Zoledronate With or Without Thalidomide in Treating Patients With Early Stage Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Zoledronate may prevent bone loss and stop the growth of cancer cells in bone. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It is not yet know whether giving zoledronate together with thalidomide is more effective than zoledronate alone in treating multiple myeloma. PURPOSE: This randomized phase III trial is studying zoledronate and thalidomide see how well they work compared with zoledronate alone in treating patients with early stage multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Compare time to progression in patients with early stage multiple myeloma treated with zoledronate with or without thalidomide. Secondary Compare the response rate, 1-year progression-free survival rate, duration of response, and time to next therapy in patients treated with these regimens. Assess differences in toxicity of these regimens in these patients. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to the presence of lytic lesions on metastatic bone survey (yes vs no), beta-2 microglobulin level (high vs normal), and bone marrow labeling index (high [> 1.0%] vs low [≤ 1.0%]). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral thalidomide on days 1-28. Treatment with thalidomide repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive zoledronate IV over 15 minutes on day 1. Treatment with zoledronate repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity. Blood samples are collected for research studies at baseline and after courses 3, 6, 9, and 12. Bone marrow aspirates are performed at baseline and after courses 6 and 12. Samples are evaluated for bone marrow angiogenesis; vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2 expression; bone marrow angiogenesis-VEGF relationship; bone marrow angiogenesis/apoptosis rate relationship; bone marrow angiogenesis/plasma cell (PC) proliferation rate relationship; VEGF expression/apoptosis rate relationship; and VEGFR expression/PC proliferation rate relationship. After completion of study treatment, patients are followed every 6 months for up to 5 years. PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.

Official Title
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A Phase III Randomized Trial of Thalidomide Plus Zoledronic Acid Versus Zoledronic Acid Alone in Patients With Early Stage Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: Thalidomide
* Drug: zoledronic acid


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of multiple myeloma (MM) Previously untreated asymptomatic disease No requirement for immediate chemotherapy for active MM, such as hypercalcemia from myeloma or painful bone lesions No solitary plasmacytoma Measurable or evaluable disease as defined by one of the following: Serum monoclonal protein ≥ 1.0 g by protein electrophoresis More than 200 mg of monoclonal protein in the urine by 24-hour electrophoresis Measurable soft tissue plasmacytoma by physical exam with ruler or by MRI or positron emission tomography/CT scan If the only measurable lesion is the plasmacytoma, it must be ≥ 1.5 cm in 1 dimension Must have ≥ 10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index No amyloidosis PATIENT CHARACTERISTICS: Performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 8.0 g/dL Creatinine ≤ 2.0 mg/dL (elevation above normal range should not be felt to be related to myeloma) Not pregnant or nursing Negative pregnancy test Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 4 weeks after completion of study treatment No uncontrolled infection No other active malignancy No New York Heart Association class III or IV heart disease No pre-existing neuropathy ≥ grade 2 No concurrent major dental work PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior corticosteroids (for nonmalignant disorders) allowed Prior therapy with experimental agents not shown to have significant activity in MM, such as clarithromycin, dehydroepiandrosterone, and anakinra allowed No prior thalidomide or corticosteroids for MM No more than 3 doses of IV zoledronate or pamidronate within the past 12 months At least 3 months since prior radiotherapy, including radiotherapy for solitary plasmacytoma No concurrent oral bisphosphonate therapy for osteoporosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: Thal/ZLD<br>Thalidomide (Thal) + Zolendronic acid (ZLD) | Drug: Thalidomide<br>* 200 mg orally on days 1-28 of 28 day cycle<br>Drug: zoledronic acid<br>* 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter<br>|
| Experimental: Arm II: ZLD<br>Zoledronic acid (ZLD) | Drug: zoledronic acid<br>* 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression (TTP) | Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated. | randomization to progression (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-month Progression-free Survival (PFS) | PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization. | 12 months | 
| Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment | Response is defined as follows: CR: Complete disappearance of M-protein from serum & urine on immunofixation, <5% plasma cells in bone marrow (BM) VGPR: >=90% reduction in serum M-component; Urine M-Component <100 mg per 24 hours; <=5% plasma cells in BM PR: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels | 12 months | 
| Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) | Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method | time from start of response to progression (up to 5 years) | 
| Time to Subsequent Treatment | Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method | time from end of treatment to subsequent treatment (up to 5 years) | 
| Time to Treatment Failure | Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method | time from randomization to treatment failure (up to 5 years) | 
| Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events | Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2. Description of Grades: Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death | During treatment (up to 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I multiple myeloma