Study of High Dose Carfilzomib in Multiple Myeloma Patients Who Have Progressed On Standard Dose Carfilzomib

Inclusion Criteria: Disease-related: 1. Multiple myeloma 2. Subjects must have measurable disease, defined as one or both of the following: 1. Serum M-protein ≥ 1.0 g/dL 2. Urine M-protein ≥ 200 mg/24 hours 3. Free light chains: Only in patients without measureable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels must be at least 10 mg/dl. 3. Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. 4. Subjects must have progressed on standard dose 20/27 mg/m2 and schedule of carfilzomib without having had any carfilzomib related grade 3 or 4 toxicities. 5. Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen 6. Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide 7. Subjects must have received an alkylating agent unless contraindicated. Subjects may have received these agents alone or in combination with other myeloma treatments. Demographic: 1. Age ≥ 18 years 2. Life expectancy ≥ 3 months 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Laboratory/Radiology 1. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization 2. Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing 3. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization independent of G-CSF for ≥ 1 week and pegylated G-CSF for ≥ 2 weeks 4. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to randomization (subjects may be receiving red blood cell \[RBC\] transfusions in accordance with institutional guidelines) 5. Screening platelet count ≥ 50 × 109/L independent of platelet transfusions for at least 2 weeks 6. Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization, either measured or calculated using a standard formula (eg, Cockcroft and Gault) 7. LVEF ≥ 40% within 30 days before Cycle 1 Day 1. 2-D Transthoracic Echocardiogram (ECHO) is the preferred method of evaluation; MUGA is acceptable if ECHO is not available. Exclusion Criteria: Disease-related 1. Glucocorticoid therapy (prednisone \> 10 mg/day or equivalent) within the last three weeks 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 3. Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose (unless enrolling on this study after progression CMAP compassionate use carfilzomib protocol, in which case subject may proceed with current study treatment on next expected date of treatment) 4. Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose 5. Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater (unless enrolling after progression on CMAP compassionate use carfilzomib protocol) Concurrent Conditions 1. Pregnant or lactating females 2. Major surgery within 21 days prior to randomization 3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization 4. Known human immunodeficiency virus infection 5. Known active hepatitis B or C infection 6. Unstable angina or myocardial infarction within 4 months prior to randomization, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker 7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization 8. Nonhematologic malignancy within the past 3 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 9. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization 10. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 11. Contraindication to any of the required concomitant drugs or supportive treatments, including antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment 12. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization 13. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent