Study to Compare VMP With HDM Followed by VRD Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Phase III Study to Compare Bortezomib, Melphalan, Prednisone (VMP) With High Dose Melphalan Followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bortezomib, Melphalan, Prednisone (VMP)
* Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)
* Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: R1: 4 cycles Bortezomib, Melphalan, Prednisone (VMP)<br>All patients randomized to VMP treatment, will be treated with Bortezomib, Melphalan, Prednisone(VMP, 4 cycles) and will start intensification with VMP between 4 and 6 weeks after stem cell collection. | Drug: Bortezomib, Melphalan, Prednisone (VMP)<br>* Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11,22,25,29,32 Melphalan _ 9 mg/m² _ p.o. _ days 1-4 Prednisone _ 60 mg/m² _ p.o. _ days 1-4<br>|
| Experimental: R1: 1 (2) cycle(s) HDM<br>All patients randomized to intensification with High Dose Melphalan will start intensification with HDM (in hospitals with a policy of double intensification, patients will be randomized between VMP, 1 HDM and 2 HDM) between 4 and 6 weeks after stem cell collection. | Drug: 1 or 2 cycle(s) HDM (High Dose Melphalan)<br>* - Melphalan _ 100 mg/m² _ i.v. rapid infusion _ -3, -2* *Patients with renal insufficiency 100 mg/m2 only at day -3 If a patient is randomized to receive 2 x HDM a second course of High Dose Melphalan may be administered between 2 and 3 months after the first course when the patient achieved at least PR.<br>|
| No Intervention: R2: none<br>No consolidation, patients will continue to Lenalidomide maintenance. | |
| Experimental: R2: 2 cycles of VRD<br>In patients randomized to consolidation treatment, 2 cycles of Bortezomib, Lenalidomide,Dexamethasone (VRD) will start at 8 weeks after the end of the last course of VMP or HDM. | Drug: 2 cycles of Bortezomib, Lenalidomide, Dexamethasone (VRD)<br>* Bortezomib _ 1.3 mg/m2 _ i.v. rapid infusion _ days 1,4,8,11 Lenalidomide _ 25 mg _ p.o. _ days 1-21 Dexamethasone _ 20 mg _ p.o. _ days 1,2,4,5,8,9,11,12<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first). | For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first). | end of trial (last patient last visit) | 
| For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first | For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first | end of trial (last patient last visit) | 
| For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first | For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first | end of trial (last patient last visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive. | Overall survival measured from the time of registration /randomization R1/ randomization R2. Patients still alive or lost to follow up are censored at the date they were last known to be alive. | end of trial (last patient last visit) | 
| Toxicity | Toxicity | End of trial (last patient last visit) | 
| Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment. | Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment. | end of trial (last patient last visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma (Kahler's disease)