Study of Bortezomib and Dexamethasone With or Without Cyclophosphamide in Patients With Relapsed or Not Controllable Multiple Myeloma

• Time to progression (TTP) [ Time Frame: Up to progressive disease (PD) or death ] [ Designated as safety issue: No ]
  The TTP is the time from randomization to progressive disease, death or drop out without progression.
  
  

• Overall survival (OS) [ Time Frame: Up to PD or death ] [ Designated as safety issue: Yes ]
  The OS is the time from randomization to death from any cause.
  
  
• Progression free survival (PFS) [ Time Frame: Up to PD or death ] [ Designated as safety issue: No ]
  The PFS is the time from randomization to myeloma progression according to International Myeloma Working Group (IMWG) criteria or death from any cause.
  
  
• Best response rate [ Time Frame: Up to end of treatment (EOT) ] [ Designated as safety issue: No ]
  The proportion of patients with complete response (inclusive sCR) or partial response (inclusive very good partial response) at the EOT according to IMWG criteria. EOT is EOT is the visit 46 days after last dose of bortezomib.
  
  
• Change in Karnofsky Index [ Time Frame: Baseline to EOT ] [ Designated as safety issue: No ]
  The Karnofsky Performance Scale is an assessment tool intended to assist clinicians and caretakers in gauging a patient's functional status and ability to carry out activities of daily living. The score ranges from 0 (dead) to 100 (Normal, no complaints, no evidence of disease).
  
  
• Quality of life [ Time Frame: Day 1 of cyles 1, 4, and 8, EOT and at the follow-up ] [ Designated as safety issue: No ]
  The european quality (EQ-5D) questionnaire is a standardised instrument for use as a measure of health outcome. This questionnaire has Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression.
  
  
• Number of skeletal related events [ Time Frame: EOT and follow up ] [ Designated as safety issue: No ]
  Skeletal-related events includes pathological fracture (vertebral, non-vertebral, combined), radiotherapy, spinal cord compression, orthopaedic surgery due to a multiple myeloma associated bone lesion and hypercalcaemia.
  
  
• Number of necessity for dialysis due to renal insufficiency [ Time Frame: Up to PD or death ] [ Designated as safety issue: No ]
  
• Number of patients with adverse events [ Time Frame: EOT or until 30 days after last dose of study drug or until start of alternative anti-myeloma therapy ] [ Designated as safety issue: No ]
  

This is a prospective, multi-centre, randomized (the study drug is assigned by chance), controlled, open-label (all people involved in the study know the identity of the assigned drug), parallel (each group of patients will be treated at the same time) group phase III study to determine the efficacy of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide for primary refractory or relapsed myeloma patients (1st - 3rd relapse). The study will consist of screening period, which may last from day -14 until day -1 before application of the first dose of bortezomib (on cycle 1, day 1), treatment phase begins on cycle 1 day 1 and continues until completion or discontinuation of all study drugs and follow-up phase. All patients will be followed up after end of treatment regardless of their response. Eligible patients will be randomized in 1:1 ratio to receive either treatment arms (Group A: receiving bortezomib plus dexamethasone or Group B receiving bortezomib plus dexamethasone plus cyclophosphamide). Patients will receive up to eight 3-weeks treatment cycles, unless they experience either unacceptable toxicity or if the patients request to withdraw from the study. The maximum number of cycles is dependent on patient response and investigator's discretion. It is recommended that patients with a confirmed complete response (CR) receive 2 additional cycles beyond a confirmation. Patients who do not achieve a CR but a partial response will receive a total of 8 cycles. For patients achieving stable disease it is within the investigator's discretion to continue study treatment beyond 6 cycles, after discussion with the sponsor. After completion of treatment the patients will be followed up every 12 weeks for up to 72 weeks. If the study is still ongoing a further follow up period will be done every 26 weeks until study end, or until the patient reaches progressive disease or start of alternative anti-myeloma therapy, if earlier. In case progressive disease (PD) has already been established during the treatment phase the patients will not enter the follow-up phase. In case of PD or start of alternative anti-myeloma treatment before the end of study the follow-up phase will be discontinued for the patient but the date of death of the patient will be documented (if applicable) before the end of study.