UARK 2013-13, Total Therapy 4B - Formerly 2008-01 - A Phase III Trial for Low Risk Myeloma

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. * Patients must be either untreated or have not had more than one cycle of systemic MM therapy, excluding bisphosphonates and localized radiation. * Participants must have low-risk disease, as defined by any of the following: * GEP risk score of \< 0.66 * lack of GEP-defined TP53 deletion (Affymetrix signal \<727) * No metaphase based abnormalities of 1q or 1p * LDH \<360 U/L Rule out hemolysis, infection, and contact PI for Clarification * Zubrod ≤ 2, unless solely due to symptoms of MM-related bone disease. * 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 ≥ 40% * Patients must have adequate pulmonary function studies \> 50% of predicted on mechanical aspects (FEV1, FVC, etc) and diffusion capacity (DLCO) \> 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 principal 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: * High risk disease defined by high-risk gene array features as determined by any of the following: * GEP risk score of ≥ 0.66 or * Presence of GEP-defined TP53 deletion, or * Presence of abnormalities of chromosome 1 (amp1q, del 1p). * 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. * Platelet count \< 30 x 109/L, unless myeloma-related. * Grade \> 2 peripheral neuropathy. * Hypersensitivity to bortezomib, boron, or mannitol. * Recent (\< 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. * Patients must not have light chain deposition disease or creatinine \> 3 mg/dl * No prior malignancy is allowed 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. Prior malignancy is acceptable provided there has been no evidence of disease within the three-year interval or if the malignancy is considered much less life threatening than the myeloma. * 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.