A Phase 2, Multicentre, Randomised, Open-Label, Parallel Group Study to Evaluate the Effect of VELCADE on Myeloma Related Bone Disease

This is a randomized, open-label (all people involved know the identity of the intervention), multicenter, multi-country parallel group study (each group of patients will be treated at the same time) in patients with Multiple Myeloma (MMY) who have received high dose chemotherapy and autologous stem cell transplantation for primary treatment of MMY (single- or double-transplant). The purpose of the study is to assess the effect of bortezomib on myeloma-related bone disease by analyzing bone mineral density. Approximately 80% of patients with MMY may experience myeloma-related bone disease. Myeloma-related bone disease may cause skeletal complications, including bone pain, bone lesions, abnormal fractures and super-elevated calcium concentrations in the blood. This study is investigating the safety and efficacy of an experimental drug, bortezomib, to consolidate the response to the primary treatment compared to no such consolidation treatment. The analyses in this study will be exploratory in nature, since the study will not address any pre-defined statements but is designed to generate valid hypotheses on safety and efficacy issues. Bortezomib is currently marketed for the treatment of different types of cancer including MMY. Bortezomib has been shown to promote bone formation and increase the number of bone-regenerating cells in preliminary studies. In the present study, the effect of bortezomib on bone formation will be assessed by dual energy x-ray absorptiometry (DXA) measuring bone mineral density, which is a measure for the quality of the bone structures. Several bone markers will be measured on serum samples. Bone markers are indicators of the bone activity. Patients will be evaluated for eligibility within a 14-day screening period, after providing written informed consent. Eligible patients will then be randomised to either bortezomib or observation alone. Baseline efficacy and safety assessments should be available on Cycle 1 Day 1 prior to administration of study medication. Randomization will be stratified by bisphosphonate treatment (use or not) at baseline and age (65 years or more versus less than 65 years). The treatment period is defined as the time the patient is actively receiving study treatment. Patients in the bortezomib arm will receive treatment of bortezomib for a total of 4 cycles or until start of alternative MMY treatment if earlier. Each cycle will consist of 5 weeks treatment. Subjects in the treatment group will receive bortezomib 1.6 mg/m2 on Days 1, 8, 15, and 22 of each cycle followed by a 13-day rest period (Days 23 to 35). Bisphosphonate therapy can be administered as medically indicated and according to local practice. Patients are to attend study center visits on Days 1, 8, 15, and 22 of each treatment cycle or at Days 1, 36, 71, and 106 in the observation arm and at end of treatment (EOT) Visit. During these visits, different evaluations will be conducted to follow treatment safety: symptom directed physical examination, vital signs and laboratory tests. In addition, at Day 1 of Cycle 3 (prior to dosing) or Day 71 in the observation arm, patients will be assessed for disease progression or relapse by measurements of M-protein in serum and urine. If needed, absence of M-protein in serum and urine will be confirmed by immunofixation. Additional evaluations may be performed to document patient's clinical status and ability to tolerate additional therapy as clinically indicated. All patients will be followed for a total of 24 months since baseline. After end of the treatment phase, there will be a long-term follow-up period with visits at 4, 6, 12 and 18 months after the EOT Visit. In case the patient started alternative MMY treatment before completing the 18 months of follow-up, study assessments will stop, except for QoL assessments, which are to be continued up to 18 months of follow-up, and for a long-term follow-up for survival, which will be collected every 6 months by either a telephone call or a visit to the study site. The follow-up for survival will continue for all patients until the last patient has completed follow-up. In addition to scheduled visits, patients may have additional visits as clinically indicated. Every patient who was randomized should enter the long-term follow-up phase. Assessment of progressive disease (PD) or relapse from complete response (CR) should be performed according to the International Myeloma Working Group (IMWG) 2009 criteria. Changes in serum and urine M-protein (monoclonal paraprotein) levels will be confirmed by immunofixation in patients without measurable serum and urine M-protein levels. Karnofsky performance status will also be assessed. Safety will be assessed by monitoring of adverse events, physical examination (including neurological/peripheral neurological examinations), vital signs measurements and clinical laboratory tests. A total of two exploratory analyses will be performed for the present study: The first analysis (main analysis) will be presented after completion of the EOT Visit (24-weeks data). The second analysis will be the analysis at the end of the study on 18 months follow-up data. Patients in the bortezomib arm will receive treatment of bortezomib 1.6 mg/m² as a bolus infusion on Days 1, 8, 15, and 22 every 5 weeks for a total of 4 cycles