Velcade (Bortezomib) Consolidation After Transplant

Study Overview
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Brief Summary
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The purpose of this study is to determine if bortezomib when added to consolidation treatment with thalidomide and prednisolone leads to an improved response in patients with multiple myeloma who have undergone autologous stem cell transplant and initial treatment with bortezomib, cyclophosphamide, and dexamethasone.

Detailed Description
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This is an open-label (patients will know the identity of study treatments), randomized (patients will be assigned by chance to different treatments) study of bortezomib administered as consolidation therapy (therapy given once a remission is achieved) with thalidomide and prednisolone versus thalidomide and prednisolone alone in previously untreated patients with multiple myeloma. Multiple myeloma is a cancer of your plasma cells, a type of white blood cell present in your bone marrow. Patients in this study will receive initial therapy with bortezomib, cyclophosphamide, and dexamethasone (referred to as VCD induction therapy) and will undergo autologous stem cell transplant (ASCT) (a procedure where patients receive an infusion of immature blood cells [stem cells] from their own body to replenish the body's supply of healthy blood-forming cells) before randomization to one of two treatments: Treatment A (thalidomide for up to 12 months or until disease progression and prednisolone on alternate days continued indefinitely or until disease progression) or Treatment B (bortezomib for 32 weeks in addition to thalidomide up to 12 months or until disease progression and prednisolone on alternate days, continued indefinitely or until disease progression. Throughout the study, the patient's response to therapy will be assessed according to protocol-defined efficacy evaluations and by implementing defined disease response criteria (International Myeloma Working Group [IMWG] criteria). Safety will be evaluated throughout the study. Follow up for progression-free survival (PFS) and overall survival (OS) will be conducted from time of randomization to 3 years post-randomization. Two interim analyses are planned. The final analysis will be conducted after all patients have completed 12-month consolidation treatment phase or discontinued. The primary endpoint of number and percent of patients with complete response and very good partial response defined by IMWG criteria for multiple myeloma will be examined in the interim and final analyses after approximately 12 months of consolidation therapy. At the completion of the study, updated analyses of PFS and OS will be performed.

Official Title
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An Open-label, Randomised Trial of Bortezomib Consolidation (With Thalidomide and Prednisolone) Vs Thalidomide and Prednisolone Alone in Previously Untreated Subjects With Multiple Myeloma After Receiving Bortezomib, Cyclophosphamide, Dexamethasone (VCD) Induction and Autologous Stem Cell Transplant

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Thalidomide
* Drug: Bortezomib
* Drug: Cyclophosphamide
* Drug: Dexamethasone
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Previously diagnosed with multiple myeloma based on international myeloma working group (IMWG) criteria.and meet all of the following; Serum M-protein greater than or equal to (>=) 1 gram per deciliter (g/dL) (>=10 gram per liter); Urine M-protein >=200 milligram (mg) per 24 hour and Serum Free Light chain (FLC) assay: Involved FLC Level >=10 mg/dL (>=100 mg/L) provided serum FLC ratio is normal Meet the pretreatment laboratory criteria as specified in the study protocol at and within 21 days before baseline (Day 1 of Cycle 1, before bortezomib administration for induction). Have ECOG status 0-2. Men and women must practice an appropriate method of birth control as specified in the study protocol from signing of the informed consent form though to the 12-month visit/early termination visit. Exclusion criteria: Has previously received treatment for multiple myeloma (including prior therapy with radiation or pulsed dexamethasone) as specified in the study protocol. Has a history of any other malignancy within 5 years before enrolment as specified in the study protocol. Has had major surgery as specified in the study protocol within 30 days before enrolment. Had a myocardial infarction within 6 months of enrolment or has New York Heart Association (NYHA) Class III or IV heart failure (or other clinically significant cardiac medical history as specified in the study protocol). Has any condition that, in the opinion of the investigator, would make participation not be in the best interest (eg, compromise the well-being) of the patient or that could prevent, limit, or confound the protocol-specified assessments.

