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

Overview

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.

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

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Triple (Participant, Care Provider, Investigator)
• Study Primary Completion Date: October 2008

Detailed Description

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.

Interventions

• Drug: dexamethasone
  • Given orally
• Drug: lenalidomide
  • Given orally
• Other: placebo
  • Given orally

Arms, Groups and Cohorts

• Experimental: Arm I
  • 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.
• Active Comparator: Arm II
  • 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.

Clinical Trial Outcome Measures

Primary Measures

• Progression-Free Survival
  • Time Frame: From date of initial registration to date of progression/relapse of disease or death from any cause, whichever came first, up to 5 years
  • 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.

Secondary Measures

• Toxicity
  • Time Frame: 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
  • Compare the toxicity profile of these regimens, including thrombotic complications, in these patients, based on CTCAE v. 3.0.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • SWOG Cancer Research Network
• Collaborator
  • National Cancer Institute (NCI)
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Jeffrey A. Zonder, MD, Study Chair, Barbara Ann Karmanos Cancer Institute

Citations Reporting on Results

Zonder JA, Crowley JJ, Bolejack V, et al.: A randomized Southwest Oncology Group study comparing dexamethasone (D) to lenalidomide + dexamethasone (LD) as treatment of newly-diagnosed multiple myeloma (NDMM): impact of cytogenetic abnormalities on efficacy of LD, and updated overall study results. [Abstract] J Clin Oncol 26 (Suppl 15): A-8521, 2008.

Zonder JA, Crowley J, Hussein MA, et al.: Superiority of lenalidomide (Len) plus high-dose dexamethasone (HD) compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232. [Abstract] Blood 110 (11): A-77, 2007.