• Phase I: Determine the MTD of cyclophosphamide when given in combination with VELCADE, Pegylated Liposomal doxorubicin and dexamethasone in newly diagnosed multiple myeloma patients. Phase II: Evaluate objective response rate (CR+PR). [ Time Frame: dependent upon results ] [ Designated as safety issue: Yes ]
  

• To collect data on the progression free survival, disease-free survival, and overall survival in all patients and in patients stratified by risk. [ Time Frame: dependent upon results ] [ Designated as safety issue: Yes ]
  

The first cohort of three subjects enrolled into Phase I of the study will receive dose level 1. A full safety evaluation will be conducted when these subjects have completed one cycle (21 days) of combination therapy. Further patient accrual will be suspended while the safety data is evaluated at each dose level.

Dose escalation for subsequent patients will proceed through dose levels 2, 3 and 4 as follows:

• If no Dose Limiting Toxicity (DLT) is reported in the first three subjects at a dose level, that dose level will be considered safe and three subjects will be enrolled at the next dose level. If 1/3 subjects in a cohort at a dose level has a DLT, the dose level will be expanded to obtain six evaluable subjects.
• If > 1 of 3 subjects in a cohort experience DLT, that dose level will not be considered safe. No further dose escalation will take place, and the immediate lower dose level will be considered the MTD if six patients had been enrolled at that dose level. Otherwise, expand the immediate lower dose level to six evaluable patients*.
• If there are < 2 subjects with a DLT among the expanded cohort of six evaluable subjects, a cohort of three subjects will be enrolled in the next higher dose level.
• If there are 2 or more subjects with a DLT among the expanded cohort of six evaluable subjects, that dose level will not be considered safe. No further dose escalation will take place, and the immediate lower dose level will be considered the MTD if six patients had been enrolled at that dose level. Otherwise, expand the immediate lower dose level to six evaluable patients*.

Inclusion Criteria:

• Understand and voluntarily sign informed consent form; equal to or greater than 18 years of age at time of consent.
• Able to adhere to the study visit schedule and other protocol requirements.
• Diagnosed active multiple myeloma.
• Measurable myeloma paraprotein levels in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g excreted in a 24-hour urine collection sample).
• ECOG Performance Status of 0-2.
• Performance status of 3 allowed if related to bony disease.
• Bilirubin < 1.5x upper limits of normal (ULN).
• Liver enzymes (ALT or AST) < 2.5 x ULN. In presence of liver metastases, AST / ALT, alkaline phosphatase and total bilirubin must not exceed 3x upper limit of normal.
• Adequate bone marrow function:
• Absolute neutrophil count > 1,000 cells/mm3 (1.0 x 10^9/L). Patients with bone marrow >50% plasma cells are permitted to have a neutrophil count of < 1,000 cells/mm3.
• Platelets ≥ 100,000 cells/mm3. Patients with bone marrow >50% plasma cells are permitted to have a Platelet count < 100, 000 cells/mm3
• Hemoglobin > 8 g/dL (transfusion allowed to increase the Hgb)
• Adequate renal function: Creatinine ≤ 2.5 mg/dL
• Must have 2-d echocardiogram or MUGA scan indicating LVEF ≥ 50% within 42 days prior to first dose of study drug. A MUGA scan or 2- d Echocardiogram may be used, but the same test must be used throughout study) to evaluate LVEF.
• Women of childbearing potential (WCBP)† must have negative serum or urine pregnancy test 10 to 14 days prior to starting therapy. Patients with reproductive potential must use an adequate contraceptive method during treatment and for three months after completing treatment. Patients treated with local radiotherapy with or without concomitant exposure to steroids, for pain control or management of cord/nerve root compression, are eligible. Four weeks must have lapsed since last date of radiotherapy.
• Patients who require concurrent radiotherapy should have entry to the protocol deferred until radiotherapy is completed and 4 weeks have passed since last date of therapy

Exclusion Criteria:

• Ongoing severe infection requiring intravenous antibiotic treatment.
• Life expectancy < 3 months.
• Prior malignancy, except; adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, or other cancer from which the subject has been disease-free for at least 5 years. Concurrent prostate cancer for which patient is receiving therapy will not be considered an exclusion if PSA has been stable for 3 years.
• Solitary bone or solitary extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia.
• Patients receiving therapeutic dosages of steroids for multiple myeloma.
• Myocardial infarct within 6 months before enrollment, NYHA Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
• Uncontrolled medical problems such as diabetes mellitus, coronary artery disease, hypertension, unstable angina, arrhythmias, pulmonary, hepatic and renal diseases unless renal insufficiency is felt to be secondary to multiple myeloma.
• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
• Pregnant or breast-feeding females. Lactating females must agree not to breast-feed.
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
• Prior chemotherapy for multiple myeloma, except for radiation to symptomatic bony disease, plasmapheresis for hyperviscosity, kyphoplasty and/or vertebroplasty.
• History of hypersensitivity reactions attributed to a conventional formulation of doxorubicin HCL or the components of DOXIL®
• Prior anthracycline dose exceeding 360 mg/m2 for doxorubicin (including DOXIL) or 720 mg/m2 for epirubicin
• Grade 2 or higher peripheral neuropathy on clinical examination within 14 days before enrollment
• POEMS syndrome or plasma cell leukemia
• Hypersensitivity to bortezomib, boron or mannitol.
• Has received other investigational drugs within 14 days before enrollment.