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

• Progression-free survival [ Time Frame: From randomization to the earlier of progression or death of any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
  Tested using one-sided 0.95 confidence limits.
• Mean change of the FACT-Ntx TOI score (QOL) [ Time Frame: From registration to course 24 ] [ Designated as safety issue: No ]
  Differences between treatment arms are detected by 2-sample t-test, with 80% power, at a two-sided 0.05 significance level.

• Progression-free survival [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]

• Response rates (CR+VGPR+PR) [ Time Frame: Assessed up to 10 years ] [ Designated as safety issue: No ]
  Compared between arms using the Fisher's exact test.
• Overall survival [ Time Frame: Assessed up to 10 years ] [ Designated as safety issue: No ]
  Estimated using the method of Kaplan and Meier. Compared between the two arms using two-sided stratified log-rank test.
• Toxicity in terms of rates of grade 3 or higher SAE‟s on the two arms, graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. [ Time Frame: Assessed up to 10 years ] [ Designated as safety issue: Yes ]
  Compared using the Fisher's exact test.
• Impact of the differential treatment survival on QOL measured by FACT-Ntx TOI [ Time Frame: Assessed up to course 38 ] [ Designated as safety issue: No ]

• Response rates and depth of response comparison [ Designated as safety issue: No ]
• Toxicity [ Designated as safety issue: Yes ]
• Quality-of-life (QOL) change comparison of arms measured by FACT-Ntx TOI from baseline to course 24 [ Designated as safety issue: No ]
• Differential treatment response on QOL measured by FACT-Ntx TOI from baseline to course 38 [ Designated as safety issue: No ]
• TC classification validation of myeloma as a prognostic tool using gene expression profiling [ Designated as safety issue: No ]

This randomized phase III trial is studying giving melphalan and prednisone together with thalidomide to see how well it works compared with giving 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 or by stopping them from dividing. 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.

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 both arms. II. To compare response rates and depth of response in these patients. III. To compare the incidence of toxicities in these patients. IV. To validate the TC classification 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 FACT-Ntx TOI from baseline to the end of course 24 (maintenance therapy).

II. To examine the impact of differential treatment responses on QOL based on the FACT-Ntx TOI up to course 38.

III. To obtain prospective data on myeloma specific QOL attributes.

OUTLINE: This is a multicenter study. Patients are stratified according to ISS stage (I-II vs III) and age (< 65 vs ≥ 65). Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive oral melphalan and oral prednisone once daily on days 1-4, and oral thalidomide once daily 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 oral thalidomide once daily and continue in the absence of disease progression.

ARM II:

INDUCTION THERAPY: Patients receive oral melphalan and oral prednisone once daily on days 1-4, and oral lenalidomide 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 oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression.

Quality of life is assessed at baseline and periodically during treatment.

Peripheral blood and bone marrow samples are collected at baseline for gene expression profiling analysis.

After completion of study treatment, patients will be followed periodically for 10 years.

• Stage I Multiple Myeloma
• Stage II Multiple Myeloma
• Stage III Multiple Myeloma

• Drug: melphalan
  Given orally
  Other Names:

  • Alkeran
  • CB-3025
  • L-PAM
  • L-phenylalanine mustard
  • L-Sarcolysin
• Drug: prednisone
  Given orally
  Other Names:

  • DeCortin
  • Deltra
• Drug: thalidomide
  Given orally
  Other Names:

  • Kevadon
  • Synovir
  • THAL
  • Thalomid
• Drug: lenalidomide
  Given orally
  Other Names:

  • CC-5013
  • IMiD-1
  • Revlimid

• Active Comparator: Arm I (thalidomide)
  Patients receive oral melphalan and oral prednisone once daily on days 1-4, and oral thalidomide once daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral thalidomide once daily and continue in the absence of disease progression.
  Interventions:

  • Drug: melphalan
  • Drug: prednisone
  • Drug: thalidomide
• Experimental: Arm II (lenalidomide)
  Patients receive oral melphalan and oral prednisone once daily on days 1-4, and oral lenalidomide on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression.
  Interventions:

  • Drug: melphalan
  • Drug: prednisone
  • Drug: lenalidomide

Inclusion Criteria:

• Newly diagnosed multiple myeloma (MM), meeting the following criteria:

  • Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma

  • Symptomatic disease with evidence of end-organ damage at initial diagnosis that prompted the initiation of therapy, including ≥ 1 of the following:

    • Anemia
    • Hypercalcemia
    • Bone disease (lytic bone lesions or pathologic fracture)
    • Renal dysfunction

• No smoldering MM, defined by all of the following:

  • Serum monoclonal protein ≥ 3 g/dL
  • Bone marrow plasma cells ≥ 10% or greater
  • Absence of anemia, hypercalcemia, lytic bone lesions, or renal dysfunction

• No monoclonal gammopathy of undetermined significance, defined by all of the following:

  • Serum monoclonal protein < 3 g/dL
  • Bone marrow plasma cells ≤ 10%
  • Absence of anemia, hypercalcemia, lytic bone lesions, or renal dysfunction
• Previously untreated for MM
• Patients 18 to 64 years old must not be a candidate for autologous stem cell transplantation or have declined transplantation or other alternative treatment
• ECOG performance status 0-2
• Hemoglobin > 7 g/dL
• Platelet count > 75,000/mm³
• ANC > 1,000/mm³
• Creatinine < 2.5 mg/dL AND creatinine clearance (measured or calculated) ≥ 60 mL/min
• Direct bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2.5 times upper limit of normal

• No uncontrolled intercurrent illness that would limit compliance with the study including, but not limited to, any of the following:

  • Uncontrolled hypertension
  • Symptomatic congestive heart failure
  • Unstable angina
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled psychiatric illness or social situation
  • Prior history of Stevens Johnson syndrome
• No peripheral neuropathy ≥ grade 2
• No active uncontrolled infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-barrier contraception 4 weeks prior to, during, and 4 weeks after completion of study treatment
• Must be able to take prophylactic aspirin 325mg/day or low-molecular weight heparin or Coumadin
• No second active malignancy requiring treatment within the past 2 years, except for basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix
• Concurrent localized radiation therapy is allowed for pain control at the physician's discretion

• No prior treatment for myeloma except for either of the following:

  • Prednisone or dexamethasone treatment for myeloma for a duration of less than 4 weeks
  • Prednisone or dexamethasone in combination with thalidomide or lenalidomide for a duration of less than 2 weeks total
• Concurrent bisphosphonates or growth factors (i.e., erythropoietin) for MM allowed