Official Title: “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”

This is a randomized, open label, multicenter clinical trial to compare the efficacy and safety of VELCADE dexamethasone versus VELCADE, thalidomide, and dexamethasone versus VELCADE, melphalan, and prednisone in patients with previously untreated multiple myeloma who are not considered candidates for high-dose chemotherapy and autologous stem cell transplantation. This study will consist of a Screening period (generally 4 weeks or less), an Induction Treatment period (approximately 6 months), a Maintenance Treatment period (approximately 6 months), and a Post-treatment period.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment

Study Primary Completion Date: December 2010

Intervention(s) in this Clinical Trial

• Drug: bortezomib, thalidomide, and dexamethasone (VTD)
  • VELCADE® (bortezomib): 1.3 mg/m2/dose administered as a 3- to 5-second IV bolus injection on Days 1, 4, 8, and 11 of each 21-day cycle during Cycles 1-8. Thalidomide: 100 mg PO QD on Days 1-21 of a 21-day cycle during Cycles 1-8. Dexamethasone: 20 mg orally (PO) once daily (QD) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle during Cycles 1-4 (ie, on the day of and day after VELCADE® administration), and then 20 mg PO QD on Days 1, 2, 4, and 5 of a 21-day cycle during Cycles 5-8 Dosing Schedule for the Maintenance Treatment Periods (Cycles 9 though 13) All subjects will receive VELCADE® at 1.6 mg/m2/dose IV (as above) on Days 1, 8, 15, and 22 of a 35-day cycle during Cycles 9-13.
• Drug: bortezomib and dexamethasone (VD)
  • VELCADE® (bortezomib): 1.3 mg/m2/dose administered as a 3- to 5-second IVbolus injection on Days 1, 4, 8, and 11 of each 21-day cycle during Cycles 1-8. Dexamethasone: 20 mg orally (PO) once daily (QD) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle during Cycles 1-4 (ie, on the day of and day after VELCADE® administration), and then 20 mg PO QD on Days 1, 2, 4, and 5 of a 21-day cycle during Cycles 5-8. Dosing Schedule for the Maintenance Treatment Periods (Cycles 9 though 13) All subjects will receive VELCADE® at 1.6 mg/m2/dose IV (as above) on Days 1, 8, 15, and 22 of a 35-day cycle during Cycles 9-13.
• Drug: bortezomib, melphalan and prednisone (VMP)
  • VELCADE® (bortezomib): 1.3 mg/m2/dose administered as a 3- to 5-second IVbolus injection on Days 1, 4, 8, and 11 of each 21-day cycle during Cycles 1-8. Melphalan: 9 mg/m2 PO QD on Days 1-4 every other cycle during Cycles 1-8. Prednisone: 60 mg/m2 PO QD on Days 1-4 every other cycle during Cycles 1-8. Dosing Schedule for the Maintenance Treatment Periods (Cycles 9 though 13) All subjects will receive VELCADE® at 1.6 mg/m2/does IV (as above) on Days 1, 8, 15, and 22 of a 35-day cycle during Cycles 9-13.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Bortezomib, Thalidomide, and Dexamethasone (VTD)
• Experimental: 2
  • Bortezomib and Dexamethasone (VD)
• Experimental: 3
  • Bortezomib, melphalan, and prednisone (VMP)

Primary Measures

• Progression Free Survival.
  • Time Frame: Up to 3 years after treatment is completed
    Safety Issue?: No

Secondary Measures

• - Overall response rate - Overall survival - Time to alternative therapy
  • Time Frame: Up to 3 years after treatment is completed
    Safety Issue?: Yes

Inclusion Criteria:

• Male or female subjects 18 years of age or older
• Subject is 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).
• Subject 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 IgG 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 subject at any time without prejudice to future medical care.

Exclusion Criteria:

• Diagnosis of smoldering multiple myeloma or 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 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 subjects 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/mm3
• Platelets <100,000 × 109/L, or <70 × 109/L if thrombocytopenia is considered by the investigator to be due to myeloma infiltration of bone marrow
• Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) >2× the ULN
• Serum creatinine >2 mg/dL (>176.8µmol/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 subject 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 subject has been disease-free for at least 3 years.
• Female subject who is pregnant or breastfeeding. Female subjects 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Millennium Pharmaceuticals

Overall Clinical Trial Officials and Contacts

Overall Contact: Christine Colby, Pharm.D. 1-866-835-2233 medical@mlnm.com

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00507416

Study ID Number: C05009

ClinicalTrials.gov Identifier: NCT00507416

Health Authority: United States: Institutional Review Board

If you would like more information on this study, please click on the link provided or call 1-877-MPI-DRUG (1-877-674-3784).