This phase II trial studies how well lenalidomide works in treating patients with progressive or recurrent multiple myeloma after a donor stem cell transplant. Lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. It may also stimulate the immune system in different ways and stop cancer cells from growing.

PRIMARY OBJECTIVES:

I. To evaluate response of relapsed or progressive multiple myeloma to lenalidomide after allogeneic stem cell transplant.

II. Proportion of patients achieving a complete, partial or minor response.

SECONDARY OBJECTIVES:

I. Evaluate toxicity and tolerability of lenalidomide in this setting.

II. For patients with chronic graft-versus-host disease (GVHD), evaluate the response to lenalidomide.

III. Evaluate time to progression (TTP).

IV. Evaluate overall survival (OS).

OUTLINE:

Patients receive lenalidomide orally (PO) on days 1-21. Courses repeat every 28 days for 2 years or longer in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form
• Able to adhere to the study visit schedule and other protocol requirements
• Multiple myeloma, having undergone an allogeneic stem cell transplant from a matched or mismatched related or unrelated donor and have relapsed or have disease progression
• Relapse is defined as reappearance of monoclonal protein in serum or urine by immunofixation, new or increased bone lesions or hypercalcemia
• Disease progression is define as a 25% increase in monoclonal protein in serum or a 50% increase in 24 hour urinary monoclonal protein from the lowest level attained at any time point after allogeneic transplant or new or increased bone lesions or hypercalcemia
• All previous cancer therapy, including radiation, hormonal therapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study, excluding corticosteroids for GVHD
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry
• Absolute neutrophil count >= 1.5 x 10^9/L
• Platelet count >= 50 x 10^9/L
• Serum creatinine =< 2.0 mg/dL
• Total bilirubin =< 1.5 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2 x upper limit of normal (ULN) or =< 5 x ULN if hepatic metastases are present
• Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the Revlimid REMS™ program; FCBP must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and 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
• 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
• Disease free of prior malignancies for >= 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
• Able to take aspirin 81 or 325 mg daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid [ASA] may use Coumadin or low molecular weight heparin)
• All study participants must be registered into the mandatory Revlimid REMS™ program, and be willing and able to comply with the requirements of Revlimid REMS™

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Pregnant or breast feeding females; (lactating females must agree not to breast feed while taking lenalidomide)
• 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
• Use of any other experimental drug or therapy within 28 days of baseline
• Known hypersensitivity to thalidomide
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
• Resistance to prior use of lenalidomide
• Concurrent use of other anti-cancer agents or treatments
• Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C
• Acute GVHD grades 3 or 4