Overcoming Chemotherapy Resistance In Refractory Multiple Myeloma With Simvastatin and Zoledronic Acid

Inclusion Criteria:

1. have a definitive diagnosis of Multiple Myeloma (using the International Myeloma Working Group Guidelines).
2. meet one of the following two requirements:

   * Have achieved minimal response (MR) or stable disease (SD) in current treatment regimen after a minimum of two cycles.
   * Have partial response but show no further improvement in paraprotein levels in the latest two measurements.
3. must have measurable active or symptomatic disease. Measurable disease may be paraprotein or free light chains in serum or urine, or the presence of bone marrow plasma cells, defined by one or more of the following criteria:

   * Presence of serum M-protein concentration \> 1g/dL.
   * Urine M-protein excretion \> 200mg in 24-hour urine collection.
   * Serum free light chain concentration ≥ 10mg/dL and abnormal kappa/lambda ratio.
   * Urine free light chain concentration ≥ 100mg/L and abnormal kappa/lambda ratio.
   * Bone marrow plasma cell percentage ≥ 30% (if no detectable M-protein or FLC.)
4. Age \> 18 years of age.
5. If female with reproductive capacity: on effective means of birth control during the entire duration of the treatment.
6. Patients must have recovered from acute toxicities resulting from therapy administered prior to entering this study to grade 1 or less (CTCAE 4) Alopecia may not be resolved.
7. Ability to understand and willingness to sign a written informed consent document.
8. Life expectancy of greater than 8 weeks.
9. ECOG performance status 0, 1, or 2 (Karnofsky \> 60%; see Appendix A).
10. have adequate bone marrow function as defined below:

    * absolute neutrophil count \> 500/ul
    * platelets \> 30,000/ul
11. have adequate liver function as defined below:

    * total bilirubin \< 2 times the upper limit of normal
    * AST(SGOT), ALT(SGPT) \< 3 x upper limit of normal
12. have adequate renal function as defined by a creatinine clearance \> 40 mL/min (measured or estimated by the Cockcroft-Gault formula).
13. have no signs of significant rhabdomyolysis determined by CPK levels with a CK \< 5 times the upper limit of normal.

Exclusion Criteria:

1. have not received any chemotherapy treatment for multiple myeloma prior to being enrolled in the study.
2. show progressive disease or are not tolerating current chemotherapy regimen.
3. were receiving simvastatin (dose \> 40mg/day) while receiving current chemotherapy regimen for multiple myeloma.
4. failed or progressed on more than two chemotherapy regimens, including current treatment; prior to enrolling in this study.
5. receiving any other investigational agent(s).
6. Active second malignancy in the last 5 years except for non-melanoma skin cancer or carcinoma-in-situ.
7. Pregnant women are ineligible, as treatment involves unforeseeable risks to the embryo or fetus. Female patients with reproductive capacity are required to use effective means of birth control during the entire duration of the treatment.
8. History of hypersensitivity reactions attributed to simvastatin or zoledronic acid.
9. receiving medications that may increase risk of rhabdomyolysis such as itraconazole, ketoconazole, erythromycin, cyclosporine, amiodarone, verapamil, clarithromycin, nefazodone, ranolazine, HIV protease inhibitors, gemfibrozil, posaconazole, danazol, amiodarone, diltiazem and amlodipine.
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myopathy, untreated hypothyroidism, hereditary myopathy in the family history, unstable angina pectoris, liver disease not due to multiple myeloma, cardiac arrhythmia that is symptomatic or not rate controlled, active connective tissue disease, active autoimmune disease, or psychiatric illness/social situations that would limit compliance with study requirements.