A randomized Phase II clinical trial will be conducted to assess the impact on progression free survival (PFS) with the addition of ixazomib and daratumumab to lenalidomide as a maintenance treatment following induction with lenalidomide, ixazomib, dexamethasone, and daratumumab.

Patients will be randomized to either:

Arm A: 12 cycles of lenalidomide, ixazomib, daratumumab, and dexamethasone followed by lenalidomide until disease progression or unacceptable toxicity or a maximum of 2 years of maintenance therapy.

Arm B: 12 cycles of lenalidomide, ixazomib, daratumumab and dexamethasone, followed by lenalidomide, ixazomib, and daratumumab until disease progression or unacceptable toxicity or a maximum of 2 years maintenance therapy.

Induction Phase: 28-day treatment cycle. Treatment continues until disease progression or for a maximum of 12 cycles as follows:

Cycles 1-2:

• Lenalidomide - 15 mg PO QD on Days 1-21
• Ixazomib - 4 mg PO on Days 1, 8, 15
• Daratumumab Subcutaneous - 15mL/1800mg on Days 1, 8, 15, 22
• Dexamethasone - 20 mg PO on Days 1, 2, 8, 9, 15, 16, 22, 23; For participants ≥75, dexamethasone administered on days 1, 8, 15, 22

Cycles 3-6:

• Lenalidomide - 15 mg PO QD on Days 1-21
• Ixazomib - 4 mg PO on Days 1, 8, 15
• Daratumumab Subcutaneous - 15mL/1800mg on Days 1, 15
• Dexamethasone - 20 mg PO on Days 1, 2, 8, 9, 15, 16; For participants ≥75, dexamethasone administered on days 1, 8, 15

Cycles 7-12:

• Lenalidomide - 15 mg PO QD on Days 1-21
• Ixazomib - 4 mg PO on Days 1, 8, 15
• Daratumumab Subcutaneous - 15mL/1800mg on Day 1
• Dexamethasone - 20 mg PO on Days 1, 2, 8, 9, 15, 16; For participants ≥75, dexamethasone administered on days 1, 8, 15

Maintenance Phase: 28-day treatment cycle. Treatment continues until progression or a maximum of 2 years of maintenance treatment:

Arm A

• Lenalidomide - 10 mg PO QD on Days 1-21

Arm B

• Lenalidomide - 10 mg PO QD on Days 1-21
• Ixazomib - 3 mg (or last tolerated dose from the induction phase) PO on Days 1, 8, and 15
• Daratumumab Subcutaneous - 15mL/1800mg on Day 1
• Dexamethasone - 20mg PO on Day 1; Unless patient is ≥75 then 10mg po day 1

In the maintenance phase, dexamethasone, 20 mg PO orally or IV will be administered to patients as a pre-infusion medication prior to daratumumab dosing. When dexamethasone is reduced to 20 mg/week and is given as pre-infusion medication, patients may receive low-dose methylprednisolone (≤20 mg) orally (or equivalent in accordance with local standards) for the prevention of delayed IRRs as clinically indicated.

If the investigator wishes to continue the maintenance regimen at the end of the 2 years maintenance treatment, patients may continue current maintenance as per standard of care.

Inclusion Criteria:

1. Patient must be at least 18 years of age.

2. Subject must have documented multiple myeloma:

   • Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma

   • Following CRAB features and/or myeloma-defining events (MDEs):

     • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:

       • Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL) OR
       • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 mol/L (>2 mg/dL) OR
       • Anemia: hemoglobin value of >2 g/dL below the lowest limit of normal, or a hemoglobin value <100 g/L OR
       • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR

     • OR any one or more of the following biomarkers of malignancy (MDEs):

       • Sixty percent (60%) or greater clonal plasma cells on bone marrow examination.
       • Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100 mg/L (A patient's involved free light chain, either kappa or lambda, is the one that is above the normal reference range; the uninvolved free light chain is the one that is typically in, or below, the normal range).
       • More than one focal lesion on MRI that is at least 5 mm or greater in size.

3. Measurable disease as defined by any of the following:

   • IgG myeloma: serum monoclonal paraprotein (M-protein) level ≥0.5 g/dL; or
   • IgA, IgM, or IgD multiple myeloma: serum M-protein level ≥0.5 g/dL; or
   • Urine M-protein level ≥200 mg/24 hours; or
   • Serum free light chain ≥100 mg/L and abnormal serum immunoglobulin kappa lambda free light chain ratio

4. Newly diagnosed and not considered candidate for high-dose chemotherapy with stem cell transplant due to:

   • Age ≥70 years, OR
   • In patients <70 years: presence of important comorbid condition(s) likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation (ASCT) and/or site investigator's discretion due to concern regarding acute and long-term toxicity.

