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.