A Phase II Study of Carfilzomib in Relapsed Waldenström's Macroglobulinemia (WM) IST-CAR-531

Inclusion Criteria: * Biopsy proven WM with relapsed/refractory symptomatic disease are eligible for enrollment. * Bone marrow lymphoplasmacytosis with: * \> 10% lymphoplasmacytic cells (measured within 28 days prior to registration OR * Aggregates or sheets of one of the following: lymphocytes, plasma cells or lymphoplasmacytic cells on the bone marrow biopsy (measured within 28 days prior to registration). * Measurable disease defined as a quantitative IgM monoclonal protein of \>500 mg/dL obtained within 28 days prior to registration * CD20+ bone marrow or lymph node by immunohistochemistry or flow cytometry obtained within 28 days prior to registration * Lymph node biopsy must be done \<28 days prior to registration if used as an eligibility criterion for study entry. * Symptomatic disease, as defined by the IWWM, includes the following criteria: Hemoglobin less than 10 g/dL, platelet count less than 100,000 uL, bulky adenopathy or organomegaly, symptomatic hyperviscosity syndrome, severe neuropathy, amyloidosis, cryoglobulinemia, cold agglutinin disease, or evidence of transformation high-grade non-Hodgkin's lymphoma. * Patients must not be receiving concurrent steroids \> 10 mg prednisone (or equivalent) per day. * Prior irradiation is allowed if \> 28 days prior to registration have elapsed since the date of last treatment. * Women must not be pregnant or breast-feeding due to the fact that the reproductive risk to humans taking carfilzomib is unknown. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). * Women of childbearing potential and sexually active males must use an accepted and effective method of contraception throughout the study and for 8 weeks after completion of the study. * Patients must be \> 18 years old. * Patients must have ECOG performance status of \< 2. * Patients may have received prior bortezomib therapy. * Adequate hepatic function, with serum ALT ≤ 3times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to randomization * Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to randomization * 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) * Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if WM involvement in the bone marrow is \> 50%) within 14 days prior to randomization * Creatinine clearance (CrCl) ≥ 15 mL/minute within 7 days prior to randomization, either measured or calculated using a standard formula (e.g., Cockcroft and Gault) Exclusion Criteria: * Pre-existing peripheral neuropathy \> grade 2 with pain (CTC version 4.0). * Hematologic criteria: ANC \< 500/uL, Platelets \< 25,000 uL. * Renal function: CrCl \< 15 ml/min. * Active infection requiring intravenous antibiotics * Known Active hepatitis B or C * SGOT (AST) and SGPT (ALT) \> 3x institutional ULN * Direct bilirubin \> 1.5 mg/dL * Patients must not have any severe and/or uncontrolled medical condition or other conditions that could affect their participation in the study, including, but not restricted to: * Symptomatic congestive heart failure of New York Heart Association Class III or IV. * Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 3 months of start of study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant heart disease. * Severely impaired lung function as defined as spirometry and DLCO (corrected for Hgb) that is \<50% of the normal predicted value and/or O2 saturation \<88% at rest on room air. * Active (acute or chronic) or uncontrolled severe infections.