• Evaluate the safety and tolerability of the combination therapy [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
• Overall Response [ Time Frame: 48 months ] [ Designated as safety issue: No ]
• Stringent Complete Response Rate [ Time Frame: 48 months ] [ Designated as safety issue: No ]
• Complete Response Rate + Near Complete Response Rate [ Time Frame: 48 months ] [ Designated as safety issue: No ]
• Duration of Response [ Time Frame: time from date of first documented confirmed response to date of first documented progressive disease ] [ Designated as safety issue: No ]
• Time to Disease Progression [ Time Frame: time from date of randomization to date of first documented progressive disease ] [ Designated as safety issue: No ]
• Time to Response [ Time Frame: time from date of randomization to the date of the first documentation of a confirmed response ] [ Designated as safety issue: No ]
• Progression-free Survival [ Time Frame: time from the date of randomization to the date of the first documented progressive disease or death. ] [ Designated as safety issue: No ]
• 1-year Survival [ Time Frame: survival probability at 1 year after randomization ] [ Designated as safety issue: No ]
• Overall Survival [ Time Frame: time from the date of randomization to the date of death ] [ Designated as safety issue: No ]

The purpose of this Phase 1/2 study is to evaluate the efficacy and safety of treatment with VELCADE, dexamethasone, and Revlimid® (VDR) as well as VELCADE, dexamethasone, cyclophosphamide, and Revlimid (VDCR) in patients with multiple myeloma who have received no prior treatment. This study will evaluate whether the addition of Revlimid to VELCADE and Dexamethasone will increase the CR/ very good partial response (VGPR) rate.

• Drug: bortezomib + dexamethasone + lenalidomide

  bortezomib 1.3 mg/m2 given via IV on days 1,4,8,and 11 of a 3-week cycle for 8 cycles, then on days 1,8,15 and 22 of a 6-week cycle for 4 cycles (maintenance).

  dexamethasone 40mg orally on days 1,8, and 15 of a 3-week cycle for 8 cycles, then stop.

  lenalidomide 25mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop.

• Drug: bortezomib + dexamethasone + cyclophosphamide + lenalidomide

  bortezomib 1.3 mg/m2 intravenously on days 1,4,8,and 11 of a 3-week cycle for 8 cycles, then on days 1,8,15 and 22 of a 6-week cycle for 4 cycles (maintenance).

  dexamethasone 40mg orally on days 1,8, and 15 of a 3-week cycle for 8 cycles, then stop.

  cyclophosphamide 500mg/m2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop.

  lenalidomide 15mg orally on days 1 to 14 of a 3-week cycle for 8 cycles then stop.

• Drug: bortezomib + dexamethasone + cyclophosphamide

  bortezomib 1.3 mg/m2 intravenously on days 1,4,8,and 11 of a 3-week cycle for 8 cycles, then on days 1,8,15 and 22 of a 6-week cycle for 4 cycles (maintenance).

  dexamethasone 40mg orally on days 1,8, and 15 of a 3-week cycle for 8 cycles, then stop.

  cyclophosphamide 500mg/m2 orally on days 1 and 8 of a 3-week cycle for 8 cycles, then stop.

• Drug: Bortezomib + Dexamethasone + Cyclophosphamide

  bortezomib 1.3 mg/m2 intravenously on days 1,4,8,and 11 of a 3-week cycle for 8 cycles, then on days 1,8,15 and 22 of a 6-week cycle for 4 cycles (maintenance).

  dexamethasone 40mg orally on days 1, 8 and 15 of a 3-week cycle for 8 cycles, then stop.

  cyclophosphamide 500mg/m2 orally on days 1, 8 and 15 of a 3-week cycle for 8 cycles, then stop.

• VDR: Experimental
  bortezomib, dexamethasone, and lenalidomide
  Intervention: Drug: bortezomib + dexamethasone + lenalidomide
• VDCR: Experimental
  Bortezomib, Dexamethasone, Cyclophosphamide, Lenalidomide
  Intervention: Drug: bortezomib + dexamethasone + cyclophosphamide + lenalidomide
• VDC: Experimental
  Bortezomib, Dexamethasone, Cyclophosphamide
  Intervention: Drug: bortezomib + dexamethasone + cyclophosphamide
• VDC-mod: Experimental
  Modified dosing of Bortezomib, Dexamethasone and Cyclophosphamide
  Intervention: Drug: Bortezomib + Dexamethasone + Cyclophosphamide

Inclusion Criteria:

• Voluntary written informed consent
• Male or female subject 18 years of age or older
• A Karnofsky Performance Status score of ≥50% (Eastern Cooperative Oncology Group Performance Status score ≤2)
• Subjects must have symptomatic myeloma or asymptomatic myeloma with myeloma-related organ damage
• Diagnosed Multiple myeloma
• Subjects must have measurable disease requiring systemic therapy
• Subjects must not have been treated previously with any systemic therapy for multiple myeloma
• Two weeks must have elapsed since the date of the last radiotherapy treatment
• Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 to 14 days prior to therapy and repeated within 24 hours before starting study drug. They must commit to continued abstinence from heterosexual intercourse or begin 2 acceptable methods of birth control (1 highly effective method and 1 additional effective method) used at the same time, beginning at least 4 weeks before initiation of Revlimid treatment. Women must also agree to ongoing pregnancy testing
• Men must agree to not father a child and agree to use a latex condom during therapy and for 4 weeks after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential
• All subjects must agree to comply with the requirements of the RevAssistSM program

Exclusion Criteria:

• History of allergy to any of the study medications, their analogues, or excipients in the various formulations
• ≥Grade 2 peripheral neuropathy on clinical examination
• Myocardial infarction within 6 months prior to enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or clinically significant conduction system abnormalities.
• Female subject who is pregnant or breast-feeding
• Clinically relevant active infection or serious comorbid medical conditions
• 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 or psychiatric illness likely to interfere with participation in this clinical study
• Active prior malignancy diagnosed or treated within the last 3 years