Carfilzomib in Combination with Bendamustine Hydrochloride and Dexamethasone in Treating Patients with Newly Diagnosed Multiple Myeloma

Inclusion Criteria

• Patients must have histologically or cytologically confirmed symptomatic multiple myeloma (MM), Salmon-Durie stage II or III, or International Staging System II or III or fulfill the calcium, renal failure, anemia, and bone lesions (CRAB) criteria; patients should not have previously been treated; finally, patients must meet at least one of the following parameters of measurable disease: * Bone marrow plasmacytosis with > 10% plasma cells, or sheets of plasma cells, or biopsy proven plasmacytoma which must be obtained within 6 weeks prior to registration * Measurable levels of M-protein: >= 1 g/dL on serum protein electrophoresis (SPEP) or >= 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis (UPEP) or involved free light chain (FLC) >= 10 mg/dL (>= 100 mg/L) which must be obtained within 4 weeks prior to registration Serum and urine M-protein levels should be determined by electrophoresis rather than by quantitative immunoglobulin (Ig) measurement; exceptions are made in cases in which the M-spike value may be deemed to be unreliable (e.g. co-migrating M-spike); in these cases, quantitative Ig should be used; to assess response and progression, however, SPEP values should only be compared to SPEP values and quantitative Ig values only to quantitative Ig values
• Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture) are permitted
• Patients are allowed up to two cycles of high dose steroids (maximum total dose of 320 mg dexamethasone or equivalent) if needed for symptomatic disease before study enrollment
• Life expectancy >= 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0–2
• Serum alanine aminotransferase (ALT) =< 3.5 times the upper limit of normal
• Serum direct bilirubin =< 2 mg/dL (34 umol/L)
• Absolute neutrophil count (ANC) >= 1.0 × 10^9/L
• Hemoglobin >= 8 g/dL (80 g/L) (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
• Platelet count >= 75 × 10^9/L (>= 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%)
• Creatinine clearance (CrCl) >= 30 mL/minute, either measured or calculated using a standard formula (e.g., Cockcroft and Gault)
• Left ventricular ejection fraction (LVEF) >= 40%; 2-dimension (D) transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multi gated acquisition scan (MUGA) is acceptable if ECHO is not available
• Written informed consent in accordance with federal, local, and institutional guidelines
• Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception
• Male subjects must agree to practice contraception

Exclusion Criteria

• Patients who have had chemotherapy for MM; exception: local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture)
• Patients currently receiving high dose systemic steroids for treatment of MM in excess of 320mg total dose of dexamethasone or equivalent, patients who received an investigational agent within 5 half-lives of the agent
• Patients with non-measurable MM or primary plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
• Pregnant or lactating females
• Major surgery within 21 days prior to enrollment
• Acute active infection requiring treatment should be under control
• Known human immunodeficiency virus (HIV) infection
• Known active hepatitis B or C infection
• Unstable angina or myocardial infarction within 4 months prior to enrollment, New York Heart Association (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
• Uncontrolled hypertension or uncontrolled diabetes
• Uncontrolled, non-hematologic malignancy requiring active treatment
• Patients with known brain metastases (treated or not) will be excluded
• Significant neuropathy (grades 3–4, or grade 2 with pain)
• Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize CFZ), or similar chemical or biologic composition to bendamustine or other agents used in the study
• Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
• Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment
• 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