Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of daratumumab in combination with lenalidomide and dexamethasone to that of lenalidomide and dexamethasone in terms of progression-free survival (PFS) in participants with newly diagnosed multiple myeloma (a blood cancer of plasma cells) who are not candidates for high dose chemotherapy (treatment of disease, usually cancer, by chemical agents) and autologous stem cell transplant (ASCT).

Detailed Description
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This is a Phase 3, randomized (study drug assigned by chance), open-label (participants and researchers are aware about the treatment, participants are receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), parallel-group (each group of participants will be treated at the same time), and multicenter (when more than one hospital or medical school team work on a medical research study) study in participants with newly diagnosed multiple myeloma and who are not candidates for high dose chemotherapy and ASCT. All the eligible participants will be randomly assigned to receive either lenalidomide and dexamethasone (Rd) (Arm A) or daratumumab in combination with lenalidomide and dexamethasone (DRd) (Arm B). Daratumumab (16 milligram per kilogram [mg/kg]) will be administered weekly for first 8 weeks (Cycles 1 to 2) of treatment and then every other week for 16 weeks (Cycles 3 to 6), then every 4 weeks (from Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide will be administered at a dose of 25 mg orally on Days 1 through 21 of each 28-day cycle, and dexamethasone will be administered at a dose of 40 mg once a week for both treatment arms. Participants in both treatment arms will continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. All participants randomized to Treatment Arm B (DRd) in this study initially received daratumumab IV formulation; however, following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator. Daratumumab subcutaneous (SC) will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study completion. Participants in Arm A who have sponsor-confirmed disease progression may have the option to receive daratumumab provided by the sponsor (in any subsequent line of therapy) in the Follow-up phase. The study consists of 3 phases: Screening Phase (within 21 days prior to the first dose administration on Day 1), Treatment Phase (Day 1 up to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, consent withdrawal, or study end, whichever occurs first). The maximum duration of study will be 7 years after last participant is randomized. Efficacy will primarily be evaluated by PFS. Participants' safety will be monitored throughout the study.

Official Title
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A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Daratumumab IV
* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Daratumumab SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must have documented multiple myeloma satisfying the CRAB (calcium elevation, renal insufficiency, anemia and bone abnormalities) criteria, monoclonal plasma cells in the bone marrow greater than or equal to (>=) 10 percent (%) or presence of a biopsy proven plasmacytoma and measurable disease as defined by any of the following: (a) immunoglobulin (Ig) G myeloma (serum monoclonal paraprotein [M-protein] level >=1.0 gram/deciliter [g/dL] or urine M-protein level >=200 milligram[mg]/24 hours[hrs]; or (b) IgA, IgM, IgD, or IgE multiple myeloma (serum M-protein level >=0.5 g/dL or urine M-protein level >=200 mg/24 hrs); or (c) light chain multiple myeloma without measurable disease in serum or urine (serum immunoglobulin free light chain >=10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio) Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Participants who are newly diagnosed and not considered for high-dose chemotherapy due to: being age >=65 years; or participants less than (<) 65 years with presence of important comorbid condition(s) likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. Sponsor review and approval of participants below 65 years of age is required before randomization Women of childbearing potential must commit to either abstain continuously from sexual intercourse or to use 2 methods of reliable birth control simultaneously as deemed appropriate by the Investigator. Contraception must begin 4 weeks prior to dosing and must continue for 3 months after the last dose of daratumumab Man, who is sexually active with a woman of child-bearing potential must agree to use a latex or synthetic condom, even if he had a successful vasectomy, must agree to use an adequate contraception method as deemed appropriate by the Investigator, and must also agree to not donate sperm during the study and for 4 weeks after last dose of lenalidomide and 4 months after last dose of daratumumab Exclusion Criteria: Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (presence of serum M-protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the M-protein), or smoldering multiple myeloma (asymptomatic multiple myeloma with absence of related organ or tissue impairment end organ damage) Participant has a diagnosis of Waldenström's disease, or other conditions in which IgM M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions Participant has a history of malignancy (other than multiple myeloma) within 5 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator, with concurrence with the Sponsor's medical monitor, is considered cured with minimal risk of recurrence within 5 years) Participant has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for 4 days) of corticosteroids before treatment Participant has had radiation therapy within 14 days of randomization Participant has known chronic obstructive pulmonary disease (COPD) (defined as a forced expiratory volume in 1 second [FEV1] <50% of predicted normal), persistent asthma, or a history of asthma within the last 2 years (controlled intermittent asthma or controlled mild persistent asthma is allowed) Participants with known or suspected COPD must have a FEV1 test during Screening Participant is known to be seropositive for human immunodeficiency virus (HIV) or hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or antibodies to hepatitis B surface and core antigens [anti-HBs and anti-HBc, respectively]) or hepatitis C (anti-HCV antibody positive or HCV-ribonucleic acid [RNA] quantitation positive)

