Summary

This phase III trial studies how well lenalidomide and dexamethasone works with or without daratumumab-hyaluronidase in treating patients with high-risk smoldering myeloma. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Anti-inflammatory drugs, such as dexamethasone lower the body’s immune response and are used with other drugs in the treatment of some types of cancer. Daratumumab-hyaluronidase is a monoclonal antibody, daratumumab, that may interfere with the ability of cancer cells to grow and spread, and hyaluronidase, which may help daratumumab work better by making cancer cells more sensitive to the drug. Giving lenalidomide and dexamethasone with daratumumab-hyaluronidase may work better in treating patients with smoldering myeloma.

Objectives

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.