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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to examine the effect of simvastatin and zoledronic acid on M-protein and/or free light chains when added to conventional chemotherapy for the treatment of multiple myeloma patients.

Detailed Description
-----------------
We hypothesize that the addition of simvastatin and zoledronic acid to bortezomib, thalidomide, melphalan or dexamethasone based regimens will decrease drug resistance when treating refractory multiple myeloma. We hypothesize that the addition of simvastatin and zoledronic acid will not increase the chemotherapy toxicity significantly and will be tolerable for patients. We believe simvastatin and zoledronic acid have antitumor properties and will contribute to reversal of resistance. Treatment will be significantly enhanced when these agents are combined

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

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: Simvastatin and zoledronic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: have a definitive diagnosis of Multiple Myeloma (using the International Myeloma Working Group Guidelines). 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. 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.) Age > 18 years of age. If female with reproductive capacity: on effective means of birth control during the entire duration of the treatment. 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. Ability to understand and willingness to sign a written informed consent document. Life expectancy of greater than 8 weeks. ECOG performance status 0, 1, or 2 (Karnofsky > 60%; see Appendix A). have adequate bone marrow function as defined below: absolute neutrophil count > 500/ul platelets > 30,000/ul 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 have adequate renal function as defined by a creatinine clearance > 40 mL/min (measured or estimated by the Cockcroft-Gault formula). have no signs of significant rhabdomyolysis determined by CPK levels with a CK < 5 times the upper limit of normal. Exclusion Criteria: have not received any chemotherapy treatment for multiple myeloma prior to being enrolled in the study. show progressive disease or are not tolerating current chemotherapy regimen. were receiving simvastatin (dose > 40mg/day) while receiving current chemotherapy regimen for multiple myeloma. failed or progressed on more than two chemotherapy regimens, including current treatment; prior to enrolling in this study. receiving any other investigational agent(s). Active second malignancy in the last 5 years except for non-melanoma skin cancer or carcinoma-in-situ. 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. History of hypersensitivity reactions attributed to simvastatin or zoledronic acid. 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. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm<br>Study Arm | Drug: Simvastatin and zoledronic acid<br>* Simvastatin 80 mg PO daily starting two days before starting chemotherapy and stopping two days after chemotherapy. Zoledronic acid 4 mg IV over 15 minutes on day 1 and then monthly.<br>* Other names: Zocor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Paraprotein Level and Free Light Chain (FLC) Ratio From Baseline Measurement | The effect of simvastatin and zolendronic acid on M-Protein and FLC ratio will be measured 4 weeks after treatment begins, then every 4 weeks until progression of disease. | 4 weeks after treatment begins | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | OS(Overall survival) is measured from date of study enrollment until death. | At start of year 2 of follow-up on all surviving participants | 
| Duration of Response | Response will be accessed by one of the study investigators at each monthly follow up visit during year one. | Year 1 follow up visits occur monthly | 
| Progression Free Survival (PFS) | Study will estimate PFS when there is one year of follow up data for all surviving participants | At start of year 2 follow up on all surviving participants | 
| Duration of Response | Response will be assessed by one of the study investigators at each three month follow up visit for Year 2 | Year 2 follow up visit occur every three months | 
| Duration of Response | Response will be assessed by one of the study investigators at each six month follow up visit for Year 3-5 | Year 3-5 follow up visit occurs every six months | 
| Incidence Rate of Toxicity | Descriptive statistics will be provided regarding incidence rates of toxicity. Patients will be monitored for safety throughout the study. | Every 12 months up to one month after treatment completion | 
| Comparison of Quality of Life Scores | The QOL scores taken at the start of the study and every 4 months after treatment starts will be analyzed using Wilcoxon test for paired differences | Up to 2 months after last treatment has been completed | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
refractory multiple myeloma