RATIONALE: Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. An autologous stem cell transplant may be able to replace blood-forming cells that were destroyed by lenalidomide and azacitidine. Giving autologous lymphocytes after the transplant may help destroy any remaining cancer cells.

PURPOSE: This pilot trial is studying how well giving lenalidomide together with azacitidine works when followed by autologous stem cell transplant and autologous lymphocyte infusion in treating patients with multiple myeloma.

OBJECTIVES:

Primary

• Determine the feasibility of mobilizing and infusing autologous lymphocytes (ALI) following immunomodulatory therapy comprising azacitidine and lenalidomide in patients with multiple myeloma.

Secondary

• Determine the ability to proceed with autologous stem cell transplantation in these patients.
• Determine the complete response rate at 6 months following transplant in patients treated with this regimen.
• Determine the progression-free survival and overall survival of patients treated with this regimen.
• Determine the time to progression in patients treated with this regimen.
• Monitor the toxicity of post-autologous stem cell infusion of autologous lymphocytes.
• Measure the pre- and post-ALI immune response to cancer testis antigens (CTA) (CTA-specific Ig and T-cell repertoire).
• Study the expression of CTA in multiple myeloma before and after azacitidine therapy.

OUTLINE:

• Immunomodulatory therapy: Patients receive azacitidine subcutaneously on days 1-5 and oral lenalidomide on days 6-21. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
• Lymphapheresis: Patients undergo autologous lymphocyte harvest on day 22 of courses 2 and 3.
• Autologous stem cell transplantation (ASCT): Patients undergo single or tandem ASCT using standard protocols.
• Autologous lymphocyte infusion (ALI): Patients undergo ALI approximately 28-60 days after ASCT.

Blood samples are collected at baseline and periodically during study for correlative laboratory studies, including CTA-specific immune monitoring by RT-PCR, ELISPOT assays, and flow cytometry. Tissue samples from bone marrow aspirates are also collected at baseline, during course one, and after course three for CTA expression and methylation studies.

After completion of study therapy, patients are followed periodically.

Inclusion criteria:

• Patients with a diagnosis of multiple myeloma, who have residual measurable disease (in partial remission or with stable disease) and are eligible to undergo an autologous stem cell transplant will be able to participate in this trial; measurable disease will comprise of either, quantifiable serum or urinary, M protein or free light chains in the presence of a positive immunofixation or bone marrow plasma cells > 5%
• Patients who have received prior lenalidomide therapy will be eligible if >= partial response (PR) was observed on a prior lenalidomide containing regimen and patients did not progress while receiving lenalidomide; isolated bone lytic lesions in the absence of measurable para-proteins will not be considered measurable disease
• A minimum period of two weeks must have elapsed following the prior myeloma therapy; this does not include therapy with bisphosphonates
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• No clinical evidence of uncontrolled viral, fungal, bacterial infection
• Negative serology for human immunodeficiency virus (HIV)
• Serum bilirubin =< 1.5 times upper limit of normal (ULN)
• Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) =< 3x ULN
• Calculated creatinine clearance >= 60ml/min by Cockcroft-Gault formula; creatinine clearance >= 60 ml/min or serum creatinine =< 2.0 mg/dL
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelet count >= 100,000/ uL
• Hemoglobin (Hgb) >= 10 g/dL following recovery from last therapy
• Cardiac and pulmonary function adequate for transplant
• Ability to sign informed consent
• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
• 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 and again 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

Exclusion criteria:

• Known or suspected hypersensitivity to azacitidine or mannitol
• Patients with multiple myeloma refractory to therapy with lenalidomide; progression following discontinuation of prior therapy with lenalidomide is allowed as long as patients have not failed rechallenge with lenalidomide
• Pregnant or breast feeding
• Other concomitant malignancies
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
• Concurrent use of other anti-cancer agents or treatments
• Known hypersensitivity to thalidomide or lenalidomide

Multiple Myeloma in either first or subsequent partial remission with measurable disease, eligible for autologous SCT.

1 year the subject will be on study and evaluated for adverse events.

Medical history and physical before treatment, Days 1, 5 and 22 of the 1st cycle and before cycles 2 and 3, before ALI. Blood for study specific tests drawn before ALI and 2, 4 and 8 weeks after and if relapse occurs. Chest x ray before ALI. Bone marrow Biopsy at baseline and after cycle 3.