Melphalan, Prednisone, and Thalidomide or Lenalidomide in Treating Patients With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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This randomized phase III trial studies melphalan and prednisone with thalidomide to see how well it works compared to melphalan and prednisone together with lenalidomide in treating patients with newly diagnosed multiple myeloma. Drugs used in chemotherapy, such as melphalan and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Thalidomide and lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. It is not yet known whether melphalan and prednisone are more effective when given together with thalidomide or lenalidomide in treating multiple myeloma.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare progression-free survival between patients receiving melphalan, prednisone, and thalidomide versus melphalan, prednisone, and lenalidomide in newly diagnosed multiple myeloma patients who are not candidates for high-dose therapy. SECONDARY OBJECTIVES: I. To compare overall survival between the arms. II. To compare response rates and depth of response. III. To compare the incidence of toxicities. IV. To validate the translocation classification (TC) of myeloma as a prognostic tool using gene expression profiling at diagnosis. TERTIARY OBJECTIVES: I. To compare quality-of-life (QOL) change between arms based on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) Trial Outcome Index (TOI) from registration (prior to initiation of treatment) to the end of cycle 24 (maintenance therapy). II. To examine the impact of differential treatment response (PFS), if observed, on QOL based on the FACT-Ntx TOI up to cycle 38 (maintenance therapy). III. To obtain prospective data on myeloma specific QOL attributes. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION THERAPY: Patients receive melphalan orally (PO) and prednisone PO once daily (QD) on days 1-4, and thalidomide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive thalidomide PO QD and continue in the absence of disease progression. ARM II: INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO QD on days 1-4, and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive lenalidomide PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression. After completion of study treatment, patients are followed up periodically for 10 years.

Official Title
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An Intergroup Phase III Randomized Controlled Trial Comparing Melphalan, Prednisone and Thalidomide (MPT) Versus Melphalan, Prednisone and Lenalidomide (Revlimid(TM))(MPR) in Newly Diagnosed Multiple Myeloma Patients Who Are Not Candidates for High-Dose Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Drug: Melphalan
* Drug: Prednisone
* Other: Quality-of-Life Assessment
* Drug: Thalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a confirmed diagnosis of symptomatic myeloma; for the original diagnosis of myeloma patients should have met the following criteria at one point in their disease course: Bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma Patient must have had symptomatic disease at initial diagnosis that prompted the initiation of therapy as well as evidence of end-organ damage at the time of diagnosis namely; at least one of the following: anemia, hypercalcemia, bone disease (lytic bone lesions or pathologic fracture), or renal dysfunction NOTE: Patients with asymptomatic smoldering myeloma (serum m protein >= 3 gm/dL or bone marrow plasma cells >= 10% or greater plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) and monoclonal gammopathy of undetermined significance (serum m protein < 3 gm/dL and bone marrow plasma cells < 10% plus no evidence of anemia, hypercalcemia, lytic bone lesions or renal dysfunction) are not eligible Patients must be > 65 and have declined alternative treatment OR patients who are >= 18 < 65 are eligible if they: Are not a candidate for autologous stem cell transplantation in the opinion of the treating physician OR Have declined transplant or other alternative treatment Eastern Cooperative Oncology Group (ECOG) performance status =< 2 All tests below must be performed within 28 days prior to randomization: Serum free light chain assay Kappa free light chain Lambda free light chain NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine; measurable disease in the serum is defined as having a serum M-spike >= 1 g/dL; measurable disease in the urine is defined as having a urine M-spike >= 200 mg/24 hr NOTE: urine protein electrophoresis (UPEP) (on a 24 hour collection) is required, no substitute method is acceptable; urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr; 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 Total 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 Patients must be previously untreated for myeloma, although prior treatment for myeloma with prednisone or dexamethasone for less than 4 weeks total dosing alone or in combination with thalidomide or lenalidomide for less than 2 weeks total dosing is allowable Patients may be receiving bisphosphonates or growth factors (erythropoietin) for multiple myeloma; although erythropoietin is allowed, it is strongly discouraged due to increased risk of thrombosis when employed alongside thalidomide and/or lenalidomide therapy 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 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 