A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to compare the effectiveness of daratumumab when combined with lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free survival in participants with relapsed or refractory multiple myeloma.

Detailed Description
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This is a randomized (participants will be assigned by chance to study treatments), open-label (all participants and study personnel will know the identity of the study treatments), active-controlled (none of the study treatments are placebo), parallel-group (both treatment arms will run at the same time), multicenter study. In this study, daratumumab, lenalidomide, and low-dose dexamethasone (DRd) will be compared with lenalidomide and low dose dexamethasone (Rd) in participants with relapsed or refractory multiple myeloma. Participants will be randomized in a 1:1 ratio to receive either DRd or Rd. The study will include a Screening Phase, a Treatment Phase (involving treatment cycles of approximately 28 days in length), and a Follow-up Phase. The Treatment Phase will extend from the administration of the first dose of study medication until disease progression or unacceptable toxicity. Participants will also discontinue study treatment if: they become pregnant; have their dose held for more than 28 days (or if 3 consecutive planned doses of daratumumab are missed for reasons other than toxicity); or for safety reasons (for example, adverse event). The Follow-up Phase will begin at the end of treatment and will continue until death, loss to follow-up, consent withdrawal for study participation, or the final overall survival (OS) analysis, whichever occurs first. Eligible participants from Rd group who have had sponsor confirmed disease progression will be offered the option for treatment with daratumumab monotherapy (of 28 days cycle). The primary endpoint will be progression-free survival (PFS). Analysis of the primary endpoint was performed at a pre-specified point determined by PFS events with a clinical cutoff of March 7, 2016 when 169 events of death or progression had occurred. The end of study is anticipated at approximately 6 years after the last participant is randomized. Blood and urine samples will be obtained at time points during the study, together with bone marrow aspirates/biopsies and skeletal surveys. Participant safety will be assessed throughout the study.

Official Title
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Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have documented multiple myeloma and measurable disease Must have received at least 1 prior line of therapy for multiple myeloma and achieved a response (partial response or better) to at least one prior regimen Must have documented evidence of progressive disease as defined by the International Myeloma Working Group criteria on or after their last regimen Must have an Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2 If a participant has received subsequent anticancer therapy (salvage therapy), the participant must have a wash-out period defined as 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the planned start date of daratumumab monotherapy. The only exception is the emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 milligram per day for a maximum of 4 days) before Daratumumab monotherapy Exclusion Criteria: Has received any of the following therapies: daratumumab or other anti-CD38 therapies Has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment Disease shows evidence of refractoriness or intolerance to lenalidomide or if previously treated with a lenalidomide-containing regimen the participant is excluded if he or she discontinued due to any adverse event related to prior lenalidomide treatment Has received autologous stem cell transplantation within 12 weeks before the date of randomization, or previously received an allogenic stem cell transplant (regardless of timing), or planning to undergo a stem cell transplant prior to progression of disease History of malignancy (other than multiple myeloma) within 5 years before the first dose of daratumumab monotherapy (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion, 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)

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: Daratumumab + lenalidomide + dexamethasone<br>During each 28-day treatment cycle, participants will receive daratumumab, lenalidomide, and dexamethasone. | Drug: Daratumumab<br>* Daratumumab 16mg/kg will be administered as an intravenous (IV) infusion (into the vein) as per the following schedule: once a week during treatment cycles 1 and 2; every 2 weeks during treatment cycles 3 to 6; and every 4 weeks for cycles 7 and onwards. Following amendment 8, participants receiving daratumumab IV have the option to switch to daratumumab subcutaneous (SC) 1800 mg/dose until documented progression, unacceptable toxicity, or the end of study on Day 1 of any cycle, at the discretion of the investigator.<br>Drug: Lenalidomide<br>* Lenalidomide will be administered at a dose of 25 mg orally (by mouth) on Days 1 through 21 of each treatment cycle.<br>Drug: Dexamethasone<br>* Dexamethasone (or equivalent in accordance with local standards) will be administered as a total dose of 40 mg weekly (or 20 mg weekly for participants > 75 years old or with a body mass index < 18.5).<br>|
| Active Comparator: Lenalidomide + dexamethasone<br>During each 28-day treatment cycle, participants will receive lenalidomide and dexamethasone. | Drug: Lenalidomide<br>* Lenalidomide will be administered at a dose of 25 mg orally (by mouth) on Days 1 through 21 of each treatment cycle.<br>Drug: Dexamethasone<br>* Dexamethasone (or equivalent in accordance with local standards) will be administered as a total dose of 40 mg weekly (or 20 mg weekly for participants > 75 years old or with a body mass index < 18.5).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS: duration from date of randomization to either progressive disease (PD)/death, whichever occurred first. PD: defined as meeting any 1 of following criteria: Increase of greater than equal to (>=)25 percent(%) in level of serum M-protein from lowest response value and absolute increase must be >=0.5 gram per deciliter (g/dL); Increase of >=25% in 24-hours(h) urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24h; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 mg/dL; Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) attributed solely to plasma cell (PC) proliferative disorder. | From randomization to either disease progression or death whichever occurs first (up to 21 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression (TTP) | TTP was defined as time from date of randomization to date of first documented evidence of progressive disease (PD). PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5 g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 milligram per deciliter (mg/dL); Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new 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 (up to 21 months) | 
| Percentage of Participants Who Achieved Very Good Partial Response (VGPR) or Better | VGPR or better is defined as the percentage of participants who achieved VGPR, complete response (CR) and stringent complete response (sCR) according to the International Myeloma Working Group criteria (IMWG). IMWG criteria for VGPR: 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, if the serum and urine M-protein are not measurable, a decrease of >90% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria. In addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry. | From randomization to disease progression (up to 21 months) | 
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | Minimal residual disease was assessed for all participants who achieved a complete response (CR) or stringent complete response (sCR). CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry. The MRD negativity rate was defined as the percentage of participants who had negative MRD assessment at any time point after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood at 10^ minus (-) 4, 10^-5, 10^-6 threshold. | From randomization to the date of first documented evidence of PD (up to 87.5 months) | 
| Overall Response Rate | Overall response rate was defined as the percentage of participants who achieved a partial response (PR) or better according to the International Myeloma Working Group (IMWG) criteria, during or after study treatment. IMWG criteria for 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, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required. | From randomization to disease progression (up to 21 months) | 
| Overall Survival (OS) | Overall survival was measured from the date of randomization to the date of the participant's death. | From randomization to date of death due to any cause (up to 87.5 months) | 
| Time to Response | Time to response was defined as the time between the date of randomization and the first efficacy evaluation that the participant met all criteria for partial response (PR) or better. | From randomization up to first documented CR or PR (up to 21 months) | 
| Duration of Response (DOR) | DOR was defined for participants with confirmed response (PR or better) as time between first documentation of response and disease progression/death due to PD, whichever occurs first. PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be >10mg/dL; Definite increase in size of existing bone lesions/soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5mg/dL) that can be attributed solely to PC proliferative disorder. | From randomization to the date of first documented evidence of PD (up to 21 months) | 
| Time to Subsequent Anticancer Treatment | Time to subsequent anticancer treatment was defined as the time from randomization to the start of subsequent anticancer treatment or death due to progressive disease (PD), whichever occurs first. | From randomization to date of start of subsequent anticancer treatment or death due to PD, whichever occured first (up to 87.5 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Relapsed Multiple Myeloma, Refractory Multiple Myeloma, Daratumumab, Lenalidomide, Dexamethasone