Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Able to adhere to the study visit schedule and other protocol requirements
* Refractory or relapsed multiple myeloma
* Measurable disease defined as at least one of the following: Serum m-spike ≥ 1g/dL, urine m-spike ≥ 200mg/24hrs, serum free light chains ≥ 100mg/L (provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells ≥ 30%
* Previous therapy with IMiD™ compounds (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study.
* Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, and vinca alkaloids), radiation therapy to the pelvis, and any experimental therapy other than carfilzomib or pomalidomide must have been discontinued at least 28 days prior to entry onto this study.
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry.
* Laboratory test results within these ranges:

  * Absolute neutrophil count ≥ 1,500 /mm³
  * Platelet count ≥ 75,000/mm³
  * Calculated creatinine clearance (Cockcroft-Gault) ≥ 30ml/min.
  * Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
  * Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase \[ALT\]) levels ≤2 x ULN
* 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.
* Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) if no additional risk factor for venous thromboembolic event (VTE) other than myeloma diagnosis according to IMW guidelines
* Able to take low molecular weight heparin or warfarin if ≥ 1 additional risk factor for VTE according to IMW guidelines

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 or azacitidine)
* 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 experimental drug or therapy other than carfilzomib and pomalidomide within 28 days of treatment start on this protocol.
* Neuropathy \> Grade 2
* Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol
* The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or lenalidomide drugs
* Concurrent use of other anti-cancer agents or treatments, concurrent radiation to the pelvis. Palliative radiation to areas outside the pelvis is allowed
* Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockcroft-Gault at the time of previous lenalidomide treatment (25mg day 1-21 every 28 days if CrCl \> 60ml/min, 10mg lenalidomide d1-21 every 28 days if CrCl \< 60mL/min but \> 30mL/min, lenalidomide 15mg every 48 h d1-21 every 28 days if CrCl \< 30mL/min but not requiring dialysis, lenalidomide 5mg daily, day 1-21 every 28 days if CrCl \< 30mL/min and requiring dialysis).