and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide; 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; a FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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 must not have uncontrolled inter-current illness that would limit compliance with the study including: Uncontrolled hypertension Symptomatic congestive heart failure Unstable angina Uncontrolled cardiac arrhythmia Uncontrolled psychiatric illness or social situation Prior history of Stevens Johnson syndrome Patients must not have grade 2 or higher peripheral neuropathy Patients must not have an active, uncontrolled infection Female patients MUST NOT be pregnant or breastfeeding; the use of these drugs in this patient population is ABSOLUTELY CONTRAINDICATED; for women of childbearing potential, a negative serum pregnancy test is required within 10-14 days prior to randomization; for female patients of childbearing potential a negative serum pregnancy test must be repeated within 24 hours prior to initiation of treatment, weekly for the first 4 weeks of treatment and then every 4 weeks if the patient's periods are regular or every 2 weeks if they are not; women of childbearing potential must be willing to refrain from sexual intercourse or must be willing to employ a dual method of contraception, one of which is highly effective [intrauterine device (IUD), birth control pills, tubal ligation or partner's vasectomy] and another additional method (condom, diaphragm or cervical cap) starting 4 weeks prior to and while taking lenalidomide and thalidomide and for four weeks after discontinuing this therapy; the male partner of a female using a single form of birth control should use a condom regardless of his vasectomy status Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse with any woman, while taking lenalidomide and thalidomide and for 4 weeks after stopping treatment Patients must not have had a second active malignancy requiring treatment within the last 2 years, with the exceptions of basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix

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 |
| --- | --- |
| Active Comparator: Arm I (thalidomide)<br>INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO QD on days 1-4, and thalidomide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive thalidomide PO QD and continue in the absence of disease progression. | Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Melphalan<br>* Given PO<br>* Other names: WR-19813;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Thalidomide<br>* Given PO<br>* Other names: Thalomid;|
| Experimental: Arm II (lenalidomide)<br>INDUCTION THERAPY: Patients receive melphalan PO and prednisone PO QD on days 1-4, and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive lenalidomide PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression. | Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Drug: Melphalan<br>* Given PO<br>* Other names: WR-19813;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as the time from randomization to the earlier of progression or death of any cause. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as time from randomization to death from any cause. | Assessed every 3 months for 2 years, then every 6 months for 3 years, then annually for 10 years from the date of randomization. | 
| Very Good Partial Response (VGPR) Rate | Response evaluation was based on the International Myeloma Working Group (IMWG) response criteria. VGPR rate was defined as patients achieving at least VGPR which include patients who achieving complete response (CR) and VGPR. CR refers to patients who have complete disappearance of an M-protein and no evidence of myeloma in the bone marrow. VGPR refers to patients who meet the following criteria: Serum and urine M-component detectable by immunofixation but not on electrophoresis; Or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 hours; If the serum and urine M protein are unmeasurable and the immunoglobulin free light chain parameter is being used to measure response, a ≥ 90% decrease in the difference between involved and uninvolved free light chain (FLC) levels is required in place of the M protein criteria. | Assessed every cycle (1 cycle=28 days) for the first 12 cycles, and then every 2 cycles while on treatment. Post treatment assessed every 3 months < 2 years from study entry, every 6 months if 2-5 years, every 12 months if 6-10 years from study entry. | 
| Change in Functional Assessment of Cancer Therapy-Neurotoxicity Trial Outcome Index (FACT-Ntx TOI) Score From Baseline to Cycle 12 | A combined scale was used to assess the quality of life (QOL) comprising of the well established and validated functional well-being (FWB) and physical well-being (PWB) components of FACT-G version 4 (14 questions), which will address the physical and functional well-being of multiple myeloma patients plus the FACT-neurotoxicity (NTX, 11 questions), which will evaluate symptoms of neurotoxicity. This pooled scale is referred to as the FACT Ntx TOI. The FACT-Ntx TOI has 25 items and the score ranges from 0 (worst possible outcome) to 100 (best possible outcome). | Administered at registration, the beginning of cycle 7 d1, the end of cycle 12 d28, then at the end of cycle 18, 24, and 38 d28. For patients who discontinue treatment early, assessed at time of discontinuation and at the next quarterly follow-up visit. |