Multiple Myeloma
Conditions
Keywords
refractory multiple myeloma
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
Interventions
DRUGSimvastatin and zoledronic acid
1. Simvastatin 80 mg PO daily starting two days before starting chemotherapy and stopping two days after chemotherapy. 2. Zoledronic acid 4 mg IV over 15 minutes on day 1 and then monthly.
Sponsors
James Graham Brown Cancer Center
University of Louisville
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Paraprotein Level and Free Light Chain (FLC) Ratio From Baseline Measurement | 4 weeks after treatment begins | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | At start of year 2 of follow-up on all surviving participants | OS(Overall survival) is measured from date of study enrollment until death. |
| Duration of Response | Year 1 follow up visits occur monthly | Response will be accessed by one of the study investigators at each monthly follow up visit during year one. |
| Progression Free Survival (PFS) | At start of year 2 follow up on all surviving participants | Study will estimate PFS when there is one year of follow up data for all surviving participants |
| Incidence Rate of Toxicity | Every 12 months up to one month after treatment completion | Descriptive statistics will be provided regarding incidence rates of toxicity. Patients will be monitored for safety throughout the study. |
| Comparison of Quality of Life Scores | Up to 2 months after last treatment has been completed | 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 |
Countries
United States
Participant flow
Recruitment details
7 subjects were enrolled into this trial by the investigator from medical clinic
Participants by arm
| Arm | Count |
|---|---|
| Study Arm Study Arm
Simvastatin and zoledronic acid: 1. Simvastatin 80 mg PO daily starting two days before starting chemotherapy and stopping two days after chemotherapy.
2\. Zoledronic acid 4 mg IV over 15 minutes on day 1 and then monthly. | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Study Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Age, Continuous | 63 years |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
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.
Time frame: 4 weeks after treatment begins
Population: NA = Not available, Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
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
Time frame: Up to 2 months after last treatment has been completed
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
Duration of Response
Response will be accessed by one of the study investigators at each monthly follow up visit during year one.
Time frame: Year 1 follow up visits occur monthly
Population: Study Terminated, zero total participants analyzed
Secondary
Duration of Response
Response will be assessed by one of the study investigators at each three month follow up visit for Year 2
Time frame: Year 2 follow up visit occur every three months
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
Duration of Response
Response will be assessed by one of the study investigators at each six month follow up visit for Year 3-5
Time frame: Year 3-5 follow up visit occurs every six months
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
Incidence Rate of Toxicity
Descriptive statistics will be provided regarding incidence rates of toxicity. Patients will be monitored for safety throughout the study.
Time frame: Every 12 months up to one month after treatment completion
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
Overall Survival
OS(Overall survival) is measured from date of study enrollment until death.
Time frame: At start of year 2 of follow-up on all surviving participants
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study
Secondary
Progression Free Survival (PFS)
Study will estimate PFS when there is one year of follow up data for all surviving participants
Time frame: At start of year 2 follow up on all surviving participants
Population: Study was terminated and PI has left the institution. Sincere efforts were made to gather and report the data, however, no data is available for the study