Pharmacogenomic Study in Myeloma Patients Treated With Melphalan-prednisone-thalidomide or Lenalidomide-dexamethasone

This protocol (in patients aged 65 and over suffering from previously untreated multiple myeloma), represents the first worldwide, pharmacogenomic study on this scale in terms of the number of patients analyzed and the implemented molecular diagnostics resources. The goal is to be able to identify patients who will best respond to the study treatments or experience the fewest associated side effects and improve prognosis, in order to optimize care management in multiple myeloma.

To this end, the study seeks to predict the following parameters in these patients:

• The treatment response and occurrence of adverse events linked to a lenalidomide-dexamethasone combination or a melphalan-prednisone-thalidomide combination.
• Progression-free survival and overall survival.

Prediction of the treatment response and the occurrence of adverse effects will be based on:

• An analysis of constitutive genetic traits linked to single nucleotide polymorphisms and DNA copy number variations.
• An analysis of changes in the tumor's genotype (change in the DNA copy number) and phenotype (altered gene and micro-RNA expression).

Prediction of progression-free survival and overall survival will be based on an analysis of changes in the tumor's genotype and phenotype.

• Drug: melphalan-prednisone-thalidomide
• Drug: lenalidomide-dexamethasone

• Active Comparator: melphalan-prednisone-thalidomide
  Intervention: Drug: melphalan-prednisone-thalidomide
• Active Comparator: lenalidomide-dexamethasone
  Intervention: Drug: lenalidomide-dexamethasone

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form
• Age ≥ 65 years at the time of signing consent

• Previously untreated, symptomatic multiple myeloma as defined by the 3 criteria below: MM diagnostic criteria (all 3 required)

  • Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a biopsy-proven plasmacytoma
  • Monoclonal protein present in the serum and/or urine

  • Myeloma-related organ dysfunction (at least one of the following):

    • Calcium elevation in the blood (serum calcium > 10.5 mg/l or upper limit of normal)
    • Renal insufficiency (serum creatinine > 2 mg/dl)
    • Anemia (hemoglobin < 10 g/dl or 2 g < normal)
    • Lytic bone lesions or osteoporosis

• have measurable disease by protein electrophoresis analyses as defined by the following:

  • IgG multiple myeloma: Serum monoclonal paraprotein (M-protein)level ≥ 1.0 g/dL or urine M-protein level ≥ 200 mg/24 h
  • IgA multiple myeloma: Serum M-protein level ³ 0.5 mg/dL or urine M-protein level³ 200 mg/24 h
  • IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dL or urine Mprotein level ≥ 200 mg/24h
  • IgD multiple myeloma: Serum M-protein level ≥ 0.05 g/dL or urine M-protein level ≥ 200 mg/24h
  • Light chain multiple myeloma: Serum M-protein level ≥ 1.0 g/dL or urine Mprotein level ≥ 200 mg/24 hours
• ECOG performance status of 0, 1, or 2
• Treated by either melphalan-prednisone-thalidomide or lenalidomide- dexamethasone

Exclusion Criteria:

• Previous treatment with antimyeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid [i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 28 days (4 weeks) of randomization]
• Any serious medical condition that places the patient at an unacceptable risk if he or she participates in this study

• Any of the following laboratory abnormalities :

  • Absolute neutrophil count (ANC) < 1,000 cells/µL (1.0 x 109/L)
  • Platelet count < 50,000 cells/µL (50 x 109/L) for patients in whom < 50% of bone marrow nucleated cells are plasma cells; but platelet count < 30,000/µL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells
  • Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)
  • Creatinine clearance ≤ 30 mL/min (Cockroft-Gault calculation)

• Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for ≥ 3 years. Exceptions include the following:

  • Basal cell carcinoma of the skin
  • Squamous cell carcinoma of the skin
  • Carcinoma in situ of the cervix
  • Carcinoma in situ of the breast
  • Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
• Patients who have are unable or unwilling to undergo antithrombotic therapy
• Peripheral neuropathy of > grade 2 severity
• Known HIV positivity or active infectious hepatitis, type A, B, or C.
• Primary AL amyloidosis and myeloma complicated by amyloidosis.
• Renal failure requiring dialysis