A Safety and Efficacy Study of Carfilzomib and Pomalidomide With Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Inclusion Criteria:

• Cytopathologically or histologically confirmed diagnosis of multiple myeloma
• Relapsed or refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion.
• All patients must have received prior lenalidomide therapy and been determined to be refractory. Refractory will be defined as ≤ 25% response or progression during therapy or within 60 days after completion of a regimen containing full or maximally tolerated dose of lenalidomide administered for at least two completed cycles of therapy.
• Measurable disease, as indicated by one or more of the following:

Serum M-protein ≥ 0.5 g/dL Urine Bence Jones protein ≥ 200 mg/24 hr Elevated Free Light Chain as per IMWG criteria, and abnormal ratio

• Males and females ≥ 18 years of age
• Life expectancy of more than 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN
• Uric acid must be within laboratory normal range
• Creatinine Clearance ≥ 50 mL/min
• Additional Laboratory Requirements Absolute neutrophil count (ANC) ≥1.0 x 109/L Hemoglobin ≥8 g/dL(transfusion permitted) Platelet count ≥50.0 x 109/L
• Screening ANC should be independent of granulocyte-and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks
• Patients may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, in accordance with institutional guidelines
• Screening platelet count should be independent of platelet transfusions for at least 2 weeks.
• Written informed consent in accordance with federal, local, and institutional guidelines
• Females of childbearing potential (FCBP)must agree to ongoing pregnancy testing
• FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, beginning 2 weeks prior to initiating treatment with pomalidomide, during treatment, during treatment delay, and continuing for 4 weeks following discontinuation of pomalidomide therapy. If a hormonal method or IUD is not medically possible for the patient, the patient may use another highly effective method or two barrier methods at the same time.
• Male patients must agree to never have unprotected sexual contact with a female who can become pregnant and must agree to either completely abstain from sexual contact with females who are pregnant or are able to become pregnant, or he must use a latex condom every time he engages in sexual contact with females who are pregnant or may become pregnant while he is taking pomalidomide and for 4 weeks after he stops taking the drug, even if he has had a successful vasectomy. The patient must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks for any reason that his sexual partner may be pregnant.
• Male patients cannot donate semen or sperm while taking pomalidomide and for 28 days after completing the study.
• All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
• Patients must agree to take enteric-coated aspirin 81 mg orally daily, or if history of prior thrombotic disease, must be fully anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism (PE)at the investigator's discretion

Exclusion Criteria:

• Patients with known sensitivity to any immunomodulatory drugs (IMiDs)
• • Use of any other experimental drug or therapy within 21 days prior to first dose
• Exposure to any prior chemotherapy, steroid use, or other myeloma treatment within 14 days prior to first dose. Patients currently on long term steroids do not require any washout period. in addition, steroid use for spinal cord compression is permitted and does not require a washout period.
• Radiation therapy within 14 days prior to first dose
• Known allergies to carfilzomib or Captisol
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
• Plasma cell leukemia
• Waldenström's macroglobulinemia
• Major surgery within 21 days prior to first dose
• Pregnant or lactating females
• Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six months prior to first dose.
• Uncontrolled hypertension
• Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 14 days prior to first dose
• Patients receiving active treatment or intervention for any other malignancy or patients who, at the Investigator's discretion, may require active treatment or intervention for any other malignancy within 8 months of starting study treatment.
• Serious psychiatric or medical conditions that could interfere with treatment
• Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment
• Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (e.g. lansoprazole), enteric-coated aspirin or if a history of prior thrombotic disease, warfarin or low molecular weight heparin
• Patients in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g. due to pre-existing pulmonary, cardiac, or renal impairment
• Patients with primary systemic amyloidosis
• Patients who have received prior treatment with carfilzomib (Phase II only)
• Patients who have received prior treatment with pomalidomide (Phase II only)