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: Bortezomib + Cyclophosphamide + Dexamethasone [VCD Induction]<br>Bortezomib (Velcade) 1.3 milligram per square meter (mg/m^2) subcutaneously (SC) on Days 1, 4, 8, and 11; cyclophosphamide 300 mg/m^2 orally on Days 1, 8, and 15; and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11, and 12 in three 21-day treatment cycles. Participants who completed induction phase entered into the consolidation treatment phase. | Drug: Bortezomib<br>* Bortezomib 1.3 milligram per square meter (mg/m^2) solution for injection subcutaneously (SC).<br>Drug: Cyclophosphamide<br>* Cyclophosphamide 300 mg/m^2 orally.<br>Drug: Dexamethasone<br>* Dexamethasone 20 mg orally.<br>|
| Experimental: Thalidomide + Prednisolone [TP Consolidation]<br>Thalidomide 100 mg orally, once daily until disease progression (up to maximum of 12 months) and prednisolone 50 mg orally, on every alternate day until disease progression. | Drug: Thalidomide<br>* Thalidomide 100 mg tablet, orally.<br>Drug: Prednisolone<br>* Prednisolone 50 mg orally.<br>|
| Experimental: Bortezomib + Thalidomide + Prednisolone [VTP Consolidation]<br>Bortezomib 1.3 mg/m^2 SC every 2 weeks for 32 weeks in addition to thalidomide 100 mg orally, once daily for a maximum of 12 months or until disease progression and prednisolone 50 mg orally, on every alternate day until disease progression. | Drug: Thalidomide<br>* Thalidomide 100 mg tablet, orally.<br>Drug: Bortezomib<br>* Bortezomib 1.3 milligram per square meter (mg/m^2) solution for injection subcutaneously (SC).<br>Drug: Prednisolone<br>* Prednisolone 50 mg orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Consolidation Phase: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) at Month 12 | CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and less than (<) 5 percent plasma cells in bone marrow. VGPR as per IMWG criteria is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90 percent or greater reduction in serum M-protein plus urine M-protein level <100 milligram (mg) per 24 hours. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Consolidation Phase: Percentage of Participants With Complete Response (CR) at Months 3, 6, 9 and 12 | CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5 percent plasma cells in bone marrow. | Months 3, 6, 9 and 12 | 
| Consolidation Phase: Percentage of Participants With Stringent Complete Response (sCR) at Months 3, 6, 9 and 12 | sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5 percent plasma cells in bone marrow. | Months 3, 6, 9 and 12 | 
| Progression Free Survival (PFS) | PFS, calculated as the time between randomization to disease progression or death (regardless of cause), whichever occurred first. Progressive disease as per IMWG criteria: increase of >= 25 percent from lowest response level in Serum M-component and/or (the absolute increase must be >=0.5 gram per deciliter [g/dL]) Urine M-component and/or (the absolute increase must be >=200 mg/24 hour. Only in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: the absolute percent must be >=10 percent. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.65 millimole per liter (mmol/L) that can be attributed solely to the plasma cell proliferative disorder. | Baseline until progressive disease (up to 5 years) | 
| Disease-free Survival (DFS) | DFS, defined as the duration from the start of CR to the time of relapse from CR. DFS applied only to participants in CR. CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5 percent plasma cells in bone marrow. Relapse from CR: reappearance of serum or urine M-protein by immunofixation or electrophoresis; development of >= 5 percent plasma cells in the bone marrow; appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcaemia). | Up to 5 years | 
| Overall Survival (OS) | OS was defined as the time between randomization and death. Death of a participant regardless of the cause was considered as an event. | Up to 5 years | 
| Consolidation Phase: Change From Baseline in AQOL-6D Scores at the End of the Consolidation Phase | The assessment of quality of life-6D (AQoL-6D) is a multi-attribute health-related quality of life instrument (QoL). It comprises dimension scores for independent living, relationships, mental health, coping, pain, senses, and utility score for AQol-6D. Each scale ranges between 1 (best QoL) and -0.04 (worst possible QoL). | Baseline, Month 12 | 
| Consolidation Phase: Change From Baseline in FACT/GOG-NTX Total Score at the End of the Consolidation Phase | Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) consists of 10 items and evaluates symptoms and concerns associated specifically with chemotherapy-induced neuropathy. 1 FACT/GOG-NTX total score has a range of 0 to 108 with a higher score indicating better quality of life. | Baseline, Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Bortezomib, VELCADE, Consolidation therapy, Subcutaneous, Thalidomide, Prednisolone, Autologous stem cell transplant (ASCT), VELCADE, cyclophosphamide, dexamethasone (VCD) induction therapy