Velcade,Thalidomide, and Dexamethasone Versus Velcade and Dexamethasone Versus Velcade, Melphalan, and Prednisone

Study Overview
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Brief Summary
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This is a randomized, open label, multicenter clinical trial to compare the efficacy and safety of Velcade (bortezomib) and dexamethasone versus Velcade, thalidomide, and dexamethasone versus Velcade, melphalan, and prednisone in patients with previously untreated multiple myeloma not considered candidates for high-dose chemotherapy and autologous stem cell transplantation.

Official Title
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Randomized Phase 3b Study of Three Treatment Regimens in Subjects With Previously Untreated Multiple Myeloma Who Are Not Considered Candidates for High-Dose Chemotherapy and Autologous Stem Cell Transplantation: VELCADE, Thalidomide, and Dexamethasone Versus VELCADE and Dexamethasone Versus VELCADE, Melphalan, and Prednisone

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Melphalan
* Drug: Prednisone
* Drug: Thalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18 years of age or older Not a candidate for high-dose chemotherapy and stem cell transplantation (HDT/SCT) due to age, presence of important comorbid condition(s) likely to have a negative impact on tolerability of HDT-SCT, or subject preference. A Karnofsky Performance Status score of ≥50% Symptomatic multiple myeloma or asymptomatic multiple myeloma with related organ or tissue damage. Asymptomatic multiple myeloma-related organ or tissue damage can include presence of an asymptomatic lytic bone lesion or plasmacytoma, the presence of anemia (hemoglobin <10 g/dL), renal function impairment (serum creatinine > upper limit of normal [ULN]) or hypercalcemia (serum calcium >ULN). Must have measurable disease requiring systemic therapy. Measurable disease is defined by at least 1 of the following criteria: Quantifiable serum M-protein value (>1 g/dL of immunoglobulin (Ig)G or IgM M-protein, >0.5g/dL of IgA M-protein, >0.5 g/dL of IgD M-protein) Urine light-chain excretion ≥200 mg/24 hours Voluntary written informed consent must be given before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. Exclusion Criteria: Diagnosis of smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of lytic bone lesions. MGUS is defined by presence of serum monoclonal protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the monoclonal protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less. Diagnosis of Waldenström's disease or other conditions in which immunoglobulin M (IgM) M-protein is present in the absence of a clonal plasma cell infiltration or lytic bone lesions. Previously or currently treated with any systemic therapy for multiple myeloma. Prior treatment of hypercalcemia or spinal cord compression with corticosteroids or radiation therapy, respectively, does not disqualify the subject (the dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in 2-week period). Radiation therapy within 2 weeks before randomization. Enrollment of patients who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy. Major surgery within 30 days before randomization (Kyphoplasty is not considered major surgery) History of allergy to any of the study medications, their analogues, or excipients in the various formulations ≥Grade 2 peripheral neuropathy on clinical examination within 21 days before enrollment. Any of the following clinical laboratory values within 21 days prior to enrollment: Absolute neutrophil count (ANC) <1000 cells/mm^3 Platelets <100,000 × 10^9/L, or <70 × 10^9/L if thrombocytopenia is considered by the investigator to be due to myeloma infiltration of bone marrow Aspartate aminotransferase [serum glutamic oxaloacetic transaminase] (AST [SGOT]) or alanine aminotransferase [serum glutamic-pyruvic transaminase] (ALT [SGPT]) >2× the upper limit of normal (ULN) Serum creatinine >2 mg/dL (>176.8 µmol/L); if the rise in creatinine is related to myeloma and there has been demonstrated a response to hydration, the subject may be enrolled. Myocardial infarction within 6 months prior to enrollment or New York Hospital Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities in the opinion of the investigator. Prior to study entry, any abnormality on electrocardiogram at screening must be determined and documented by the investigator as not medically relevant. Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the patient at unacceptable risk if he/she were to participate in the study. This includes but is not limited to serious medical conditions or psychiatric illness likely to interfere with participation in this clinical study. Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer, or other cancer for which the patient has been disease-free for at least 3 years. Female who is pregnant or breastfeeding. Female participants of childbearing potential must have a negative pregnancy test with a sensitivity of at least 50 mIU/mL during Screening. Use of any investigational drugs within 30 days before randomization.

