The primary efficacy objective of this study is to determine whether the addition of VELCADE (Bortezomib for Injection) to standard melphalan/prednisone (MP) therapy improves the time to disease progression (TTP) in subjects with previously untreated multiple myeloma.

The secondary objectives of this study are to determine whether the addition of VELCADE to standard MP therapy in subjects with previously untreated multiple myeloma improves the following: overall survival (OS), progression free survival (PFS), complete response (CR) rate, overall response rate (CR + partial response [PR]), time to response, and duration of response. An additional secondary objective is to measure and test global health status as measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, a patient-reported outcome (PRO) instrument.

Other objectives include collection of medical resource utilization (MRU) information and use of a preference-based PRO instrument (EQ-5D) to calculate utility values, both of which may be used in future economic evaluation models.

Safety of the VELCADE/melphalan/prednisone (Vc-MP) combination will also be assessed, including selected measures of clinical benefit (e.g., incidence of Grade 3 and 4 infections).

The impact of melphalan and prednisone on the clinical pharmacokinetics of VELCADE will also be evaluated.

Exploratory objectives of this study are pharmacogenomics and proteomics. Pharmacogenomics will evaluate variations in drug metabolizing genes and their relationship to pharmacokinetic disposition parameters, as well as variations in genes that may be related to response to VELCADE or susceptibility to, or prognosis of, multiple myeloma. Proteomics will explore the association between patterns of proteins, peptides, or small molecule components in serum, and response to VELCADE or susceptibility to, or prognosis of, multiple myeloma.

OVERVIEW OF STUDY DESIGN:

This is a randomized, open-label, multicenter study consisting of 3 phases: a Pre-randomization (Screening) Phase, an Open-label Treatment Phase, and a Post-treatment Phase. Study eligibility will be determined during the Screening Phase. Subjects with previously untreated multiple myeloma who are not candidates for high dose chemotherapy with stem cell transplant (HDT/SCT) will be enrolled.

Approximately 680 subjects will be randomly assigned to 1 of 2 treatment groups and will be stratified according to baseline beta 2-microglobulin, baseline albumin levels, and region (North America, Europe, other). Subjects will be randomized in a 1:1 allocation to receive either Vc-MP (Treatment Group A) or MP (Treatment Group B). Subjects in Treatment Group A will receive VELCADE (twice weekly [Weeks 1, 2, 4, and 5] for four 6-week cycles [8 doses per cycle] followed by once weekly [Weeks 1, 2, 4, and 5] for five 6-week cycles [4 doses per cycle]) in combination with melphalan and prednisone once daily on Days 1 to 4 of each 6-week cycle. Subjects in Treatment Group B will receive 9 cycles of melphalan and prednisone once daily on Days 1 to 4 of each 6-week cycle. For both groups, treatment will continue for a maximum of 9 cycles (54 weeks) and will be discontinued if disease progression or an unacceptable treatment-related toxicity occurs, or if a subject withdraws consent. Throughout the Open-label Treatment and Post-treatment Phases, the investigator will assess the subject's response to therapy using the results of efficacy evaluations conducted at equivalent frequency in each treatment group and by implementing defined disease response criteria.

In the Post-treatment Phase, subjects will be followed until death or a maximum of 4.5 years after the last subject is randomized on the study. The primary end point is TTP. Secondary end points include OS, PFS, CR rate, overall response rate, time to response, duration of response, and PROs.

Efficacy assessments include: myeloma protein measurements in serum and 24 hour urine, bone marrow examination, skeletal survey, documentation of extramedullary plasmacytomas, and serum calcium adjusted for albumin.

Patient-reported outcomes will be assessed in this study through the EORTC QLQ C30, the Functional Assessment of Chronic Illnesses-Fatigue (FACIT-F), and the EQ-5D scales. Medical resource utilization information will also be collected throughout the study. Full plasma concentration-time profiles will be created for VELCADE using blood samples from a subset of approximately 16 subjects in Treatment Group A.

Safety will be evaluated throughout the study by assessment of adverse events, including selected measures of clinical benefit, changes in physical examinations, Karnofsky performance status scores, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) scores, vital signs, and clinical laboratory findings. The FACT/GOG-Ntx scale will be used as a checklist to assist with the clinical safety evaluation of neuropathic pain and peripheral neuropathy symptoms. Protocol-specified dose modifications of VELCADE, melphalan, or prednisone will be made, as necessary. Subjects will be evaluated for toxicity before any new dose of study drug is prescribed. Investigators will focus on hematologic toxicity (especially thrombocytopenia), on early indications of neuropathy, and on other nonhematologic toxicity. Doses can be held or reduced based on the severity of, and the recovery from, a previous toxicity. Dose re-escalations are not allowed for any of the study drugs.

There are 2 interim analyses planned. The first interim analysis for safety monitoring will be performed when approximately 100 subjects (50 per arm) have been on study long enough to complete 1 treatment cycle (all doses of melphalan and prednisone, and at least 6 of the 8 doses of VELCADE) or have been terminated early. The second interim analysis to re-evaluate the sample size, based on accumulated study data and to monitor safety data, will be performed when approximately 570 subjects have been enrolled. Interim analyses will be performed by an independent statistician. An Independent Data Monitoring Committee (IDMC) will meet, following completion of each interim analysis, to evaluate safety data and results of the prospectively defined interim analysis of efficacy.

Pharmacogenetic and proteomic/metabolic exploratory analyses are planned on blood samples from subjects who agree to participate in these parts of the study.

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

• Male or female
• Subject is not a candidate for HDT/SCT due to: age - subject is 65 years or older or in subjects less than 65 years of age - presence of important comorbid condition(s) likely to have a negative impact on tolerability of HDT/SCT. Sponsor review of these comorbid conditions and approval is required before randomization.
• 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 asymptomatic lytic bone lesion or plasmacytoma, or presence of anemia (hemoglobin <10 g/dL), renal function impairment (serum creatinine > upper limit of normal [ULN]) or hypercalcemia (serum calcium >ULN), as long as the criteria for pre-treatment clinical laboratory values indicated below are met.
• Presence of measurable disease, defined as:
  • For secretory multiple myeloma, measurable disease is defined as any quantifiable serum monoclonal protein value (>1 g/dL of IgG or IgM M-protein, >0.5 g/dL of IgA M-protein, >0.05 g/dL of IgD M protein, OR urine light-chain excretion of more than 200 mg/24 hours).
  • For oligosecretory or nonsecretory multiple myeloma, measurable disease is defined by the presence of measurable soft tissue or organ (not bone) plasmacytomas as determined by clinical examination or applicable radiographs (i.e., magnetic resonance imaging [MRI], computed tomography [CT] scan). A measurable lesion is defined as a lesion with minimum largest diameter of >20 mm (if measured by conventional techniques such as physical examination, conventional CT scan, or MRI) or of >10 mm (if measured by spiral CT scan) in one dimension. Oligosecretory myeloma is defined as the presence of M-protein in serum or urine but in quantities less than indicated above. Nonsecretory multiple myeloma is defined as the absence of M protein in serum AND in urine by immunofixation.
• Karnofsky performance status score of equal or greater then 60%.
• Willing and able to complete the PRO instruments
• Agrees to use an acceptable barrier method for contraception for the duration of the study (for male subjects); If female subjects are still having menstrual periods and are not surgically sterile, they must be practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry, and throughout the study, and have a negative serum B-HCG pregnancy test at screening.
• Have pretreatment clinical laboratory values meeting the following criteria within 14 days before randomization: *platelet count of equal or greater than 100x10^9/L; *hemoglobin of equal or greater than 8 g/dL (equal or greater than 4.96 mmol/L) (prior RBC transfusion or recombinant human erythropoietin use is allowed); *absolute neutrophil count (ANC) equal or greater than 1.0x10^9/L; *aspartate aminotransferase (AST) equal or less than 2.5 times the upper limit of normal; *alanine aminotransferase (ALT) equal or less than 2.5 times the upper limit of normal; *total bilirubin equal or less than 1.5 times the upper limit of normal; *serum creatinine equal or less than 2mg/dL (equal or less than 176.8 mcmol/L); *corrected serum calcium <14 mg/dL (<3.5 mmol/L); Serum Calcium Corrected for Albumin, for formula
• Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

Potential subjects who meet any of the following criteria will be excluded from participating in the study:

• 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.49 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 with lytic bone lesions
• Prior or current systemic therapy for multiple myeloma including steroids (with the exception of emergency use of a short course [maximum of 4 days] of steroids before randomization or of prior or current use of bisphosphonates)
• Radiation therapy within 30 days before randomization
• Plasmapheresis within 30 days before randomization
• Major surgery within 30 days before randomization (kyphoplasty is not considered major surgery)
• History of allergic reaction attributable to compounds containing boron or mannitol
• Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0
• Uncontrolled or severe cardiovascular disease, including myocardial infarction, within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (see Attachment 3), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
• Other malignancy within the past 5 years. Exceptions if treated and not active include the following: *basal cell or nonmetastatic squamous cell carcinoma of the skin, *cervical carcinoma in situ or *International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix
• Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes) that is likely to interfere with study procedures or results, or that, in the opinion of the investigator would constitute a hazard for participating in this study
• Use of any investigational drugs within 30 days before randomization
• Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, or family members of the employees or the investigator.