MMVAR - Velcade: Study of Velcade for the Treatment of Myeloma Patients After Autologous Transplantation
MMVAR - Velcade: Study of Velcade for the Treatment of Myeloma Patients After Autologous Transplantation
This is an international study in adult patients diagnosed with multiple myeloma who have
 already received at least one autologous stem cell transplantation and who have responded but
 later progressed, or relapsed, at least one year after transplantation.

 Eligible patients will be randomly assigned to one of two treatments: either Velcade plus
 Thalidomide plus Dexamethasone or Thalidomide plus Dexamethasone.

 Thalidomide and Velcade are two new agents that have recently become available for the
 treatment of multiple myeloma, especially in relapsed patients. This study therefore aims to
 test the hypothesis that the combination treatment with Velcade plus Thalidomide plus
 Dexamethasone will result in a longer time to progression (measure of time after the disease
 is treated until it starts to get worse) than Thalidomide plus Dexamethasone alone.
Primary Objectives:

 * Test the hypothesis that treatment with Velcade plus Thalidomide plus Dexamethasone in
 combination, will result in a longer time to progression (TTP) than Thalidomide plus
 Dexamethasone in subjects with relapsed or progressive myeloma after autologous
 transplantation.

 Secondary Objectives:

 * Compare the treatment groups for: overall survival; response rate (complete & partial &
 minimal) using standard criteria and treatment related complications.

 Study design and methodology:

 This is a prospective, randomized, parallel-group, open-label phase III, on an intention to
 treat, multicenter study. The main endpoint is time-to-failure (TTP=time to progression). The
 power is based on an initial assumption of a median TTP of 1.5 years in the experimental
 (Velcade) group and 1 year in the control group. The design of the study is group sequential.
 There will be 4 interim analyses and one final analysis. The study is designed to have a
 priori 90% power to detect the clinically relevant difference at completion of the study at
 0.025 level. Patients with multiple myeloma whose disease has either progressed or relapsed
 at least one year after one or two autologous transplantations will be enrolled. Prior to
 random assignment, subjects will be stratified on center and number of autologous
 transplants.Subjects will be randomly assigned to treatment in a 1: 1 allocation within each
 stratum to Velcade plus Thalidomide plus Dexamethasone (VTD) or Thalidomide plus
 Dexamethasone. Velcade 1.3 mg/m2 will be given as an i.v. bolus on Days 1, 4, 8 and 11
 followed by a 10-day rest period (Days 12 to 21) for 8 cycles (6 months) and then on Days 1,
 8, 15, and 22 followed by a 20-day rest period (Days 23 to 42) for 4 cycles (6 months). In
 both arms, Thalidomide will be given at 200 mg/day per os for one year and Dexamethasone 40
 mg/day per os four days every three weeks for one year.Treatment will continue until disease
 progression, or the occurrence of unacceptable treatment-related toxicity, or up to a total
 of 12 cycles of Velcade except for those subjects who have a continuing decrease in the
 levels of paraprotein after 12 cycles. These subjects may continue for as long as treatment
 is tolerated, and they continue to respond. If a subject has a CR, then treatment should
 continue at least 2 cycles after the objective response is confirmed. For subjects with a PR
 or stable disease, treatment may continue after a maximum objective response is confirmed
 unless the subject experiences unacceptable treatment-related toxicity or the subject has
 completed 12 cycles of treatment. Disease assessment will occur at the start of each cycle.
 If a subject discontinues treatment without disease progression, disease assessment will be
 performed every 3 weeks for 48-weeks from the start of the first dose of study entry drug.
 Subjects who have not progressed at the end of 48-week follow up period will be assessed
 every 6 weeks until disease progression is documented
Inclusion Criteria:

 -  Male or female ≥18 years-of-age

 -  Multiple myeloma with evaluable disease

 -  Relapsing or having a progressive disease

 -  Karnofsky performance status > 50 %

 -  Life expectancy of at least 3 months

 -  Female of child-bearing potential must have a method of birth control and a negative
 serum or urine beta--human chorionic gonadotropin (β-HCG) pregnancy test at screening
 and all through the study

 -  Male must use contraception

 -  Voluntary written informed consent

 Exclusion Criteria:

 -  Non-secretory multiple myeloma

 -  Platelet count < 40,000 X 10^9/L

 -  Absolute neutrophil count <1.0 X 10^9/L

 -  Creatinine clearance <30 mL/minute

 -  Peripheral neuropathy >= Grade 2

 -  Seropositive for HIV, or active hepatitis A, B or C infection

 -  Pregnant or breastfeeding female

 -  Patient has hypersensitivity to bortezomib, boron or mannitol

 -  Other investigational drugs

 -  Serious medical or psychiatric illness

 -  Previous or concurrent malignancies at other sites

 -  Poorly controlled hypertension, uncontrolled or severe cardiovascular disease or
 uncontrolled diabetes mellitus