There have been four previous Total Therapy (TT1 through IIIB) studies for multiple myeloma at the MIRT from 1989 to present. Results have shown that participants treated on these studies had better outcomes (meaning they have lived longer and had better responses to treatment) when compared to individuals treated with standard chemotherapy.

Past studies conducted at the MIRT have shown that participants presenting to MIRT who have already received treatment for myeloma tend to have shorter remissions (disappearance of signs and symptoms of myeloma) and do not survive as long as participants who come to MIRT with untreated myeloma. Researchers at MIRT think that one reason for this is may be that the myeloma cells re-grow in the time when participants are not receiving treatment because they are recovering from high-dose chemotherapy. In this study, participants will receive several chemotherapy drugs previously shown to be effective in myeloma, but in lower doses and in shorter cycles. It is hoped that by giving the drugs in this way, myeloma cells will not have time to re-grow between cycles, therefore resulting in longer remissions. This study is being done in an attempt to improve the remission rate and the survival time for participants with high-risk myeloma.

• To find out if giving multi-agent chemotherapy in lower and more frequent doses to make the timely delivery of chemotherapy cycles possible, will result in better myeloma responses
• To find out if changing the way the drugs are given during the transplant phase will also result in fewer side effects, while still being effective
• To find out if giving treatment between transplants (called "inter-therapy") will prevent the myeloma from re-growing between transplants
• To find out if long-term maintenance therapy will result in longer remissions
• To find out what the effects (good and bad) of this overall treatment will be
• To learn more about the biology and genetics of multiple myeloma by performing imaging tests and collecting blood, bone marrow aspirate and biopsies, and biopsies of lesions seen on MRI or PET scans. Bone marrow aspirates and biopsies are tissue sample collected from the bone cavity.

Inclusion Criteria:

• Patients with symptomatic multiple myeloma (MM), with at least one prior line of chemotherapy or newly diagnosed without any prior therapy.
• Zebroid ≤ 2, unless solely due to symptoms of MM-related bone disease (Appendix 4).
• Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
• Patient must not have had a prior auto- or allotransplant.
• Patient must have signed an IRB-approved informed consent and understand the investigational nature of the study.
• Patients must have adequate pulmonary function studies ≥ 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) ≥ 50% of predicted, within 60 days prior to enrollment. Patients unable to complete pulmonary function tests because of myeloma-related chest pain, must have a high resolution CT scan of the chest and must also have acceptable arterial blood gases defined as P02 greater than 70.
• Ejection fraction by ECHO or MUGA must be ≥ 40% and must be performed within 60 days prior to enrollment, unless the patient has received chemotherapy within that period of time (dexamethasone and thalidomide excluded), in which case the LVEF must be repeated.
• Patients must not have 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 not received treatment for one year prior to enrollment. Other cancers will only be acceptable if the patient's life expectancy exceeds five years.
• Patients must be able to receive full doses of Mel-VRD-PACE, in the opinion of the treating investigator, with the exception that patients with creatinine clearance 30-50 ml/min will receive only 50% of the cisplatin dose.

Exclusion Criteria:

• Fever or active infection requiring intravenous antibiotic, defined as fever or antibiotics within 72 hours from registration.
• Severe renal dysfunction, defined as a creatinine > 3mg/dl or a creatinine clearance of < 30ml/min.
• Significant neurotoxicity, defined as grade ≥ 3 neurotoxicity per NCI Common Toxicity Criteria (See Appendix).
• Platelet count < 30,000/mm3, and ANC < 1,000/μl
• POEMS Syndrome: (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes
• Clinically significant hepatic dysfunction as noted by direct bilirubin or AST >3 times the upper normal limit or clinically significant concurrent hepatitis.
• New York Heart Association (NYHA) Class III or Class IV heart failure (Appendix 4).
• Recent (≤ 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias are ineligible.
• Patients with a history of treatment for clinically significant ventricular cardiac arrhythmias.
• Poorly-controlled hypertension, diabetes mellitus, or other serious medical illness or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
• Prior cumulative total of Adriamycin exposure >450 mg/m2.
• Prior exposure to thalidomide which resulted in severe toxicity requiring drug discontinuation.
• Prior exposure to Revlimid which resulted in severe toxicity requiring drug discontinuation
• Hypersensitivity to boron, or Mannitol. Prior exposure to bortezomib which resulted in severe toxicity requiring drug discontinuation.
• Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Women/men of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.