Inclusion Criteria:

• Age 18 years or older.
• The following laboratory values obtained £14 days prior to registration:
  • Calculated creatinine clearance (using Cockcroft-Gault equation below)* >=30 mL/min;
  • Absolute neutrophil count (ANC) ³1500/mm3;
  • Untransfused Platelet count ³75000/mm3;
  • Hemoglobin ≥8.0 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • ALT and AST ≤ 2.5 x ULN.
  • *Cockcroft-Gault Equation:
    • Creatinine clearance for males = (140 - age)(actual body weight in kg)/(72)(serum creatinine in mg/dL);
    • Creatinine clearance for females = (140 - age)(actual body weight in kg)(0.85)/(72)(serum creatinine in mg/dL).
• Measurable disease of multiple myeloma as defined by at least ONE of the following:
  • Serum monoclonal protein ³1.0 g/dL (see Section 11.1 for definition);
  • >200 mg of monoclonal protein in the urine on 24 hour electrophoresis;
  • Serum immunoglobulin free light chain ³10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio.
• ECOG performance status (PS) 0, 1 or 2 (Appendix IV).
• Previously untreated for myeloma or have received no more than one cycle of any treatment regimen.
  • NOTE: Prior radiation therapy for the treatment of solitary plasmacytoma is permitted. Prior therapy with clarithromycin, DHEA, anakinra, pamidronate or zoledronic acid is permitted. Any additional agents not listed must be approved by the Principal Investigator.
• Provide informed written consent.
• Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.
• Willing to follow strict birth control measures.
• Female patients: If they are of childbearing potential, agree to one of the following:
  • Practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, AND must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Male patients: even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug; OR
  • Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable; OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Negative hepatitis B test (defined by a negative test for hepatitis B surface antigen [HBsAg], or antibodies to hepatitis B surface and/or core antigens [antiHBs or antiHBc) (added as of addendum 9).
  • Note:   Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willing to follow the requirements of the Revlimid REMS program.
• Willing to provide bone marrow and blood samples for planned research.

Exclusion Criteria:

• MGUS or smoldering myeloma.
• Diagnosed or treated for another malignancy ≤ 2 years prior to registration or previously diagnosed with another malignancy and have any evidence of residual disease.  NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant women;
  • Nursing women;
  • Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Other concurrent chemotherapy, or any ancillary therapy considered investigational. 
  • NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment.
• Peripheral neuropathy ≥ Grade 2 on clinical examination or grade 1 with pain during the screening period.
• Major surgery ≤14 days prior to registration.
• Systemic treatment with strong CYP3A4 inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, St. John’s wort) ≤14 days prior to registration.
• Evidence of current uncontrolled cardiovascular conditions, including hypertension, cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial infarction ≤6 months.  Note: Prior to  entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Radiotherapy  ≤ 14 days prior to registration.
  • NOTE: If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the ixazomib.
• Known human immunodeficiency virus (HIV) positive.
• Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or Investigator's Brochure), or known sensitivity to mammalian-derived products.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, lenalidomide or dexamethasone including difficulty swallowing.
• Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence of antidiarrheals.