Inclusion Criteria:

• All participants must be registered into the mandatory POMALYST REMS program and be willing and able to comply with the requirements of the POMALYST REMS program.
• Confirmed diagnosis of Multiple Myeloma having received 1 and 3 prior lines of treatment
• Relapsed and/or refractory disease
• Measurable disease
• Life expectancy of more than 3 months
• ECOG performance status of 0, 1, or 2
• No prior progression on pomalidomide
• All pts must have received prior lenalidomide therapy and been determined to be relapsed and/or refractory.
• Adequate hepatic function
• Adequate renal function
• Additional Laboratory Requirements
  1. ANC ≥1.0 x 10^9/L, Hgb ≥8 g/dL (transfusion permitted)
  2. Platelet count ≥75 x 10^9/L (≥ 50x10^9/L if bone marrow plasma cells are ≥50% of cellularity)
• Women of child-bearing potential and men with partners of child-bearing potential must agree to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity from the time of signing the informed consent for through 120 days after the last dose of study medication.
• Women of childbearing potential have negative pregnancy test within 72 hours of initiating study drug dosing.
• Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
• Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program.
• Subjects must agree to take enteric-coated aspirin 81 mg orally daily, or if history of prior thrombotic disease, must be fully anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism (PE) at the investigator's discretion.

Exclusion Criteria:

• Current or anticipated use of other investigational agents.
• Prior daratumumab or ixazomib use
• Patients who are refractory to pomalidom
• Non-secretory or hyposecretory multiple myeloma defined as:
• Plasma cell leukemia (>2.0 x 10 9/L circulating plasma cells by standard differential)
• Waldenström's macroglobulinemia or IgM myeloma
• Known central nervous system involvement by multiple myeloma
• Radiotherapy to multiple sites or immunotherapy within 2 weeks before enrollment (localized radiotherapy to a single site at least 1 week before start is permissible)
• Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater. Non-interventional trials (i.e. observational trials) are permitted at any time point
• Female patients who are lactating or have a positive serum pregnancy test during the screening period.
• Major surgery within 3 weeks prior to first dose
• Myocardial infarction within 6 months prior to enrollment, NYHA (New York Heart Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
• Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
• Known or suspected HIV infection, known HIV seropositivity
• Active hepatitis infection
• 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 nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Subjects with known or suspected light chain amyloidosis of any organ.
• Known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, Daratumumab, or its excipients. or known sensitivity to mammalian-derived products.
• Has known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal
• Has known moderate or severe persistent asthma within the past 2 years per asthma guidelines
• Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of ixazomib or pomalidomide, including difficulty swallowing