5. Patient must have an ECOG performance status score of 0, 1, or 2.

6. Patient must have adequate pretreatment clinical laboratory values meeting the following criteria ≤14 days of registration date:

   • Hemoglobin ≥7.5 g/dL (prior red blood cell transfusion or recombinant human erythropoietin use is permitted).
   • Absolute neutrophil count (ANC) ≥1x109/L (granulocyte colony stimulating factor (GCSF use is permitted).
   • Platelet count ≥75x109/L for patients in whom <50% of bone marrow nucleated cells are plasma cells; otherwise, platelet count >50×109/L (transfusions are not permitted to achieve this minimum platelet count).
   • Aspartate aminotransferase (AST) ≤3xULN.
   • Alanine aminotransferase (ALT) ≤3xULN.
   • Total bilirubin ≤1.5xULN, except in patients with congenital bilirubinemia, such as Gilbert syndrome (direct bilirubin ≤2xULN).
   • Creatinine clearance (CrCl) ≥30 mL/min. (Creatinine clearance may be calculated using the Cockcroft-Gault formula
   • Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium <6.5 mg/dL (<1.6 mmol/L).

7. Women of childbearing potential (WOCBP) must commit to either abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device [IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to initial dosing. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy. A man who is sexually active with a WOCBP must agree to use a latex or synthetic condom, even if they had a successful vasectomy. All men must also not donate sperm during the study, for 4 weeks after the last dose of lenalidomide, and for 4 months after the last dose of daratumumab. A WOCBP must have 2 negative serum or urine pregnancy tests first within 10 to 14 days prior to the registration date.

8. All study patients must be registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of the REMS program.

9. Females of reproductive potential must agree to adhere to the scheduled pregnancy testing as required in the Revlimid REMS program.

10. At the time of registration, confirmation of adequate contraceptive method(s) should be documented in the medical record.

11. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Patient has primary AL amyloidosis.

2. Prior history of Waldenström's disease, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.

3. Prior or current systemic therapy or stem cell transplantation (SCT) for MM, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before initial dosing. 1 cycle or less of urgent systemic treatment may be allowed after discussion with the Study Chair.

4. Patients undergoing treatment for a malignancy within 5 years prior to study enrollment with the exception of non-invasive malignancies that in the opinion of the site investigator are considered cured or have minimal risk of recurrence within 5 years. Patient must not have active concomitant, invasive malignancy. Note: patients on chronic hormonal therapy for localized breast or prostate cancer with no evidence for the primary malignancies or prostate cancer undergoing active surveillance can be included.

5. Radiation therapy ≤14 days prior to C1D1.

6. Plasmapheresis ≤28 days prior to C1D1.

7. Exhibiting clinical signs of meningeal involvement of MM ≤28 days prior to screening.

8. Known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume [FEV] in 1 second <60% of predicted normal), persistent asthma, or a history of asthma ≤ 2 years prior to screening (intermittent asthma is allowed).

   Note: Patients with known or suspected COPD or asthma must have a FEV1 test within 28 days prior to screening.

9. Patient has history or evidence of unstable/uncontrolled medical or psychiatric disorder, condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the site investigator, would pose a risk to subject safety or interfere with study evaluation, procedures or completion.

10. Clinically significant cardiac disease, including:

    • myocardial infarction ≤1 year prior to screening, or an unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV).
    • uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0 Grade ≥2) or clinically significant ECG abnormalities;
    • 12-lead ECG performed ≤28 days prior to screening showing a baseline QT interval as corrected by Fridericia's formula (QTcF) >470 msec.

11. 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.

12. History of plasma cell leukemia (by WHO criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of more than 2×10^9/L) or POEMS syndrome (ie, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).

13. Patient is:

    • seropositive for human immunodeficiency virus (HIV)
    • seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs 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.
    • seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

14. A woman who is pregnant, or breast-feeding, or planning to become pregnant during the study period or a man who plans to father a child during the study period. See Section 12.8 for further details.

15. Major surgery ≤14 days prior to screening or has not fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study.

    Note: Kyphoplasty or vertebroplasty is not considered major surgery.

16. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device ≤28 days prior to initial dosing or is currently enrolled in an interventional investigational study.

17. Contraindications to required protocol prophylaxis for deep vein thrombosis and pulmonary embolism.

18. Peripheral neuropathy Grade 2 or severe ≤28 days prior to screening.

19. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort ≤14 days prior to screening.