Inclusion Criteria: 

• Patient must be ≥ 18 years of age.                    
• Patient must be diagnosed with asymptomatic high-risk smoldering multiple myeloma (SMM) within the past 12 months. High-risk is defined by the presence of 2 or more of the following factors:
  • Abnormal serum free light chain (FLC) ratio of involved to uninvolved >20, but less than 100 if the involved FLC is >10 mg/dL by serum FLC assay;
  • Serum M-protein level > 2 gm/dL;
  • Presence of t(4;14) or del 17p or 1q gain by conventional cytogenetics or FISH studies;
  • > 20% plasma cells on biopsy or aspirate;
• A bone marrow aspirate and/or biopsy is required to be performed within 28 days prior to randomization and must demonstrate 10-59% clonal plasma cells.
• 1.  
• Patient must have measureable disease as defined by having one or more of the following, obtained within 28 days prior to randomization:
  • ≥ 1 g/dL on serum protein electrophoresis;
  • ≥ 200 mg of monoclonal protein on a 24 hour urine protein electrophoresis.
• NOTE: In the rare situation where the SPEP is felt to be unreliable, then quantitative immunoglobulin levels on nephelometry or turbidometry can be accepted. SPEP, UPEP, and serum FLC are required to be performed within 28 days prior to randomization.
• NOTE:      UPEP (on a 24-hour collection) is required; no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is ≥ 200 mg/24 hr, and urine in addition to serum must be followed in order to confirm a VGPR or higher response.
• Patient must have no lytic lesions, no known plasmacytoma, and no unexplained hypercalcemia (i.e., > 11 mg/dL or 1mg/dL above ULN). Specifically, local interpretation of MRI and PET scans will be used to exclude lytic lesions or plasmacytomas and must be obtained within 60 days prior to randomization.
• Patient must not have known COPD with FEV1 < 50% or known moderate or severe persistent asthma within 2 years prior to randomization.
• Patient must have adequate organ and marrow function as defined below (obtained within 28 days prior to randomization):
  • Hemoglobin ≥ 11 g/dL;
  • Platelet count ≥ 100,000 cells/mm^3;
  • Absolute neutrophil count ≥ 1500 cells/mm^3;
  • Calculated creatinine clearance ≥ 30 mL/min;
  • Bilirubin ≤ 1.5 mg/dL;
  • SGPT (ALT) and SGOT (AST) ≤ 2.5 times the upper limit of normal.
• Patient must not have any prior or concurrent systemic or radiation therapy for the treatment of myeloma. Patient must also not have contraindication to DVT prophylaxis/aspirin.
• Patient must not have more than one focal marrow lesion on MRI of either pelvis or spine.
• Concurrent use of erythropoietin is not allowed while on study therapy.
• Prior or glucocorticosteroid therapy for the treatment of multiple myeloma is not permitted.
• Prior systemic glucocorticosteroid use for the treatment of non-malignant disorders is permitted; concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day. Prior or concurrent topical or localized glucocorticosteroid therapy to treat non-malignant comorbid disorders is permitted.
• Patient must not have active, uncontrolled seizure disorder. Patient must not have had a seizure in the last 6 months.
• Patient must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson Syndrome.
• Patient must have an ECOG performance status 0, 1, or 2.
• Patients with monoclonal gammopathy of undetermined significance are not eligible.
• Patient must not have Grade 2 or higher peripheral neuropathy per CTCAE.
• Patient must not have active, uncontrolled infection.
• Patient may have a history of current or previous deep vein thrombosis or pulmonary embolism but are required to take some form of anti-coagulation as prophylaxis if they are not currently on full- dose anticoagulation.
• Patient should not have New York Heart Association classification III or IV heart failure at baseline.
• Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for the time period considered appropriate for cure of the specific cancer.
• Patient must agree to register into the mandatory REMS program and be willing and able to comply with the requirements of REMS.
• Women must not be pregnant due to potential harm to the fetus from Daratumumab and Lenalidomide. All females of childbearing potential (FCBP) must have a blood test or urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the first dose of lenalidomide and again within 24 hours prior to the first dose of lenalidomide. FCBP must also agree to ongoing pregnancy testing while on treatment. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; 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 in the preceding 24 consecutive months).
  • Females of childbearing potential (FCBP) must either abstain from sexual intercourse for the duration of their participation in the study or agree to use TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2) while participating in the study; 3) during dose interruptions; and 4) for at least 28 days after the last dose of protocol treatment (FCBP who are assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment). Women must also agree to not breastfeed during this same time period. Men must agree to either abstain from sexual intercourse for the duration of their participation in the study or use a latex condom during sexual contact with a FCBP while participating in the study and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy (Men assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment).
  • Men must also agree to abstain from donating sperm while on study treatment and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy. Both women and men must both agree to abstain from donating blood during study participation and for at least 28 days after the last dose of protocol treatment.
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial. 
  • Patient should not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to daratumumab, lenalidomide, or dexamethasone.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.