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 and at other institutions have shown that participants with high-risk features by gene array studies tend to have shorter remissions (disappearance of signs and symptoms of myeloma) and do not survive as long as participants with low-risk myeloma. Researchers at MIRT think that one reason for this is 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 treatment outcomes
• 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-transplant 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 for research

Inclusion Criteria:

• Patients must have newly diagnosed active MM requiring treatment. Patients with previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy.
• Patients must be either untreated o have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation.
• Patients must have high-risk disease, as defined by any one of the following:
• GEP risk score of > or = 0.66 or
• LDH > or = 360 U/L Rule out hemolysis, infection an contact PI for clarification
• Zubrod < or = 2, unless solely due to symptoms of MM-related bone disease.
• Patients must have a platelet count of > or = 50,000/uL, unless lower levels are explained by extensive bone marrow plasmacytosis.
• Patients must be at least 18 years of age and not older than 75 years of age at the time of registration.
• Participants must have preserved renal function as defined by a serum creatinine level of < 3 mg/dL.
• Participants must have an ejection fraction by ECHO or MUGA scan > or = 45%
• Patients must have adequate pulmonary function studies > or = 50% of predicted on mechanical aspects (FEV squared, FVC, etc) and diffusion capacity (DLCO) > or = 50% of predicted. If the patient is unable to complete pulmonary function tests due to MM related pain or condition, exception may be granted if the principle investigator documents that the patient is a candidate for high dose therapy.
• Patients must have signed an IRB-approved informed consent indicating their understanding of the proposed treatment and understanding that the protocol has been approved by the IRB.

Exclusion Criteria:

• Does not have high-risk disease
• 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.
• 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.
• Pregnant or nursing women may not participate. Women of childbearing potential must have a negative pregnancy documented within one week of registration. Subjects of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.