This phase III trial studies how well lenalidomide and dexamethasone works with or without daratumumab in treating patients with high-risk smoldering myeloma. Drugs used in chemotherapy, such as lenalidomide and dexamethasone, 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. Immunotherapy with monoclonal antibodies, such as daratumumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide and dexamethasone with daratumumab may work better in treating patients with smoldering myeloma.
PRIMARY OBJECTIVES: I. To compare overall survival in patients with high-risk smoldering multiple myeloma randomized to daratumumab-lenalidomide (revlimid)-dexamethasone or revlimid-dexamethasone. SECONDARY 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 OBJECTIVES: I. To measure treatment exposure and adherence. II. To estimate treatment duration and time to progression. PATIENT-REPORTED OUTCOMES OBJECTIVES: 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 between arms. II. To compare change in FACT-G scores from treatment end to 6-months post-treatment end between arms. III. To describe changes in FACT-G scores over study therapy and shortly after treatment discontinuation and evaluate correlation with survival. IV. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse events (Patient Reported Outcomes \[PRO\]-Common Terminology Criteria for Adverse Events \[CTCAE\]) longitudinally. V. To derive an overall PRO-CTCAE score at each assessment time point. VI. To measure the likelihood of medication adherence (ASK-12) at 6 month intervals throughout treatment. VII. To assess the association of overall PRO-CTCAE score with FACT-G score. VIII. To compare select PRO-CTCAE items and related provider-reported CTCAEs. IX. To evaluate association between treatment adherence and Adherence Starts with Knowledge 12 (ASK-12) score. X. To assess correlation of treatment adherence and ASK-12 score with FACT-G score. XI. To tabulate PRO compliance and completion rates. LABORATORY OBJECTIVES: I. To compare minimal residual disease negative 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. IV. To evaluate agreement and discordance between methods determining disease-free status. V. To assess the prognostic value of minimal residual disease status at 12 cycles for overall and progression-free survival. IMAGING OBJECTIVES: I. To evaluate the association of baseline fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging with progression-free survival. II. To assess the ability of baseline FDG-PET/CT to predict minimal residual disease status after 12 cycles of study therapy and at the end of study therapy. III. To describe the results of subsequent FDG-PET/CT imaging studies in the subset of patients with baseline abnormal FDG-PET/CT, and to associate these results with progression-free survival (PFS). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive daratumumab intravenously (IV) on days 1, 8, 15, and 22 of courses 1-2, days 1 and 15 of courses 3-6, and day 1 of courses 7-24. Patients also receive lenalidomide orally (PO) daily on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22 in courses 1-12. Treatment repeats every 28 days for up to 24 courses 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 courses 1-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. After completion of study, patients will be followed up every 3, 6 or 12 months for up to 15 years from study entry.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
288
Given IV
Given PO
Given PO
Ancillary studies
Ancillary studies
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
RECRUITINGAnchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
RECRUITINGAnchorage Radiation Therapy Center
Anchorage, Alaska, United States
SUSPENDEDAlaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Overall survival (OS)
Will be estimated using the Kaplan-Meier (KM) method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate.
Time frame: From randomization to death due to any cause, or censored at date last known alive, assessed up to 15 years
Functional Assessment of Cancer Therapy-General (FACT-G) score
A general effect size measure of half standard deviation will be used to establish the minimally important difference. Descriptive statistics (mean, standard deviation \[SD\], median, range) will be used to evaluate the distribution of levels and changes for the set of health-related quality of life (QOL) evaluations. Levels and changes will also be assessed graphically. Changes from baseline will be analyzed using linear mixed models based on restricted maximum likelihood estimation with covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. If there is substantial missingness, will analyze the data according to the methods described in Schluchter and Schluchter, Greene and Beck.
Time frame: Baseline to 24 cycles of treatment (each cycle is 28 days)
Progression-free survival (PFS)
Will be estimated using the KM method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate.
Time frame: From randomization until disease progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 15 years
Best response on treatment based on International Myeloma Working Group (IMWG) criteria
Response will be tabulated by category. Response rates of very good partial response (VGPR) or better and partial response (PR) or better will be compared using the Fisher's exact test. Ineligible patients are excluded from the analysis and unevaluable patients are counted in the denominator.
Time frame: At 12 and 24 months
Incidence of adverse events by worst grade and type for treated patients determined using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Will monitor the toxicities experienced by all treated patients. Will compare rates of worst grade 3 or higher non-hematologic treatment-related events using the Fisher's exact test.
Time frame: Up to 28 days post-treatment
Incidence of grade 3 or higher infusion-related reactions over course 1 determined based on CTCAE
Will monitor the toxicities experienced by all treated patients. Will compare rates of worst grade 3 or higher non-hematologic treatment-related events using the Fisher's exact test.
Time frame: During cycle 1 of treatment (each cycle is 28 days)
Stem cell (SC) mobilization failure
Defined as not collecting a minimum of 5x10\^6 CD34 cells per kilogram weight. SC mobilization and type of growth factor support will be summarized overall and by treatment arm with descriptive statistics.
Time frame: After 4 to 6 cycles of treatment (each cycle is 28 days)
Early SC mobilization feasibility
Defined as the proportion of patients less than 65 years of age treated for 6 courses who opt for SC mobilization. SC mobilization and type of growth factor support will be summarized overall and by treatment arm with descriptive statistics.
Time frame: Up to 6 cycles of treatment (each cycle is 28 days)
Type of growth factor support
SC mobilization and type of growth factor support will be summarized overall and by treatment arm with descriptive statistics.
Time frame: During 4 to 6 cycles of treatment (each cycle is 28 days)
Change in FACT-G score
A general effect size measure of half standard deviation will be used to establish the minimally important difference. Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Changes from baseline will be analyzed using linear mixed models based on restricted maximum likelihood estimation with covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. If there is substantial missingness, will analyze the data according to the methods described in Schluchter and Schluchter, Greene and Beck.
Time frame: From treatment end to 6 months post-treatment
Levels of FACT-G score at each assessment time point
A general effect size measure of half standard deviation will be used to establish the minimally important difference. Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Changes from baseline will be analyzed using linear mixed models based on restricted maximum likelihood estimation with covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. If there is substantial missingness, will analyze the data according to the methods described in Schluchter and Schluchter, Greene and Beck.
Time frame: From baseline, at 3, f7, 13, 19 cycles of treatment, and early discontinuation of treatment, assessed up to 24 cycles of treatment (each cycle is 28 days)
Time to worsening of FACT-G
Will be analyzed with Kaplan-Meier methods and Cox regression with the related treatment arm as the only factor. Correlation between time to worsening of symptoms with PFS and OS will be assessed with Kendall's Tau adjusted for censored observations.
Time frame: From baseline until a decrease of 9 points, or censored at date of last assessment, assessed up to 6 months post-treatment
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Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
RECRUITINGAlaska Women's Cancer Care
Anchorage, Alaska, United States
RECRUITINGAnchorage Oncology Centre
Anchorage, Alaska, United States
SUSPENDEDKatmai Oncology Group
Anchorage, Alaska, United States
RECRUITINGProvidence Alaska Medical Center
Anchorage, Alaska, United States
RECRUITINGFairbanks Memorial Hospital
Fairbanks, Alaska, United States
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