Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma

Study Overview
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Brief Summary
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This randomized phase III trial studies lenalidomide and low-dose dexamethasone to see how well it works compared to lenalidomide and standard-dose dexamethasone, given with or without thalidomide, in treating patients with multiple myeloma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide and thalidomide may also stop the growth of multiple myeloma by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide, thalidomide, and dexamethasone together may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the response rate and toxicity of lenalidomide (CC-5013) plus dexamethasone (standard dose) versus CC-5013 plus low dose dexamethasone in patients with newly diagnosed myeloma at any time in the first 4 cycles of treatment and to determine if CC-5013 plus low dose dexamethasone will have similar response rate with lower toxicity (First Phase). SECONDARY OBJECTIVES: I. To evaluate the response rate of thalidomide plus dexamethasone (Thal/Dex) in patients with newly diagnosed myeloma who do not achieve a complete or partial response at any time in the first 4 cycles with the CC-5013 and dexamethasone combination in either of the two arms (First Phase). II. To study the effect of CC-5013 on bone marrow microvessel density and angiogenesis grade, on plasma cell labeling index (PCLI), and on the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the marrow (First Phase). III. To study the effect of CC-5013 and dexamethasone on bone marrow mesenchymal progenitor cells (MPCs) (First Phase). IV. To evaluate in a separate expansion phase the efficacy of aspirin (325 mg/day) versus Coumadin (dose adjusted to maintain a target international normalized ratio [INR] of 2-3) in preventing deep vein thrombosis (DVT) in patients with newly diagnosed myeloma receiving CC-5013 plus standard dose dexamethasone. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21, and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20. Arm II: Patients receive lenalidomide as in Arm I and low-dose dexamethasone PO QD on days 1, 8, 15, and 22. In both arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients not responding at any point during the first 4 cycles of lenalidomide and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during treatment on Arms I or II have the option to register on salvage therapy Arms III or IV respectively. Arm III (patients with no response after treatment on Arm I): Patients receive thalidomide PO QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20. Arm IV (patients with no response after treatment on Arm II): Patients receive thalidomide as in Arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22. In both salvage therapy arms, cycles repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of 4 cycles of therapy, patients may undergo stem cell harvest (using growth factors only) for cryopreservation. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

Official Title
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A Randomized Phase III Study of CC-5013 Plus Dexamethasone Versus CC-5013 Plus Low Dose Dexamethasone in Multiple Myeloma With Thalidomide Plus Dexamethasone Salvage Therapy for Non-Responders

Conditions
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DS Stage I Multiple Myeloma, DS Stage II Multiple Myeloma, DS Stage III Multiple Myeloma

Intervention / Treatment
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* Drug: Dexamethasone
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Drug: Thalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be diagnosed with symptomatic multiple myeloma within the past 90 days confirmed by the following: Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma which must be obtained within 4 weeks prior to randomization Measurable levels of monoclonal protein (M protein): >= 1.0 g/dL on serum protein electrophoresis or >= 200 mg of monoclonal light chain on a 24 hour urine protein electrophoresis which must be obtained within 4 weeks prior to randomization; both serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are required to be performed within 28 days prior to randomization; please note that if both serum and urine m-components are present, both must be followed in order to evaluate response Hemoglobin > 7 g/dL Platelet count > 75,000 cells/mm^3 Absolute neutrophil count > 1000 cells/mm^3 Creatinine < 2.5 mg/dL and creatinine clearance (measured or calculated) >= 60 mL/min Bilirubin =< 1.5 mg/dL Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times the upper limit of normal Prior palliative and/or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to date of registration; patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma meeting all the eligibility criteria for this protocol Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method (intrauterine device [IUD], birth control pills, tubal ligation or partner's vasectomy) and one additional effective method (condom, diaphragm or cervical cap); FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy starting 4 weeks prior to and while taking CC5013 or thalidomide and for four weeks after discontinuing this therapy; a FCBP is a sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure Patients with a history of prior malignancy are eligible provided there is no active malignancy and a low expectation of recurrence within 6 months Exclusion Criteria: No prior systemic therapy with the exception of bisphosphonates for multiple myeloma Prior glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted; prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day; prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome Patients with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible Patients must not have grade 2 or higher peripheral neuropathy due to other medical conditions at the time of randomization Patients must not have active, uncontrolled infection Patients must not have a history of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy For patients registered prior to activation of Addendum # 6; patients must be willing and able to take prophylaxis with either aspirin at 325 mg/day or alternative prophylaxis with either low molecular weight heparin or Coumadin For patients registered after activation of Addendum # 6; patients entering the expansion phase of the protocol, which tests anticoagulant prophylaxis, must be able and willing to be randomized between aspirin at 325 mg/day and Coumadin Female patients MUST NOT be pregnant or breastfeeding; due to the potential teratogenic properties of CC 5013, and the known teratogenicity associated with thalidomide, the use of these drugs in this patient population is ABSOLUTELY CONTRAINDICATED

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (lenalidomide, dexamethasone)<br>Patients receive lenalidomide PO QD on days 1-21 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20. | Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|
| Experimental: Arm II (lenalidomide, low-dose dexamethasone)<br>Patients receive lenalidomide and acetylsalicylic acid as in Arm I and low-dose dexamethasone PO QD on days 1, 8, 15, and 22. | Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|
| Active Comparator: Arm III (thalidomide, dexamethasone)<br>Patients with no response after treatment on Arm I: Patients receive thalidomide PO QD on days 1-28 and standard-dose dexamethasone PO QD on days 1-4, 9-12, and 17-20 | Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Thalidomide<br>* Given PO<br>* Other names: Thalomid;|
| Experimental: Arm IV (thalidomide, low-dose dexamethasone)<br>Patients with no response after treatment on Arm II: Patients receive thalidomide as in arm III and low-dose dexamethasone PO QD on days 1, 8, 15, and 22. | Drug: Dexamethasone<br>* Given PO<br>* Other names: ZoDex;Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Thalidomide<br>* Given PO<br>* Other names: Thalomid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Objective Response (First Phase, Step 1) | Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response). As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only. | Assessed every 4 weeks for 16 weeks during Step 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Objective Response (First Phase, Step 2) | Objective response is defined as either complete response (CR) or partial response (PR). Patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow are considered to have CR. PR requires all the following: (1) ≥50% reduction in the level of the serum monoclonal paraprotein. (2) Reduction in 24-hour urinary light chain excretion either by ≥90% or to <200 mg. (3)For patients with non-secretory (or oligosecretory) myeloma only, a ≥50% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy must be documented. (4)50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination). (5) No increase in the number or size of lytic bone lesions (development of a compression fracture does not exclude response). As the expansion phase was a substudy terminated early with only 7 patients enrolled, the clinical results presented are mainly for the first phase only. | Assessed every 4 weeks for 16 weeks during Step 2 |