 1.0 X 109/L
Platelet count >= 75 X 109/L (in patients with < 50% of bone marrow nucleated cells were plasma cells) or >= 50 X 109/L (in patients with >= 50% of bone
marrow nucleated cells were plasma cells) without transfusion or growth factor support
Hemoglobin > 8 g/dL (> 80 g/L) Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion must be
7 days prior to obtaining screening hemoglobin

• Coagulation function as follows: PT/INR and PTT < 1.5 x Institutional Upper Limit of Normal (ULN)
• Renal function as follows: estimated glomerular filtration rate based on Modification of Diet in Renal Disease calculation (MDRD) > 30 mL/min/1.73 m2
• Hepatic function, as follows: AST and ALT < 3 x ULN, Total bilirubin < 1.5 x ULN (except subjects with Gilbert*s syndrome)

• Currently receiving treatment in another investigational device or drug study, or less than 28 days or 5 half-lives, whichever is shorter, since ending treatment on another investigational device ordrug study(s)
• Previously received an allogeneic stem cell transplant and the occurrence of one or more of the following:
received the transplant within 6 months prior to study day 1
received immunosuppressive therapy within the last 3 months prior to study day 1
having signs or symptoms of acute or chronic graft-versus-host disease
• Autologous stem cell transplant < 90 days prior to study day 1
• Multiple myeloma with IgM subtype
• POEM syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia (> 2.0 X109/L circulating plasma cells by standard differential)
• Waldenstrom*s macroglobulinemia
• Amyloidosis
• Requirement for plasmapheresis during the screening period
• Dexamethasone at cumulative doses of greater than 160 mg or equivalent within 21 days prior to study day 1 is not allowed. Use of topical or inhaled steroids is Acceptable
• History of other malignancy, except:
Malignancy treated with curative intent and with no known active disease present for >= 1 year before study day 1 and felt to be at low risk for recurrence by the treating physician
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated cervical carcinoma in situ without evidence of disease
Adequately treated breast ductal carcinoma in situ without evidence of disease
Prostatic intraepithelial neoplasia without evidence of prostate cancer
Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ

• Evidence of a bleeding diathesis
• Current use of therapeutic doses of anticoagulation unless agreed upon by the investigator and the Amgen Medical Monitor. Please note: thromboprophylaxis is recommended with pomalidomide treatment
• Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II).
• Infection requiring anti-infective treatments (oral or intravenous) within 2 weeks of study day 1.
• Hepatitis B and C based on the following results:
Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B)
Negative HBsAg and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B
Positive Hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C
• History of clinically significant GI hemorrhage (Grade >= 2) in the 6 months prior to study day 1, unless agreed upon by the investigator and the Amgen Medical Monitor
• Known positive results for Human Immunodeficiency Virus (HIV)
• Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 1, or to levels dictated in the eligibility criteria with the exception of Grade 2 peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for > 4 weeks may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the investigator and the Amgen Medical Monitor)

• Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 28 days or 5 half-lives, whichever is shorter, prior to study day 1.
• Prior systemic radiation therapy must have been completed at least 28 days before study day 1. Prior focal radiotherapy completed at least 14 days before study day 1
• Major surgery within 28 days prior to study day 1
• females of reproductive potential who are unwilling to use two methods of contraception, one highly effective and one additional effective contraception method while on study through 30 days after receiving the last dose of study drug.(female) Males unwilling to always use latex or synthetic condom during any sexual contact with females of reproductive potential while on study through 90 days after receiving the last dose of study drug. Males must also refrain from donating sperm for at least 90 days after the last dose of oprozomib
• Female who is breastfeeding or who plans to breastfeed while on study through 30 days after receiving the last dose of study drug
• Female with a positive pregnancy test
• Female planning to become pregnant while on study through 30 days after receiving the last dose of study drug
• Known hypersensitivity to any immunomodulatory drugs (IMiDs) or its formulation
excipients, including rash
• Known hypersensitivity or intolerance to dexamethasone or its formulation
excipients
• Prior exposure to oprozomib
• History or evidence of any other clinically significant disorder, condition or disease that, in the opinion of the investigator or Amgen medical monitor, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
• Prior use of pomalidomide if subjects required pomalidomide dose reduction or pomalidomide discontinuation due to toxicity
Subjects known to have any of the following disorders will be excluded unless
agreed upon by the investigator and the Amgen Medical Monitor:
• Galactosemia (deficiency in galctose-1-phosphate-uridylytransferase or
UDP-galactose-4-epimerase or galactokinase; Fanconi-Bickel-Syndrome)
• Hereditary lactase deficiency
• Glucose-galactose malabsorption