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

Waldenström's macroglobulinemia (WM) is a rare low-grade B-cell lymphoplasmacytic lymphoma.
Overall reported incidences approximately 3 cases per million persons per year with about
1500 and cases diagnosed annually in United States. There is a higher incidence in males
compared to females (3.4 vs 1.7 cases per 1 million person-years at risk) and WM is nearly
twice as common among whites compared to blacks.[1] A familial form of the disease is also
recognized. WM is an indolent disease with an overall median survival of 5 years although
more recent data suggest a disease-specific median survival of 11.2 years, given the
frequently older age (median 63 years) and accompanying co-morbidities at diagnosis(1). WM
is characterized by infiltration of lymphoplasmacytic cells and bone marrow and by serum
immunoglobulin M (IgM) monoclonal gammopathy. B-cell origin and some clinical cellular and
epidemiological features are shared among WM arises from intermediately mature B cells
(somatically mutated post germinal center the lymphocytes that have not yet undergone
isotype switching), as opposed to immature B cells from which chronic lymphocytic leukemia
arises in the fully mature, somatically mutated, from which cells multiple myeloma arises.

There is no standard of care for WM (2). Therefore, involving the patient's in clinical
trials is strongly recommended whenever possible.

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.