The purpose of this study is to determine the safety and efficacy of the bortezomib, lenalidomide and dexamethasone combination in patients with newly diagnosed multiple myeloma. We are looking for the highest dose of the combination that can be given safely and see how well it works as a combination in newly diagnosed patients.

• The safe dose of dexamethasone is already known. The dose of bortezomib and lenalidomide will be increased during the study until the best and safest amount (or dose) is identified. The participant's dose of the study drugs will depend on when they enter the study.
• In this study each cycle will be 21 days and participants will begin the study medication in the clinic on Cycle 1 Day 1. Lenalidomide (capsules) will be taken daily for the first 2 weeks only (Day 1-14). Dexamethasone (tablets) will be taken on Day 1, 2, 4, 5, 8, 9, 11 and 12. Bortezomib will be given intravenously in the outpatient treatment clinic on Day 1, 4, 8 and 11. The third week is a rest period and no study medication will be given.
• During the course of the study treatment, tests and procedures will be performed at designated time periods. This includes; medical history updates, physical/neurological examinations, skeletal survey (x-rays or scan), blood samples, optional bone marrow aspiration/tissue biopsy, urine samples, 12-lead ECG, and MRI/CT scan (if needed).
• It is expected that study participants will receive study treatment for 8 cycles (168 days). If the participant completes the first 8 cycles of the study, has stable or responding disease and has not experienced bad side effects, they will be allowed to continue treatment on a maintenance schedule, detailed in the protocol, at the study doctor's discretion.

Inclusion Criteria:

• Diagnosed with multiple myeloma based on standard diagnostic criteria or by the new International Myeloma Foundation 2003 Diagnostic Criteria
• Must not have been previously treated with any prior systemic therapy for the treatment of multiple myeloma
• Negative serum or urine pregnancy test
• Age 18 years or older
• Karnofsky performance status of greater or equal to 60

Exclusion Criteria:

• Greater or equal to Grade 2 peripheral neuropathy on clinical examination within 14 days before enrollment
• Renal insufficiency (serum creatinine >2.5 mg/dL)
• Evidence of mucosal or internal bleeding and/or platelet refractory
• ANC (absolute neutrophil count)< 1000 cells/mm3
• Hemoglobin < 8.0 g/dL
• AST (aspartate aminotransferase) or ALT (alanine aminotransferase) greater than or equal to 2 x ULN (upper limit of normal)
• Concomitant therapy medications that include corticosteroids
• Myocardial infarction within 6 months prior to enrollment according to NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Clinically relevant active infection or serious co-morbid medical conditions
• Prior malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer
• Pregnant or breast-feeding
• Serious medical or psychiatric illness likely to interfere with participation in study
• Uncontrolled diabetes mellitus
• Hypersensitivity to acyclovir or similar anti-viral drug
• POEMS syndrome
• Known HIV infection
• Known active hepatitis B or C viral infection
• Known intolerance to steroid therapy