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 |
| --- | --- |
| Active Comparator: Lenalidomide and Dexamethasone (Rd)<br>Participants will receive Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first. | Drug: Daratumumab IV<br>* Daratumumab will be administered at a dose of 16 milligram per kilogram (mg/kg) by intravenous (IV) infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression of disease, unacceptable toxicity, or end of study (maximum up to 7 years).<br>* Other names: JNJ-54767414;Drug: Lenalidomide<br>* Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle.<br>Drug: Dexamethasone<br>* Dexamethasone 40 mg orally or intravenously once in a week.<br>|
| Active Comparator: Daratumumab + Lenalidomide + Dexamethasone (DRd)<br>Participants will receive Daratumumab 16 milligram per kilogram (mg/kg) by intravenous infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks, Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator. Daratumumab subcutaneous (SC) will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study completion. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first. | Drug: Lenalidomide<br>* Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle.<br>Drug: Dexamethasone<br>* Dexamethasone 40 mg orally or intravenously once in a week.<br>Drug: Daratumumab SC<br>* Daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or study end. Following implementation of protocol amendment 8, participants still receiving treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion of the investigator.<br>* Other names: JNJ-54767414;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary: Progression-free Survival (PFS) | PFS is defined as time from date of randomization to either progressive disease (PD) or death, whichever occurs first based on computerized algorithm as per International Myeloma Working Group (IMWG) criteria. PD is defined as an increase of 25 percent (%) from the lowest response value in one of the following: serum and urine M-component (absolute increase must be greater than or equal to [>=] 0.5 gram per deciliter [g/dL] and >=200 milligram [mg]/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be greater than [>]10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to Plasma cell (PC) proliferative disorder. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 3.5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) or Better | CR or better is defined as percentage of participants with a CR or better (CR or stringent complete response [sCR]) based on computerized algorithm as per IMWG criteria. CR is defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (<) 5 percent (%) PCs in bone marrow. In participants with only measurable disease by serum FLC levels a normal serum FLC ratio is required. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Percentage of Participants With Very Good Partial Response (VGPR) or Better | VGPR or better is defined as the percentage of participants with a response of VGPR or better (VGPR, CR or sCR) based on computerized algorithm as per IMWG criteria. VGPR is defined as serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. In participants with only measurable disease by serum FLC levels a >90% decrease in the difference between involved and uninvolved FLC levels is required. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | MRD negativity rate is defined as the percentage of participants who had negative MRD (detection of less than 1 malignant cell among 100,000 normal cells) assessment at any timepoint after the date of randomization by evaluation of bone marrow aspirates. MRD was assessed in participants who achieved CR or better. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Overall Response Rate (ORR) | ORR is defined as the percentage of participants who achieved partial response (PR) or better (PR, VGPR, CR or sCR) based on computerized algorithm as per IMWG criteria. PR is defined as >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours. If the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required. A >=50% reduction in the size of soft tissue plasmacytomas is also required. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Overall Survival (OS) | OS was measured from the date of randomization to the date of the death. | From randomization to death, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Time to Disease Progression (TTP) | TTP is defined as the time from the date of randomization to the date of PD based on computerized algorithm as per IMWG criteria, or death due to PD. | From randomization to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Time to Response | Time to response is defined as the time from the date of randomization to the first efficacy evaluation that met criteria for PR or better based on computerized algorithm as per IMWG criteria. PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours. If the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow PCs is required. A >=50% reduction in the size of soft tissue plasmacytomas is also required. | From randomization to first response (PR or better) (up to 7.8 years) | 
| Duration of Response (DoR) | DoR is defined as the time from the date of initial response (PR or better) to the date of PD, based on computerized algorithm as per IMWG criteria. | From first response (PR of better) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Time to Subsequent Anti-myeloma Treatment | Time to subsequent anti-myeloma treatment is defined as the time from randomization to the start of first line of subsequent anti-myeloma treatment or death, whichever occurs first. | From randomization to start of first subsequent anti-myeloma treatment, death, withdrawal of consent to study participation or CCO whichever is first (up to 7.8 years) | 
| Progression-free Survival on Next Line of Therapy (PFS2) | PFS2 is defined as the time from randomization to progression on the first line of subsequent anti-myeloma therapy or death, whichever occurs first. Disease progression on first line of subsequent anti-myeloma treatment was based on investigator judgment. Participants that were censored for PFS1 were also censored for PFS2. | From randomization to disease progression on first line of subsequent anti-myeloma therapy, death, withdrawal of consent to study participation or CCO whichever occurs first (up to 7.8 years) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score to Day 1 of Cycle 3, 6, 9 and 12 | EORTC QLQ-C30 is 30 items self-reporting questionnaire, with 1 week recall period, resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global Health Status (GHS) scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaire includes 28 items with 4-point Likert type responses from 1-not at all to 4-very much to assess functioning and symptoms; 2 items with 7-point Likert scales (1= poor and 7= excellent) for global health and overall health related QoL. Scores are transformed to 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values shows deterioration in quality of life or functioning and reduction in symptom and positive values indicate improvement and worsening of symptoms. | Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days) | 
| Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) to Day 1 of Cycle 3, 6, 9 and 12 | EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. | Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days) | 
| Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score to Day 1 of Cycle 3, 6, 9 and 12 | EQ-5D-5L is standardized, participant-reported questionnaire to assess health-related quality of life. EQ-5D-5L includes 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L VAS. EQ-5D-5L descriptive system provides a profile of participant's health state 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The participant was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. Responses to the 5-dimension scores were combined and converted into single preference-weighted health utility index score 0 (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of individual (but allows for values less than 0 by United kingdom [UK] scoring algorithm). | Baseline and Day 1 of Cycle 3, 6, 9 and 12 (each Cycle of 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Daratumumab, JNJ-54767414, Lenalidomide, Dexamethasone