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
A double randomized phase III study in patients with newly diagnosed multiple myeloma to compare progression free survival (PFS) following treatment with either Bortezomib, Melphalan, Prednisone (VMP) or High Dose Melphalan followed by either Bortezomib, Lenalidomide, Dexamethasone (VRD) consolidation or no consolidation treatment, and Lenalidomide maintenance.
HOVON
1,500 participants
Sep 2, 2013
Interventional
Conditions
Summary
Despite the use of high dose chemotherapy and ASCT (a procedure where the patient's own cells are collected, high dose therapy eliminates patient's cancer cells and patient's collected cells are reinfused), multiple myeloma remains incurable. This study aims to: 1.compare induction therapy employing either a chemotherapy regimen employing Bortezomib, melphalan and prednisolone or high dose therapy and ASCT 2. compare consolidation therapy employing either a chemotherapy regimen of bortezomib, lenalidomide and dexamethasone or no treatment 3. investigate maintenance therapy employing lenalidomide The study plans to treat 1500 patients worldwide. Trial details In this study you will receive the drug bortezomib delivered intravenously (i.v) on days 1,4,8 and 11, the drug cyclophosphamide delivered i.v on days 1 and 8, and dexamethasone delivered orally on days 1,2,4,5,8,9,11 and 12 of a 21 day treatment cycle you will then be allocated to receive either option in 1. and either option in 2. below 1. either 4 cycles of the drug bortezomib delivered intravenously (i.v) on days 1,4,8, 11, 22, 25, 29 and 32, the drug melphalan delivered orally on days 1 -4 and prednisolone delivered orally on days 1-4 of a 6 week cycle;or high dose melphalan i.v 3 and 2 days before reinfusion of patient's own stem cells 2. either 2 cycles of consolidation treatment consisting of the drug bortezomib delivered intravenously (i.v) on days 1,4,8 and 11, the drug lenalidomide delivered orally on days 1-21, and dexamethasone delivered orally on days 1,2,4,5,8,9,11 and 12 of a 28 day treatment cycle or no consolidation treatment All patients will then receive repeating 28 day cycles of daily oral lenalidomide therapy as long as the therapy continues to fight the myeloma. Your response to the treatment will be assessed at routine clinical visits using the usual clinical investigations that would monitor the status of your disease. Who is it for? This study is open to male or female patients aged 18-65 with a diagnosis of multiple myeloma. The full details of this study's inclusion and exclusion criteria can be found in the relevant sections within this record.
Eligibility
Inclusion Criteria14
- Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System (ISS)
- Measurable disease as defined by the presence of M-protein in serum or urine (serum Mprotein > 10 g/l or urine M-protein > 200 mg/24 hours), or abnormal free light chain ratio;
- Age 18-65 years inclusive;
- World Health Organisation (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.
- Randomization 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 10^6 CD34+ cells/kg (or according to national guidelines).
- Randomization 2
- Bilirubin and transaminases < 2.5 times the upper limit of normal values;
- Absolute Neutrophil Count >= 0.5 x 10^9/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 Criteria23
- Known intolerance of Boron;
- Systemic light chain (AL) amyloidosis;
- Primary Plasmacell Leukemia;
- Non-secretory multiple myeloma (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 (serum bilirubin >= 30 mmol/l or transaminases >= 2.5 times normal level), unless related to myeloma;
- Patients with glomerular filtration rate (GFR) <15 ml/min,
- Patients known to be Human immunodeficiency virus (HIV)-positive;
- Patients with active, uncontrolled infections;
- Patients with neuropathy, Common Toxicity Criteria for Adverse Events (CTCAE) 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.
- Randomization 1
- Severe pulmonary, neurologic, or psychiatric disease;
- CTCAE grade 3-4 polyneuropathy during Bortezomib treatment;
- Allogeneic Stem Cell Transplantation (Allo SCT) planned;
- Progressive disease.
- Randomization 2
- Progressive disease;
- Neuropathy, except CTCAE grade 1;
- CTCAE grade 3-4 polyneuropathy during Bortezomib treatment
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Interventions
Numbers 1-4 are different treatment stages of this trial. The trial is a two arm controlled randomised trial with two subsequent randomisations. 1. 3 by 21 day cycles of: Bortezomib (1.3mg/m^2 i.v days 1,4,8,11), cyclophosphamide (500mg/m^2 i.v days 1,8), dexamethasone (40mg orally days 1,2,4,5,8,9,11,12) then cyclophosphamide mobilisation and collection of stem cells (non randomised) 2. Starting 4-6 weeks after stem cell mobilisation, 4 by 42 day cycles of VMP (Bortezomib (1.3mg/m^2 i.v days 1,4,8,11, 22,25,29,32), Melphalan (9mg/m^2 orally days1-4), Prednisolone 60mg/m^2 orally days 1-4) 3. Beginning 8 weeks after the last dose of VMP (or High Dose Melphalan from corresponding arm below) consolidation therapy of VRD consisting of 2 by 28 day cycles of Bortezomib (1.3mg/m^2 i.v days 1,4,8,11), Lenalidomide (25mg orally on days 1-21), Dexamethasone (20mg orally on days 1,2,4,5,8,9,11,12). Lenalidomide maintenenace will start immdeiately after the completion of this phase of treatment. 4. Lenalidomide maintenance (non-randomised) 10mg daily orally days 1-28 until relapse or progression
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ACTRN12612000419864