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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as melphalan, prednisone, and lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of melphalan and lenalidomide when given together with prednisone and to see how well they work in treating patients with newly diagnosed multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of melphalan and lenalidomide in combination with prednisone in patients with newly diagnosed multiple myeloma. Determine the response rate in patients treated with this regimen. Secondary Determine the toxicity of this regimen in these patients. OUTLINE: This is a dose-escalation study of melphalan and lenalidomide followed by a phase II study. Phase I: Patients receive oral melphalan and oral prednisone daily on days 1-4. Patients also receive oral lenalidomide daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of melphalan and lenalidomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. * Phase II: Patients receive oral melphalan and oral lenalidomide as in phase I at the MTD. Patients also receive oral prednisone as in phase I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 3 years.

Official Title
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Phase I/II Trial of Melphalan, Prednisone Plus Lenalidomide in Patients With Newly Diagnosed Multiple Myeloma Who Are Not Candidates for Stem Cell Transplant

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: lenalidomide
* Drug: melphalan
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of multiple myeloma Newly diagnosed disease Requires treatment, in the judgment of the treating physician Not a candidate for (or patient declines) autologous stem cell transplantation Meets 1 of the following criteria: Measurable disease, defined by any of the following: Serum monoclonal protein ≥ 1 g/dL Urine protein monoclonal light chain ≥ 200 mg/24 hours by electrophoresis Measurable serum free light chains ≥ 10 mg/dL, kappa or lambda, AND κ/λ ratio is abnormal (if serum and urine are not measurable as defined above) Evaluable disease, defined as monoclonal bone marrow plasmacytosis ≥ 30% PATIENT CHARACTERISTICS: ECOG performance status 0-3 Life expectancy > 3 months ANC ≥ 1,500/mm³ Bilirubin ≤ 2.0 mg/dL Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) AST ≤ 3 times ULN Creatinine ≤ 3.0 mg/dL Platelet count ≥ 100,000/mm³ Not pregnant or nursing Negative pregnancy test Fertile patients must use 2 effective methods of contraception, including ≥ 1 highly effective method, ≥ 4 weeks before and during study treatment No uncontrolled infection No peripheral neuropathy ≥ grade 2 No serious medical condition, laboratory abnormality, or psychiatric illness that would preclude study compliance No other active malignancy except for nonmelanoma skin cancer or carcinoma in situ - Prior malignancy allowed if treated with curative intent and is free of disease for a period appropriate for that cancer No known hypersensitivity to thalidomide No known HIV positivity No infectious hepatitis A, B or C No history of deep vein thrombosis or other medical condition requiring the use of warfarin Able to take daily prophylactic acetylsalicylic acid (81 or 325 mg) PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior radiotherapy for treatment of multiple myeloma No prior lenalidomide No other concurrent anticancer agents or treatments No concurrent steroids except prednisone ≤ 20 mg/day (or the equivalent) for concurrent illness or adrenal replacement therapy No other concurrent investigational therapy or agent for treatment of multiple myeloma No concurrent warfarin

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Lenalidomide, Melphalan, Prednisone)<br>Intervention: Drug: lenalidomide Dose determined by Phase I treatment schedule. Taken orally days 1-21 every 28 days until progression Intervention: Drug: melphalan Dose determined by Phase I treatment schedule. Taken orally days 1-4 every 28 days until progression Intervention: Drug: prednisone 60mg/m^2, orally days 1-4 every 28 days until progression | Drug: lenalidomide<br>* Phase I - dose escalating: 5mg level -1, 10mg level 0, 10mg level 1, 15mg level 2, 20mg level 3, 25mg level 4, orally days 1-21 every 28 days until progression Phase II - 10 mg orally days 1-21 every 28 days until progression<br>Drug: melphalan<br>* Phase I - dose escalating: 5mg/m^2 dose level -1, 5 mg/m^2 dose level 0, 8 mg/m^2 dose level 1 - 4, daily x 4 orally days every 28 days until progression Phase II - 5mg/m^2 orally days 1-4 every 28 days until progression<br>Drug: prednisone<br>* 60mg/m^2, orally days 1-4 every 28 days until progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Overall Confirmed Response | Response that was confirmed on 2 consecutive evaluations.> Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixations, normalization of Free Light Chain (FLC) ratio and <=5% plasma cells in bone marrow> Very Good Partial Response (VGPR): >=90% reduction in serum M-spike, Urine M-spike <100mg per 24 hours> Partial Response (PR): >=50% reduction in serum M-spike, Urine M-spike >=90% reduction or < 200mg per 24 hours, or >=50% decrease in difference between involved and uninvolved FLC levels or 50% decrease in bone marrow plasma cells | Every cycle during treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: Serum M-component (absolute increase >= 0.5g/dl) Urine M-component (absolute increase >= 200mg/24hour Difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl Bone marrow plasma cell percentage (absolute increase of >=10%) | registration to progressive disease (up to 3 years) | 
| Overall Survival (OS) at 3 Years | OS was defined as the time from registration to death due to any cause. Patients who were alive were censored at date of last follow-up. The overall survival at 3 years (a percentage) is reported below. | registration to death (up to 3 years) | 
| Duration of Response (DOR) | Duration of response was calculated from documentation of first response to date of progression in the subset of patients who responded. Patients without progression were censored at the date of last tumor evaluation. | from first response to progression or death (up to 3 years) | 
| Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) | The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. | Every cycle during treatment up to 3 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