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 and Dexamethasone (VD)<br>Participants received bortezomib (Velcade) 1.3 mg/m^2 administered as a bolus intravenous (IV) injection on Days 1, 4, 8, and 11, and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 and 12 for eight 21-day treatment cycles (Induction). Participants then received bortezomib 1.6 mg/^2 IV on Days 1, 8, 15 and 22 for five 35-day cycles (Maintenance). | Drug: Bortezomib<br>* Bortezomib bolus intravenous (IV) injection<br>* Other names: Velcade;Drug: Dexamethasone<br>* Dexamethasone for oral administration<br>|
| Experimental: Bortezomib, Thalidomide, and Dexamethasone (VTD)<br>Participants received bortezomib (Velcade) 1.3 mg/m^2 administered as a bolus IV injection on Days 1, 4, 8, and 11, and dexamethasone 20 mg orally on Days 1, 2, 4, 5, 8, 9, 11 and 12, and thalidomide 100 mg orally on Days 1-21 for eight 21-day treatment cycles (Induction). Participants then received bortezomib 1.6 mg/^2 IV on Days 1, 8, 15 and 22 for five 35-day cycles (Maintenance) . | Drug: Bortezomib<br>* Bortezomib bolus intravenous (IV) injection<br>* Other names: Velcade;Drug: Dexamethasone<br>* Dexamethasone for oral administration<br>Drug: Thalidomide<br>* Thalidomide for oral administration<br>|
| Experimental: Bortezomib, Melphalan and Prednisone (VMP)<br>Participants received bortezomib (Velcade) 1.3 mg/m^2 administered as a bolus IV injection on Days 1, 4, 8, and 11, and melphalan 9 mg/m^2 orally on Days 1-4 every other cycle and prednisone 60 mg/m^2 orally on Days 1-4 every other cycle for eight 21-day treatment cycles (Induction). Participants then received bortezomib 1.6 mg/^2 IV on Days 1, 8, 15 and 22 for five 35-day cycles (Maintenance). | Drug: Bortezomib<br>* Bortezomib bolus intravenous (IV) injection<br>* Other names: Velcade;Drug: Melphalan<br>* Melphalan for oral administration<br>Drug: Prednisone<br>* Prednisone for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomization to disease progression or death, whichever occurs first. Participants who did not progress and were still alive at the cut-off date were censored at the date of last contact. Response was assessed by the Investigator using the International Myeloma Working Group (IMWG) uniform response criteria. Progressive disease requires 1 of the following: Increase of ≥ 25% from nadir in: Serum M-component (absolute increase ≥ 0.5 g/dl) Urine M-component (absolute increase ≥ 200 mg/24 hours) In patients without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase > 100 mg/dl) Bone marrow plasma cell percentage (absolute % ≥ 10%) Development of new or increase in the size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dl) attributed solely to plasma cell proliferative disease | From randomization until disease progression. Median follow-up time was 43 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Overall Response | Overall response defined as a best overall response of complete response (CR), very good partial response (VGPR) or partial response (PR), assessed by the Investigator using the IMWG uniform response criteria. CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours (h). PR requires 1 of the following: ≥50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to <200 mg/24 h, or If M-protein not measurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels, or If FLC not measurable, a ≥ 50% reduction in plasma cells, provided baseline bone marrow plasma cell percentage was ≥30%. If present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required. | Response assessed every other cycle for up to 13 cycles (49 weeks). | 
| Percentage of Participants With a Complete Response | Participants with a best overall response of complete response, defined as negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. Response was assessed by the Investigator using the IMWG uniform response criteria. | Response assessed every other cycle, for up to 13 cycles (49 weeks). | 
| Percentage of Participants With a Complete Response or a Very Good Partial Response | Complete response is defined by negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow. Very good partial response is defined by serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. Response was assessed by the Investigator using the IMWG uniform response criteria. | Response assessed every other cycle for up to 13 cycles (49 weeks). | 
| Duration of Response | Duration of response is defined in participants with an overall response as the time between first documentation of response and disease progression. Responders without disease progression were censored at the last clinical assessment of response. | From first documented response until disease progression. Median follow-up time was 43 months. | 
| Overall Survival | Overall survival is defined as the time between randomization and death. Participants still alive at the cutoff date or lost to follow-up were censored at the date of last contact. | From randomization until death. Median follow-up time was 43 months. | 
| Time to Alternative Therapy | Time to alternative therapy is defined as the time between randomization and alternative therapy. Participants who did not receive alternative therapy were censored at the time of last contact. | From randomization until alternative therapy. Median follow-up time was 43 months. | 
| Change From Baseline in EORTC QLQ-C30 - Global Health Status | The European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL Scale is scored between 0 and 100, where higher scores indicate better Global Health Status/QOL. Negative changes from baseline indicate deterioration in QOL or functioning and positive changes indicate improvement. | Baseline and Day 1 of Cycles 3, 5, 7, 9, 11 and 13 |