• To determine, in a historical comparison with TT II (Thalidomide arm), whether two cycles of VDTPACE induction (instead of four induction cycles in TT II) followed by more timely MEL 200-based transplant with DEX + THAL between transplants can: [ Time Frame: yearly ] [ Designated as safety issue: No ]
• 1.1.1 Increase the CR frequency from 50% to 60% at 18 months from initiation of therapy; [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• 1.1.2 Increase > n-CR rate pre-transplant #1 from 20% to 40%; [ Time Frame: annually ] [ Designated as safety issue: No ]
• 1.1.3 Raise 2-year EFS rates from 55% to 75% in patients with CA and from 80% to 95%, in patients without CA. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• To determine, in a historical comparison with TT II (Thalidomide arm), whether two cycles of VDTPACE induction (instead of four induction cycles in TT II) followed by more timely MEL 200-based transplant with DEX + THAL between transplants can:
• 1.1.1 Increase the CR frequency from 50% to 60% at 18 months from initiation of therapy;
• 1.1.2 Increase > n-CR rate pre-transplant #1 from 20% to 40%;
• 1.1.3 Raise 2-year EFS rates from 55% to 75% in patients with CA and from 80% to 95%, in patients without CA.

• 1.2 To determine whether bortezomib can be safely incorporated into well tested DT-PACE induction (VDT-PACE) with PBSC mobilization, DT-PACE consolidation after MEL 200 tandem transplant and into DEX + THAL maintenance. [ Time Frame: annually ] [ Designated as safety issue: Yes ]
• 1.2.1 To evaluate whether increasing dosing frequency of bortezomib 1.0 mg/m2 compromises PBSC procurement after DTPACE with a target yield of > 20 x 106 CD34 cells/kg. [ Time Frame: annually ] [ Designated as safety issue: Yes ]
• 1.2.2 To evaluate whether DEX + THAL can be administered during ongoing hematopoietic recovery after first and second autotransplant without compromising subsequent VDTPACE tolerance. [ Time Frame: annually ] [ Designated as safety issue: Yes ]

• 1.2 To determine whether bortezomib can be safely incorporated into well tested DT-PACE induction (VDT-PACE) with PBSC mobilization, DT-PACE consolidation after MEL 200 tandem transplant and into DEX + THAL maintenance.
• 1.2.1 To evaluate whether increasing dosing frequency of bortezomib 1.0 mg/m2 compromises PBSC procurement after DTPACE with a target yield of > 20 x 106 CD34 cells/kg.
• 1.2.2 To evaluate whether DEX + THAL can be administered during ongoing hematopoietic recovery after first and second autotransplant without compromising subsequent VDTPACE tolerance.

There have been two previous Total Therapy studies for multiple myeloma (MM) at the Myeloma Institute for Research and Therapy (MIRT): Total Therapy I (from 1989 through 1994) and Total Therapy II (from 1996 to 2004). Results have shown that patients treated on these studies had better outcomes (meaning patients have lived longer and had better responses to treatment) when compared to patients treated with standard chemotherapy.

With this new study, Total Therapy III, researchers will take what they have learned from the first two studies and add new treatment strategies to try to improve the outcomes even more, especially for patients with chromosome abnormalities.

1.1 To determine, in a historical comparison with TT II (Thalidomide arm), whether two cycles of VDTPACE induction (instead of four induction cycles in TT II) followed by more timely MEL 200-based transplant with DEX + THAL between transplants can:

1.1.1 Increase the CR frequency from 50% to 60% at 18 months from initiation of therapy;

1.1.2 Increase > n-CR rate pre-transplant #1 from 20% to 40%;

1.1.3 Raise 2-year EFS rates from 55% to 75% in patients with CA and from 80% to 95%, in patients without CA.

• Drug: Velcade
• Drug: Thalidomide

Induction Inclusion Criteria:

• Patients must have newly diagnosed active MM requiring treatment. Patients with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
• Protein criteria must be present (quantifiable M-component of IgG, IgA, IgD, or IgE and/or urinary kappa or lambda light chain or Bence Jones protein) in order to evaluate response. Non-secretory patients are eligible provided the patient has > 20% plasmacytosis or multiple (>3) focal plasmacytomas on MRI or diffuse hyperintense signal on STIR images in the absence of hematopoietic growth factors.
• Patients must have received no more than one cycle of prior chemotherapy for this disease. Patients may have received prior radiotherapy provided approval has been obtained by the Principal Investigator.
• Patients must be < or = 75 years of age at the time of initial registration.
• Ejection fraction by ECHO or MUGA >40% performed within 60 days prior to registration.
• Patients must have adequate pulmonary function studies > or = 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) > or =50% of predicted, within 60 days of registration. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, there must be a pulmonary consult documenting that the patient is a candidate for high dose therapy.
• Patients must have a performance status of 0-2 based on SWOG criteria. Patients with a poor performance status (3-4), based solely on bone pain, will be eligible.
• All patients must be informed of the investigational nature of this study and must have signed an IRB-approved informed consent in accordance with institutional and federal guidelines.

Induction Exclusion Criteria:

• Platelet count < 30 x 10^9/L, unless myeloma-related
• ANC < 1.0 X 10^9/L, unless myeloma-related
• Grade > or =2 peripheral neuropathy
• Hypersensitivity to bortezomib, boron, or mannitol
• Uncontrolled diabetes.
• Recent (< or =6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias.
• Evidence of chronic obstructive or chronic restrictive pulmonary disease.
• Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease free for at least three years.
• Patients must not have significant co-morbid medical conditions or uncontrolled life threatening infection.
• Pregnant or nursing women. Women of child-bearing potential must have a negative pregnancy test documented within one week of registration. Women and men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.