The purpose of this study is to study the MRD status after VELCADE based induction therapy (VELCADE, lenalidomide, dexamethasone or VELCADE, liposomal doxorubicin, dexamethasone) in patients with previously untreated multiple myeloma and study the impact of HDC and ASCT on MRD status post-transplant. Our hypothesis is that MRD-status will continue to increase significantly at 3 months post-transplant and will validate that HDC and ASCT needs to be performed even when patients have achieved major response after induction therapy with novel agents.

Inclusion Criteria:

Confirmed Multiple Myeloma as defined below within 120 days of starting cycle 1:

• Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells or biopsy proven plasmacytoma
• Presence of M protein in serum or urine or both. Conventional M spike, serum free light chains, or 24 hour urine study. Non-secretory myeloma is not eligible for this study.
• In addition patient must have one of the following organ dysfunction criteria
• Hypercalcemia
• Renal insufficiency
• Anemia
• Bone disease manifested by lytic lesion or osteoporosis (if osteoporosis is the only organ dysfunction criteria then BM should have ≥ 30% plasma cells)
• Confirmed Multiple myeloma as defined above within 90 days of starting cycle 1
• The following study assessments must be fulfilled and must be obtained with four weeks of starting cycle 1
• Hemoglobin > 7 g/dL, Platelet count > 75 X 10 to 9th power/L, and Absolute neutrophil count > 1 X 10 to 9th power/L
• Creatinine <2.5 mg/dL or calculated creatinine clearance > 30 ml/min/1.72 m2
• Bilirubin ≤ 1.5 mg/dL X ULN
• SGPT (ALT) and SGOT (AST) ≤ 2.5 times the upper limit of normal
• Ejection fraction ≥ 45% as measured by a MUGA scan or 2 D echocardiogram
• Pulmonary function tests show >60% predicted values for FVC, FEV1, and DLCO FEV1 must be > 1 liter.
• No prior systemic therapy with the exception of bisphosphonates for MM
• Prior glucocorticoid therapy for the treatment of multiple myeloma is not permitted EXCEPT if used in conjunction with palliative radiation to prevent vasogenic edema. In that case steroids should have been used for less than 7 days. Prior steroid use for non-malignant disorders is permitted and should have been restricted to less than the equivalent of prednisone 10 mg per day. Prior or concurrent topical or localized steroid therapy to treat non-malignant disorders is permitted
• Prior palliative and/ or localized radiation therapy is permitted provided at least 4 weeks have passed from date of last radiation therapy to starting cycle 1.
• Patients with prior solitary plasmacytoma treated with radiation therapy with curative intent are eligible if the disease has now progressed to active multiple myeloma and meeting all eligibility criteria for the protocol
• ECOG PS 0, 1 or 2
• For women of childbearing potential a negative serum pregnancy test is required within 4 weeks of starting cycle 1 and then every 4 weeks during the first 4 cycles of induction therapy
• Women of child bearing potential must be willing to refrain from sexual intercourse or willing to employ a dual method of contraception, one of which is highly effective (IUD, birth control pills, tubal ligation or partner's vasectomy) and another additional method (condom, diaphragm, or cervical cap) during the entire course of the study (start of therapy until 30 days after stem cell transplant).
• Sexually active males should be willing to use a condom (even if they have had a prior vasectomy) while having intercourse with any women during the course of the study (start of therapy until 30 days after stem cell transplant).
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

• Patients with smoldering myeloma or monoclonal gammopathy of unknown significance are not eligible
• Age > 70 years or < 18 years is not eligible
• Patient has > 1.5 × ULN Total Bilirubin
• Grade 2 or higher peripheral neuropathy due to ANY cause
• High index of suspicion of primary amyloid light chain (AL) amyloidosis.
• Patients with uncontrolled inter-current illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance or a prior history of Steven Johnson syndrome
• Patients must not have a history of current or previous deep vein thrombosis or pulmonary embolism regardless of whether or not the patient is receiving anticoagulation therapy
• Female patients who are breastfeeding or pregnant.
• Patients known to be HIV positive
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see section 31.3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Patient has hypersensitivity to VELCADE, boron or mannitol.
• Patient has received other investigational drugs within 14 days before enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.