MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma

* INCLUSION CRITERIA: * Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma confirmed by the Laboratory of Pathology, NCI based on the International Myeloma Working Group Criteria: * Serum M-protein greater than or equal to 3 g/dl and/or bone marrow plasma cells greater than or equal to 10 %, * Absence of anemia: Hemoglobin \>10 g/dl * Absence of renal failure: calculated creatinine clearance (according to MDRD) \> 80 ml/min (or alternatively based on standard creatinine level criteria of 2 mg/dl) * Absence of hypercalcemia: Ca \< 10.5 mg/dl or less than or equal to 2.5 mmol/L * Absence of lytic bone lesion * High-risk SMM per Mayo Clinic2 or Spanish PETHEMA1 criteria * Measurable disease within the past 4 weeks defined by any one of the following: * Serum monoclonal protein greater than or equal to 1.0 g/dl * Urine monoclonal protein \>200 mg/24 hour * Serum immunoglobulin free light chain \>10 mg/dL AND abnormal kappa/lambda ratio (reference 0.26-1.65) * Age \>18 years. * ECOG performance status \<2. * Ability to give informed consent. * Patients must have normal organ and marrow function as defined below: * absolute neutrophil count \>1.0 K/uL * Platelets \>75 K/uL (Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.) * hemoglobin \> 8 g/dL(transfusions are permissible) * total bilirubin \<1.5 X institutional upper limit of normal * AST(SGOT)/ALT(SGPT) \< 3.0 X institutional upper limit of normal * Female patients who: * Are postmenopausal for at least 1 year before the Screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse. * The 2 methods of reliable contraception must include 1 highly effective method and 1 additional effective (barrier) method. Females of childbearing potential must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception: * Highly effective methods: * Intrauterine device (IUD) * Hormonal (birth control pills, injections, implants) * Tubal Ligation * Partner's Vasectomy Additional effective methods: * Male condom * Diaphragm * Cervical Cap -Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study treatment, OR agree to completely abstain from heterosexual intercourse. EXCLUSION CRITERIA: * Patients who are receiving any other investigational agents not included in this trial, within 21 days of the start of this trial and throughout the duration of this trial. * Prior therapy for SMM with a proteasome inhibitor. * Patients with a diagnosis of MM. * Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy. * Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. * Uncontrolled hypertension or diabetes. * Pregnant or lactating females. * Has refractory GI disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption. * Patient has greater than or equal to Grade 2 peripheral neuropathy. * Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months. * Systemic treatment, within 14 days before study enrollment, with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John s wort. * Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis. * Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. * Psychiatric illness/social situation that would limit compliance with study requirements. * QTc \> 470 milliseconds (msec) on a 12-lead EKG obtained during the Screening period. If a machine reading is above this value, the EKG should be reviewed by a qualified reader and confirmed on a subsequent EKG. * Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. * Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements or GI procedure that could interfere with the oral absorption or tolerance of treatment. * Major surgery within 1 month prior to enrollment. * Radiotherapy within 14 days before enrollment. * Central nervous system involvement (based on clinical assessment). * Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment. * No current bisphosphonate therapy (However, prior bisphosphonates or once a year intravenous bisphosphonate for osteoporosis is allowed). * Patients with Paget s disease of the bone * Recruitment Strategies * Patients from the SMM and MGUS Natural History Study (NCI Protocol: 10-C-0096) will be potential candidates. * Other participant sources will be from outside physician referrals. * Our ongoing natural history study and outside physician referral network have a high representation of minorities.