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

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.

Study Overview

• Status: Terminated
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Simvastatin and zoledronic acid

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

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Study Arm	Drug: Simvastatin and zoledronic acid; 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.; 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

Collaborators and Investigators

• Sponsor: University of Louisville
• Collaborators: James Graham Brown Cancer Center
• Investigators: Principal Investigator: Cesar Rodriguez, MD, Dept. of Med Admin.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: November 15, 2011
• First Submitted That Met QC Criteria: January 17, 2013
• First Posted (Estimate): January 21, 2013

Study Record Updates

• Last Update Posted (Actual): November 18, 2019
• Last Update Submitted That Met QC Criteria: October 29, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Bone Density Conservation Agents; Zoledronic Acid; Simvastatin
• Other Study ID Numbers: BCC-HEM-11-003