STEP 0 PRE-REGISTRATION

Patients must be considered potential candidates for participation in EAA173.

STEP 1 RANDOMIZATION

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, del 13q or 1q gain by conventional cytogenetics or fluorescence in situ hybridization (FISH) studies
* > 20% plasma cells on biopsy or aspirate.

A bone marrow aspirate and/or biopsy is required to be performed within 42 days prior to randomization and must demonstrate 10-59% clonal plasma cells.

Measurable disease as defined by having one or more of the following:
* >= 1 g/dL on serum protein electrophoresis (within 28 days prior to randomization)
* >= 200 mg of monoclonal protein on a 24 hour urine protein electrophoresis (within 28 days prior to randomization)
* NOTE: In the rare situation where the serum protein electrophoresis (SPEP) is felt to be unreliable, then quantitative immunoglobulin levels on nephelometry or turbidometry can be accepted

SPEP, urine protein electrophoresis (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 hour (hr), and urine in addition to serum must be followed in order to confirm a very good partial response (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 upper limit of normal [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 chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal or known moderate or severe persistent asthma within 2 years prior to randomization.

Hemoglobin >= 11 g/dL (within 28 days prior to randomization).

Platelet count >= 100,000 cells/mm^3 (within 28 days prior to randomization).

Absolute neutrophil count >= 1500 cells/mm^3 (within 28 days prior to randomization).

Calculated creatinine clearance >= 30 mL/min (within 28 days prior to randomization).

Bilirubin =< 1.5 mg/dL (within 28 days prior to randomization). (Except patients with known Gilbert’s Syndrome, who must have a total bilirubin less than 3.0 mg/dL).

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 times the upper limit of normal (within 28 days prior to randomization).

Patients must not have any prior or concurrent systemic or radiation therapy for the treatment of myeloma. Patients must also not have contraindication to deep vein thrombosis (DVT) prophylaxis/aspirin.

Patient must not have more than one focal marrow lesion on magnetic resonance imaging (MRI) of either pelvis or spine. Patients with indwelling pacemakers and/or ICD (implantable cardioverter-defibrillator) that is known or suspected to be MRI incompatible will be excused from this test.

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 within the 6 months prior to randomization.

Patients 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 Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.

Patients with monoclonal gammopathy of undetermined significance are not eligible.

Patients must not have grade 2 or higher peripheral neuropathy per CTCAE.

Patients must not have active, uncontrolled infection.

Patients 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.

Patients 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.

Patients must agree to register into the mandatory Risk Evaluation and Mitigation Strategy (REMS) program and be willing and able to comply with the requirements of REMS.

Patients must not be pregnant due to potential harm to the fetus from daratumumab and lenalidomide. All patients of childbearing potential 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. Patients of childbearing potential must also agree to ongoing pregnancy testing while on treatment. A patient of childbearing potential is anyone, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) 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)

Patients of childbearing potential 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 (Patients of childbearing potential who are assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment). Patients must also agree to not breastfeed during this same time period. Patients 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 partner of childbearing potential while participating in the study and for 28 days after the last dose of protocol treatment even if they have had a successful vasectomy (Patients assigned to Arm A and receive daratumumab must extend this contraception requirement to 3 months after the last dose of protocol treatment). Patients must also agree to abstain from donating sperm, even if they have had a successful vasectomy, or eggs while on study treatment and for 28 days after the last dose of protocol treatment (patients assigned to Arm A and receiving daratumumab must extend this requirement to 3 months after the last dose of protocol treatment). Patients must 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 prior to randomization are eligible for this trial.

Patients 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.

PRIMARY OBJECTIVE:
I. To compare overall survival in patients with high-risk smoldering multiple myeloma randomized to daratumumab and hyaluronidase-fihj (daratumumab-hyaluronidase subcutaneous [SC])-lenalidomide (Revlimid)-dexamethasone or Revlimid-dexamethasone.

SECONDARY CLINICAL OBJECTIVES:
I. To compare progression-free survival and response rates between arms.
II. To evaluate safety and compare toxicity rates between arms.
III. To monitor incidence of infusion-related reactions over the first cycle of daratumumab.
IV. To evaluate stem cell mobilization failure and early stem cell mobilization feasibility.

EXPLORATORY CLINICAL OBJECTIVES:
I. To measure treatment exposure and adherence.
II. To estimate treatment duration and time to progression.

PRIMARY PATIENT-REPORTED OUTCOMES OBJECTIVE:
I. To compare change in health-related quality of life (Functional Assessment of Cancer Therapy [FACT]- General [G]) from baseline to end of study therapy (cycle 24) between arms.

SECONDARY PATIENT-REPORTED OUTCOMES OBJECTIVES:
I. To compare change in FACT-G score from end of study therapy (cycle 24) or early treatment discontinuation to 6-months post-treatment end between arms.
II. To evaluate time to worsening of FACT-G score.

EXPLORATORY PATIENT-REPORTED OUTCOMES OBJECTIVES:
I To describe changes in FACT-G scores over study therapy and shortly after treatment discontinuation and evaluate correlation with survival.
II. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (Patient Reported Outcomes [PRO]-Common Terminology Criteria for Adverse Events [CTCAE]) longitudinally and compare responses with provider reported adverse events.
III. To measure the likelihood of medication adherence (ASK-12) and examine the relationship with treatment exposure.
IV. To assess correlation of treatment adherence and ASK-12 score with FACT-G score.
V. To tabulate PRO compliance and completion rates.

PRIMARY LABORATORY OBJECTIVES:
I. To compare minimal residual disease negativity rate after 12 cycles of study therapy between arms.
II. To compare minimal residual disease (MRD) positive to negative conversion rates from 12 cycles to end of treatment between arms.
III. To examine patterns of change in minimal residual disease levels during study therapy.

EXPLORATORY LABORATORY OBJECTIVES:
I. To evaluate agreement and discordance between methods determining disease-free status.
II. To assess the prognostic value of minimal residual disease status at 24 cycles for progression-free survival.

PRIMARY IMAGING OBJECTIVE:
I. To evaluate the association of baseline fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging with progression-free survival.

SECONDARY IMAGING OBJECTIVE:
I. To assess the ability of baseline 18F-FDG-PET/CT to predict minimal residual disease status after 12 cycles of study therapy and at the end of study therapy (cycle 24).

EXPLORATORY IMAGING OBJECTIVE:
I. To describe the results of subsequent 18F-FDG-PET/CT imaging studies in the subset of patients with baseline abnormal 18F-FDG-PET/CT, and to associate these results with progression free survival.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive daratumumab intravenously (IV) or daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, and day 1 of cycles 7-24. Patients also receive lenalidomide orally (PO) daily on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22 in cycles 1-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive lenalidomide PO daily on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22 of cycles 1-12. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

All patients receive fludeoxyglucose F-18 (FDG) IV and undergo positron emission tomography (PET)/computed tomography (CT) during screening and on study. Patients undergo magnetic resonance imaging (MRI) during screening. Patients also undergo bone marrow biopsy and aspiration throughout the trial and blood stem cell sample collection on the trial. 

After completion of study, patients will be followed up every 3, 6 or 12 months for up to 15 years from randomization.