Thalidomide, Lenalidomide, and Rituximab for Previously Treated Waldenstrom Macroglobulinemia

Inclusion Criteria: * Histologically confirmed diagnosis of WM * At least one prior systemic therapy * Measurable disease, defined as quantifiable monoclonal IgM \> 1000 mg/dL * Active disease requiring therapy defined as at least one of the following five criteria: 1. Rising IgM 2. Hemoglobin \< 20 g/dL 3. Platelet count \< 100 x 109/L 4. Symptomatic or bulky lymphadenopathy or organomegaly 5. Systemic manifestations of WM, including hyperviscosity, neuropathy, amyloidosis, cryoglobulinemia, B symptoms. * note: subjects with symptomatic hyperviscosity or a serum viscosity of \> 3.5 CP are eligible but should undergo plasmapheresis prior to initiation of treatment * Understand and voluntarily sign an informed consent form * Age \>18 years at the time of signing the informed consent form * Able to adhere to the study visit schedule and other protocol requirements * ECOG performance status ≤ at study entry * Laboratory test results within these ranges: 1. Absolute neutrophil count ≥ 1000/mm³ 2. Platelet count ≥ 50,000/mm³ 3. Creatinine clearance of ≥ 30 mL/min by Cockroft-Gault formula. 4. Total bilirubin ≤ 1.5 times the ULN, unless abnormality is the result of Gilbert's disease or the result of the WM 5. AST (SGOT) and ALT (SGPT) ≤ 3 x ULN * Disease free of prior malignancies for ≥ 2 years with exception of curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. * All study participants must be registered into the mandatory RevAssist ® (RASP: RevAssist ® for Study Participants) and S.T.E.P.S. ® (P-TAP: Protocol Therapy Assistant Program) programs and be willing and able to comply with the requirements of RevAssist ® and S.T.E.P.S. ®. * Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting treatment and again within 24 hours before the first dose of lenalidomide AND thalidomide. FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide and/or thalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See Appendix A: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods. * Able to take aspirin 81 or 325 mg daily or low molecular weight heparin as prophylactic anticoagulation, unless already on therapeutic anticoagulation. Subjects intolerant to ASA may use warfarin or low molecular weight heparin. Exclusion Criteria: * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent. * Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. * Concurrent use of other anti-cancer agents or treatments * Prior treatment with thalidomide or lenalidomide * Active serious infection not controlled with antibiotics * Autoimmune hemolytic anemia or thrombocytopenia requiring treatment * Known positive for HIV * Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B DNA by PCR, or hepatitis C * Pre-existing peripheral neuropathy \> grade 2 * Pregnant or breast-feeding females. (Lactating females must agree not to breast feed while taking lenalidomide and/or thalidomide). * Disease transformation to an aggressive histology * Treatment for WM within the past 28 days * Hypersensitivity to rituximab