S0232 Dexamethasone With or Without Lenalidomide in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy such as dexamethasone use different ways to stop cancer cells from dividing so they stop growing or die. Lenalidomide may stop the growth of multiple myeloma by stopping blood flow to the tumor. It is not yet known whether dexamethasone is more effective with or without lenalidomide in treating multiple myeloma. PURPOSE: This randomized phase III trial is studying dexamethasone and lenalidomide to see how well they work compared to dexamethasone alone in treating patients with previously untreated stage I, stage II, or stage III multiple myeloma.

Detailed Description
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OBJECTIVES: Compare the progression-free survival of patients with previously untreated stage I, II, or III multiple myeloma treated with dexamethasone with or without lenalidomide. Compare the overall response rate in patients treated with these regimens. Compare the major response rate (indicated by greater than 75% decrease in M-protein) in patients treated with these regimens. Compare the overall survival and time to best response in patients treated with these regimens. Compare the toxicity profile of these regimens, including thrombotic complications, in these patients. Compare the effect of these regimens on gene expression and proteomic analysis in these patients. OUTLINE: This is a randomized, double-blind, crossover, multicenter study. Patients are stratified according to disease stage by the International Staging System (I vs II vs III) and Zubrod performance status (0-1 vs 2-3). Patients are randomized to 1 of 2 treatment arms. Arm I Induction therapy: Patients receive oral dexamethasone (DM) on days 1-4, 9-12, and 17-20 and oral lenalidomide on days 1-28. Treatment repeats every 35 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Maintenance therapy: Patients receive oral DM on days 1-4 and 15-18 and oral lenalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Arm II Induction therapy: Patients receive DM as in arm I induction and oral placebo on days 1-28. Treatment repeats as in arm I induction. Patients with responding or stable disease proceed to maintenance therapy. Patients with disease progression during induction therapy cross over and receive unblinded treatment with DM and lenalidomide as in arm I induction. Patients with responding or stable disease after unblinded induction therapy receive unblinded maintenance therapy with DM and lenalidomide as in arm I maintenance. Maintenance therapy: Patients receive oral DM as in arm I maintenance and oral placebo on days 1-21. Courses repeat as in arm I maintenance. Patients with disease progression during maintenance therapy cross over and receive unblinded treatment with DM and lenalidomide as in arm I induction. Patients with responding or stable disease after unblinded induction therapy proceed to unblinded maintenance therapy with DM and lenalidomide as in arm I maintenance. Patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 500 patients (250 per treatment arm) will be accrued for this study within 4 years.

Official Title
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Phase III Trial Comparing Dexamethasone (DEX) to the Combination of DEX + CC-5013 in Patients With Previously Untreated Multiple Myeloma

Conditions
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Multiple Myeloma, Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: dexamethasone
* Drug: lenalidomide
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Previously untreated multiple myeloma Stage I, II, or III disease by the International Staging System Measurable M-protein as defined by 1 of the following: Serum M-protein at least 1.0 g/dL by serum protein electrophoresis or immunoelectrophoresis Urinary M-protein excretion at least 200 mg/24 hours No nonsecretory multiple myeloma Not planning to undergo future autologous stem cell transplantation PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-3* NOTE: *Zubrod 3 allowed only if multiple myeloma is the central cause of disability Life expectancy Not specified Hematopoietic Platelet count at least 80,000/mm^3* Absolute neutrophil count at least 1,000/mm^3* Hemoglobin at least 9 g/dL* (epoetin alfa or transfusion allowed) NOTE: *Unless due to greater than 50% marrow involvement by myeloma on biopsy Hepatic AST/ALT no greater than 3 times upper limit of normal* NOTE: *Values outside of this range are allowed at the investigator's discretion Renal Creatinine no greater than 2.5 mg/dL* NOTE: *Values outside of this range are allowed at the investigator's discretion Cardiovascular No New York Heart Association class III or IV heart failure No myocardial infarction within the past 6 months No poorly controlled hypertension Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception for 4 weeks before, during, and for 4 weeks after study treatment Female patients must use 2 reliable forms of contraception simultaneously Male patients must use effective barrier contraception No uncontrolled active infection requiring IV antibiotics No poorly controlled diabetes mellitus that would preclude ability to take oral glucocorticoids No other serious medical condition that would preclude study participation No psychiatric illness that would preclude study participation No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix Must be able to take aspirin by mouth at a dose of 325 mg per day or enoxaparin subcutaneously at a dose of 40 mg per day as a form of thrombotic prophylaxis, except if already on therapeutic anticoagulant medication PRIOR CONCURRENT THERAPY: Biologic therapy No prior interferon or thalidomide Chemotherapy No prior chemotherapy Endocrine therapy Prior high-dose dexamethasone allowed provided duration of administration was no more than 4 days Radiotherapy Prior localized radiotherapy allowed provided it was not to the sole site of evaluable disease Surgery Not specified Other No prior treatment for clinically significant ventricular cardiac arrhythmias Concurrent bisphosphonates allowed

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive induction therapy comprising oral dexamethasone (DM) on days 1-4, 9-12, and 17-20 and oral lenalidomide on days 1-28. Treatment repeats every 35 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive maintenance therapy comprising oral DM on days 1-4 and 15-18 and oral lenalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: dexamethasone<br>* Given orally<br>Drug: lenalidomide<br>* Given orally<br>|
| Active Comparator: Arm II<br>Patients receive induction therapy comprising DM as in arm I induction and oral placebo on days 1-28. Treatment repeats as in arm I induction. Some patients may then receive maintenance therapy comprising oral DM as in arm I maintenance and oral placebo on days 1-21. Courses repeat as in arm I maintenance. | Drug: dexamethasone<br>* Given orally<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Progression is defined as a > 25% increase from baseline in myeloma protein production or other signs of disease progression such as hypercalcemia, etc. In patients with a confirmed Partial Remission, Remission, or Complete Remission, relapse is defined as the first occurrence of any of the following: 1) a myeloma protein increase by than 100% from the lowest level recorded on study, provided the absolute magnitude of this increase is at least 1g/dL for a serum monoclonal protein or at least 500 mg/24 hrs of urine M-protein; 2) a myeloma protein increase above the response criteria for Partial Remission, with the same requirements for the absolute magnitude of the protein increase; 3)reappearance of any myeloma peak that had disappeared while on protocol treatment, provided it meets the same requirements listed above; 4) increase in the size and number of lytic bone lesions recognized on radiographs. | From date of initial registration to date of progression/relapse of disease or death from any cause, whichever came first, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | Compare the toxicity profile of these regimens, including thrombotic complications, in these patients, based on CTCAE v. 3.0. | From time of initiating study treatment until discontinuation of study treatment or of open-label REVLIMID + LOW DOSE DEX, whichever comes last, 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, stage II multiple myeloma, stage III multiple myeloma