The following criteria is provided for health care professionals.

Inclusion Criteria:

• Age ≥ 18 years.
• Must meet criteria of high risk smoldering MM based on the criteria described below:
• Definition of high-risk SMM:
  • Serum M protein ≥3.0g/dL (IgA, IgG, IgM, or IgD)
  • IgA SMM
  • Immunoparesis with reduction of two uninvolved immunoglobulin isotypes
  • Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)
  • ---Free Light Chain Smoldering Myeloma patients as defined in section 2.4 are not excluded
  • Progressive increase in M protein level (Evolving type of SMM)
  • ----Increase in serum monoclonal protein by ≥10% on two successive evaluations within a 6 month period
  • Bone marrow clonal plasma cells 50-60%
  • Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes
  • t (4;14) or del 17p or 1q gain
  • Increased circulating plasma cells
  • MRI with diffuse abnormalities or 1 focal lesion
  • PET-CT with one focal lesion with increased uptake without underlying osteolytic bone destruction
  • Urine monoclonal light chain excretion ≥500 mg/24 hours
• --Bone marrow clonal plasma cells ≥10% and ≤60% and any one or more of the following:
• ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)
• The following laboratory values obtained ≤ 21 days prior to registration and confirmed prior to the first dose of study drug:
  • ANC ≥ 1000/uL
  • PLT ≥ 75,000/uL. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
  • Total bilirubin ≤ 1.5 mg/dL (If total is elevated check direct and if normal patient is eligible.)
  • AST ≤ 3 x institutional upper limit of normal (ULN)
  • ALT ≤ 3 x institutional upper limit of normal (ULN)
  • Calculated creatinine clearance ≥ 30 mL/min
• Ability to understand and the willingness to sign a 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performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Female patients who are postmenopausal for at least 1 year before the screening visit or are surgically sterile. Females of childbearing potential* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMS®) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. Female patients must agree to practice two effective methods of birth control from the time of signing the informed consent form though 90 days after the last dose of study drug
• A female of childbearing potential is a sexually mature female who:
  • Has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or
  • Has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months)
• All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
• Men must agree to use a latex condom during sexual contact with a female of childbearing potential even if they have had a successful vasectomy during the entire study treatment period and through 90 days after the last dose of study drug 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.)

Exclusion Criteria:

• No evidence of CRAB* criteria or new criteria of active MM which including the following:
  • Increased calcium levels (corrected serum calcium >0.25 mmol/dL above the upper limit of normal or >.275 mmol/dL) related to MM
  • Renal insufficiency (attributable to MM)
  • Anemia (Hb 2g/dL below the lower limit of normal or <10g/dL) related to MM
  • Bone lesions (lytic lesions or generalized osteoporosis with compression fractures)
  • Bone marrow plasma cells ≥60%
  • Serum involved/uninvolved FLC ratio ≥100, provided the absolute level of the involved free light chain is at least 100 mg/L and repeated twice
  • MRI with two or more focal lesion that is at least 5 mm or greater in size
• Participants with CRAB criteria that are attributable to conditions other than the disease under study may be eligible
• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational. Prior therapy with bisphosphonate is allowed. Prior radiation therapy to a solitary plasmacytoma is allowed.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or nursing women will be excluded from the study because lenalidomide is an agent with the potential for teratogenic or abortifacient effects.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ixazomib or lenalidomide.
• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
• Major surgery within 14 days before enrollment.
• Known Amyloid involvement.
• Myeloma-related central nervous system involvement.
• Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
• Grade 2 peripheral neuropathy or higher or grade 1 with pain on clinical examination during the screening period.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.
• Previous treatment with ixazomib, or participation in a study with ixazomib whether treated with ixazomib or not.