This study will evaluate the feasibility of combining four of the most active agents available for the treatment of multiple myeloma. Further the investigators will attempt to assess the activity of this combination.

Phase I/II studies of the novel proteasome inhibitor, carfilzomib, have shown it to have significant activity in patients with advanced multiple myeloma, including patients with bortezomib refractory disease. This drug, unlike bortezomib, has minimal neurotoxicity and appears to have minimal gastrointestinal (GI) toxicity. Experience with the combination of bortezomib, lenalidomide and dexamethasone has shown both neuropathy and chronic diarrhea to be limiting.

Vorinostat is a histone deacetylase inhibitor with modest single agent activity in multiple myeloma. Dysesthesia, GI issues and fatigue have been problematic in this patient population. More recent studies combining vorinostat with lenalidomide and dexamethasone or with bortezomib have demonstrated a much more robust activity, including in patients refractory to lenalidomide or bortezomib-based combinations. Again, neuropathy, fatigue and GI issues have been problematic.

The investigators own anecdotal experience with combinations of proteasome inhibitor, histone deacetylase inhibitor, immunomodulators and dexamethasone has shown this combination to be extremely active and well tolerated. The combination of vorinostat, carfilzomib, lenalidomide and dexamethasone should offer the opportunity to maximize activity while limiting toxicities, particularly neuropathy and GI.

Inclusion Criteria:

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

Disease related:

1. Symptomatic multiple myeloma

2. Relapsed and/or refractory multiple myeloma after at least one prior therapeutic regimen for multiple myeloma

3. Prior treatment with immunomodulatory agents, proteasome inhibitors and histone deacetylase inhibitors is permitted. (Patients who have used HDAC inhibitors, including valproic acid , must have at least 5 half-lives wash out period before beginning therapy with vorinostat on this protocol.)

4. Measurable disease, as indicated by one or more of the following:

   • Serum M-protein ≥ 0.5 g/dL
   • Urine Bence-Jones protein ≥ 200 mg/24 h
   • If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein measurement (particularly for patients with IgA MM), then quantitative immunoglobulin levels can be accepted.
   • Serum free light chain ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal free light chain ratio

   Demographic

5. Males and females ≥ 18 years of age

6. Life expectancy of more than three months

7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (see Appendix B)

Laboratory

8.Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN 9.Absolute neutrophil count (ANC) ≥ 1,000/mm3 Hemoglobin ≥ 8 gm/dL Platelet count ≥ 50,000/ mm3 (≥ 30 × 109/L if myeloma involvement in the bone marrow is > 50%)

• Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G CSF for at least 2 weeks.

• Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, in accordance with institutional guidelines

• Screening platelet count should be independent of platelet transfusions for at least 2 weeks 10.Calculated or measured creatinine clearance of ≥60 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) x Mass (kg) / (72 x creatinine mg/dL)]; multiply result by 0.85 (if female). Other generally accepted calculation methods can be substituted.11.Potassium level 3.5-5.2 meq/L (institutional normal range) Ethical/Other 12.Written informed consent in accordance with federal, local, and institutional guidelines 13.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).

    14. 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) 15. All study participants must be registered into the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®.

    16. 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 17. 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) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

Exclusion Criteria

Subjects who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

Disease related

1. 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) and no measurable plasmacytoma

2. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone ≥20 mg/day within 3 weeks prior to first dose

3. Concurrent use of histone deacetylase inhibitor (eg. Valproic acid)

4. Use of any other experimental drug or therapy within 28 days of baseline

5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

6. Waldenström's macroglobulinemia

7. Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 2 weeks prior to first dose

8. Radiation therapy within 1 week prior to first dose, Immunotherapy within 3 weeks prior to first dose . Planned radiation therapy that occurs after the start of treatment

9. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater.

   Concurrent conditions

10. Pregnant or lactating females (Lactating females must agree not to breast feed while taking lenalidomide or vorinostat).

11. History of allergy to boron or mannitol

12. Major surgery within 2 weeks prior to first dose

13. 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

14. Uncontrolled hypertension

15. Acute active infection requiring intravenous antibiotics, antivirals, or antifungals within one week prior to first dose or oral antibiotics within 1 week

16. Known or suspected HIV infection, known HIV seropositivity, or active hepatitis A, B, or C infection.

17. Serious psychiatric or medical conditions that could interfere with treatment

18. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment

19. Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (e.g., lansoprazole), antiviral agents, enteric-coated aspirin or other anticoagulant, or if a history of prior thrombotic disease, warfarin or low molecular weight heparin

20. Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

21. Subjects with pleural effusions requiring therapeutic thoracentesis or ascites requiring therapeutic paracentesis