Lenalidomide + Azacitidine for Adaptive Immunotherapy -> Auto SCT in Multiple Myeloma

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