This pilot clinical trial studies the side effects of lenalidomide and ipilimumab after stem cell transplant in treating patients with hematologic or lymphoid malignancies. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide with ipilimumab may be a better treatment for hematologic or lymphoid malignancies.

PRIMARY OBJECTIVES:

I. To assess the safety of lenalidomide in combination with ipilimumab in autologous and allogeneic stem cell transplantation.

SECONDARY OBJECTIVES:

I. Overall response rate. II. Overall survival, progression-free survival. III. Cumulative incidence of acute and chronic graft-versus-host disease (GVHD) with the competing risk of relapse in allogeneic transplant patients.

OUTLINE:

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 of courses 1, 3, 5 and 7. Beginning 1-3 days after the last dose of lenalidomide patients receive one dose of ipilimumab intravenously (IV) over 90 minutes of courses 2, 4, 6 and 8. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1, 3, 6, 12, 24, and 36 months.

Inclusion Criteria:

• Hematologic or lymphoid malignancy
• Autologous patients can be included anytime within 6 months post-transplant, if they had no signs of progression and meet one of the following criteria: i. leukemia; ii. lymphoma (all types of B and T cell lymphoma); iii. multiple myeloma
• Allogeneic patients if: i. patients had engrafted donor cells (i.e., > 20% donor T-cell from peripheral blood [PB]/polymerase chain reaction [PCR]); and, ii. patients NOT in complete remission (CR) after their allogeneic transplant, and off tacrolimus and/or mycophenolate mofetil for at least 3 to 4 weeks with no signs of GVHD; or, iii. patients had evidence of relapse after their transplant who are off tacrolimus and/or mycophenolate mofetil or other immunosuppressants for GVHD for 3 to 4 weeks with no signs of GVHD (prednisone doses =< 10 mg are permitted as stated previously)
• No active infection
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets > 75 x 10^9/L
• Able to adhere to the study visit schedule and other protocol requirements
• Performance status: Eastern Cooperative Oncology Group (ECOG) 2 or less or Karnofsky of at least 60
• Cardiac ejection fraction (EF) >= 45% by 2-dimensional echocardiogram (2D-ECHO) within 3 months of study entry (or within 1 month if received chemotherapy within the past 3 months)
• Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) >= 40% within 3 months of study entry (or within 1 month if received chemotherapy within the past 3 months)
• Serum creatinine =< 1.6 mg/dL and creatinine clearance >= 30 ml/min; creatinine clearance will be calculated using the Cockcroft-Gault equation
• Serum glutamate pyruvate transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT) less than 2 x the upper limit of normal range (unless related to Gilbert's disease or medications)
• Direct bilirubin < 1.6 (unless related to Gilbert's disease or medications)
• Patient or legally authorized representative able to sign informed consent
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to study entry

Exclusion Criteria:

• Immunotherapy or chemotherapy with approved or investigational anticancer therapeutics within 4 weeks of first dose
• Patients on alemtuzumab within 6 weeks prior to consenting
• Active congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia or conduction abnormalities uncontrolled by conventional interventions; myocardial infarction within 6 months of study entry
• Deep vein thrombosis or pulmonary embolism within 3 months of study entry
• Pregnant or breast-feeding females; (lactating females must agree not to breast-feed while taking lenalidomide)
• Acute active infection requiring intravenous antibiotics, antiviral (except antiviral directed at hepatitis B), or antifungal agents within 14 days of first dose
• Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen [Sag] or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed)
• Patients with other known malignancies within the past three years except: i. adequately treated basal or squamous cell skin cancer; ii. carcinoma in situ of the cervix; iii. prostate cancer with Gleason score < 6 with stable prostate-specific antigen (PSA) over the past three months; iv. breast cancer in situ with full surgical resection
• Significant neuropathy (grades 3 to 4 or grade 2 pain)
• Known hypersensitivity to thalidomide, lenalidomide or ipilimumab
• Active life-threatening autoimmune disease
• Active GVHD or recent GVHD and still on > 10 mg prednisone (or equivalent)
• Prior auto-immune disease