Study phase: phase III

Study objective:

• Comparison of Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed autologous stem cell transplantation (ASCT)
• Comparison of Bortezomib, Lenalidomide, Dexamethasone(VRD) as consolidation versus no consolidation
• Comparison of single versus tandem high dose Melphalan with ASCT

Patient population: Patients with symptomatic multiple myeloma,previously untreated, ISS stages 1-3, age 18-65 years inclusive

Study design: Prospective, multicenter, intergroup, randomized

Duration of treatment: Expected duration of induction, stem cell collection and intensification is 6 - 9 months. Consolidation with VRD will last 2 months Maintenance therapy with Lenalidomide will be given until relapse. All patients will be followed until 10 years after registration.

Inclusion Criteria:

• Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS (see appendix A), i.e. at least one of the CRAB criteria should be present;
• Measurable disease as defined by the presence of M-protein in serum or urine (serum M-protein> 10 g/l or urine M-protein > 200 mg/24 hours), or abnormal free light chain ratio;
• Age 18-65 years inclusive;
• WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by comorbid conditions);
• Negative pregnancy test at inclusion if applicable;
• Written informed consent.

Inclusion for randomisation 1:

• WHO performance 0-2;
• Bilirubin and transaminases < 2.5 times the upper limit of normal values;
• A suitable stem cell graft containing at least 4 x 106 CD34+ cells/kg (or according to national guidelines).

Inclusion for randomisation 2:

• Bilirubin and transaminases < 2.5 times the upper limit of normal values;
• ANC >= 0.5 x 109/l and platelets > 20 x 10^9/l;
• Patient is able to adhere to the requirements of the Lenalidomide Pregnancy Prevention Risk Management Plan.

Exclusion Criteria:

• Known intolerance of Boron;
• Systemic AL amyloidosis;
• Primary Plasmacell Leukemia;
• Non-secretory MM;
• Previous chemotherapy or radiotherapy except local radiotherapy in case of local myeloma progression or corticosteroids maximum 5 days for symptom control;
• Severe cardiac dysfunction (NYHA classification II-IV);
• Significant hepatic dysfunction, unless related to myeloma;
• Patients with GFR <15 ml/min,
• Patients known to be HIV-positive;
• Patients with active, uncontrolled infections;
• Patients with neuropathy, CTC grade 2 or higher;
• Patients with a history of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
• Patients who are not willing or capable to use adequate contraception during the therapy (all men, all pre-menopausal women);
• Lactating women.

Exclusion for randomisation 1:

• Severe pulmonary, neurologic, or psychiatric disease;
• CTCAE grade 3-4 polyneuropathy during Bortezomib treatment;
• Allogeneic Stem Cell Transplantation (Allo SCT) planned;
• Progressive disease.'

Exclusion for randomisation 2:

• Progressive disease;
• Neuropathy, except CTCAE grade 1;
• CTCAE grade 3-4 polyneuropathy during Bortezomib treatment.