Vorinostat,Lenalinomide and Dexamethasone in Multiple Myeloma Refractory to Previous Lenalinomide Containing Regimens

Inclusion Criteria:

* Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study:

  * International Staging System symptomatic multiple myeloma, as recently defined (Kyle et al., 2009) or Durie-Salmon stage I-III multiple myeloma, after at least one (1) prior anti-myeloma regimen.
  * Refractory to lenalidomide (administered either with dexamethasone or in combination with other agents); refractory will be defined as no response (\<MR) or PD on or within 60 days of discontinuing a prior lenalidomide-containing regimen.
  * Measurable monoclonal protein by serum or urine; or FLC level ≥ 10mg/dL (with abnormal FLC ratio), or measurable extramedullary plasmacytomas:
  * No prior HDAC inhibitor
  * Age ≥ 18 years
  * Performance status ECOG 0-3
  * Acceptable organ function as defined by:
* Bilirubin \<2 x upper limit of normal
* ALT and AST \<2.5 x upper limit of normal
* Serum creatinine \<3.0 mg/dL
* ANC ≥1.0 x 109/L
* Platelet count ≥50 x 109/L

  * QTc interval ≤ 470ms
  * Non-pregnant and non-lactating
  * Life expectancy of more than six months
  * Written informed consent in accordance with federal, local and institutional guidelines
  * Females of Child Bearing Potential\* (FCBP) must have a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL within 10-14 days and again within 24 hours prior to prescribing lenalidomide for cycle 1 (prescription must be filled with 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO methods of acceptable methods of birth control, one highly effective method AND one additional effective method of birth control (contraception) AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy Testing. (See Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods) \*A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
  * Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy (See Appendix G: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods)
  * All study participants must be registered into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®.
  * Subjects must adhere to the study visit schedule and other protocol requirements and receive outpatient treatment and laboratory monitoring at the institute that administers the drug.
  * Subjects must agree to take enteric-coated aspirin 81-325 mg orally daily, or if history of prior thrombotic disease or allergy to aspirin, must be fully anticoagulated with warfarin (INR 2-3), Pradaxa® or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

Exclusion Criteria:

* Subjects must not meet any of the following exclusion criteria to be eligible to enroll in this study:

  * Subjects with non-secretory or hyposecretory multiple myeloma, defined as \<0.5 g/dL M-protein in serum and \<200 mg/24 hr Bence Jones protein in urine and serum free light chain \<10mg/dL (\<100 mg/L)
  * Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation
  * Pregnant or breast feeding females
  * CrCl \<30 ml/min or renal failure requiring hemodialysis
  * Prior history or malignancy other than multiple myeloma, unless patient has been disease free of the disease for ≥3 years.
  * Prior or local irradiation within two weeks before screening
  * Evidence of central nervous system (CNS) involvement
  * Unable to take corticosteroids at study entry
  * Peripheral neuropathy of ≥ grade 3 severity
  * Inability or unwillingness to comply with birth control requirements
  * Unable to take antithrombotic medicines at study entry
  * Refusal to participate in study
  * Persons protected by a legal regime (guardianship, trusteeship)
  * Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 3 weeks prior to first dose
  * Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction in the previous six months
  * Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
  * Known or suspected HIV infection, known HIV seropositivity, or active hepatitis A, B, or C infection