Lenalidomide, and Dexamethasone With or Without Daratumumab in Treating Patients With High-Risk Smoldering Myeloma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Daratumumab to Enhance Therapeutic Effectiveness of Revlimid in Smoldering Myeloma (DETER-SMM)

Conditions
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Smoldering Plasma Cell Myeloma

Intervention / Treatment
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* Biological: Daratumumab
* Drug: Dexamethasone
* Drug: Lenalidomide
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 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 ratio of involved to uninvolved >20, but less than 100 if the involved FLC is >= 10 mg/dL by serum free light chain (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 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. >= 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. Patients 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]). 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). 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. Patients 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. Patients must not have active, uncontrolled seizure disorder. Patients must not have had a seizure in the last 6 months. 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. For most diseases this time frame is 5 years. 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. 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 any woman, regardless of sexual orientation or 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). 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 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)+ patients with undetectable HIV viral loads tested within 6 months are eligible. Patients should not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to daratumumab, lenalidomide, or dexamethasone. Patients 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (daratumumab, lenalidomide, dexamethasone)<br>Patients receive daratumumab 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 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. | Biological: Daratumumab<br>* Given IV<br>* Other names: JNJ-54767414;Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (lenalidomide, dexamethasone)<br>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. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Baseline to 24 cycles of treatment (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | From baseline until a decrease of 9 points, or censored at date of last assessment, assessed up to 6 months post-treatment |