Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine if the addition of daratumumab to lenalidomide-bortezomib-dexamethasone (RVd) will increase the proportion of participants achieving stringent complete response (sCR), as defined by the International Myeloma Working Group (IMWG) criteria, by the time of completion of post autologous stem cell transplantation (ASCT) consolidation treatment, compared with RVd alone.

Official Title
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Phase 2, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma Eligible for High-Dose Chemotherapy and Autologous Stem Cell Transplantation

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Considered by the investigator to be eligible for high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) according to the institution's criteria based on age, medical history, cardiac and pulmonary status, overall health and condition, co-morbid condition(s), physical examination, and laboratory studies Has not had prior systemic therapy for multiple myeloma. An emergency course of steroids (defined as no greater than 40 milligram [mg] of dexamethasone, or equivalent per day for a maximum of 4 days (that is, a total of 160 mg) is permitted. In addition, radiation therapy is permitted prior to study entry, during screening, and during Cycles 1-2 of study treatment as needed for lytic bone disease Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 Woman of childbearing potential must have 2 negative highly sensitive serum (beta-human chorionic gonadotropin [b-hCG]) during screening, the first one within 10 to 14 days prior to the first dose of any component of study treatment and the second within 24 hours prior to the first dose of any component of study treatment A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study (including during dose interruptions), and for 4 weeks following discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the last dose Exclusion Criteria: Diagnosed or treated for malignancy other than multiple myeloma, except: a) Malignancy treated with curative intent and with no known active disease present for more than equal to (>= )3 years before randomization; b) Adequately treated non-melanoma skin cancer, lentigo maligna or in situ malignancies (including but not limited to, cervical, breast) with no evidence of disease Exhibiting clinical signs of or has a known history of meningeal or central nervous system involvement by multiple myeloma Known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) less than (<)50 percent (%) of predicted normal Known moderate or severe persistent asthma within the past 2 years or currently has uncontrolled asthma of any classification Known to be seropositive for human immunodeficiency virus, known to have hepatitis B surface antigen positivity, or known to have a history of hepatitis C. Participants who completed treatment for hepatitis C at least 6 months prior to screening and have no detectable circulating hepatitis C virus (HCV) at screening, may participate in the study. Such participants will be required to undergo regular assessment for HCV reactivation during their participation in the study. Participants who test positive for HCV at any time during these assessments will be withdrawn from the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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+Bortezomib+Dexamethasone (D-RVd)<br>Participants will receive lenalidomide, bortezomib, dexamethasone and daratumumab. | Drug: Lenalidomide<br>* Cycles 1 through 6: lenalidomide 25 (milligram) mg orally on Days 1 through 14 and each cycle is of 21-days followed by maintenance treatment with lenalidomide 10 mg on days 1-21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a tolerability concern.<br>Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 4, 8, and 11 during Cycles 1-6.<br>Drug: Dexamethasone<br>* Dexamethasone 40 mg orally every week (20 mg on Days 1, 2, 8, 9, 15, and 16).<br>Drug: Daratumumab<br>* Daratumumab intravenously at a dose of 16 milligram per kilogram (mg/kg) weekly during induction treatment (Days 1, 8, and 15 of Cycles 1 through 4), and every 3 weeks during consolidation treatment (Day 1 of Cycles 5 and 6), followed by maintenance treatment with daratumumab every 4 or 8 weeks.<br>|
| Experimental: Lenalidomide+Bortezomib+Dexamethasone (RVd)<br>Participants will receive lenalidomide, bortezomib and dexamethasone. | Drug: Lenalidomide<br>* Cycles 1 through 6: lenalidomide 25 (milligram) mg orally on Days 1 through 14 and each cycle is of 21-days followed by maintenance treatment with lenalidomide 10 mg on days 1-21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a tolerability concern.<br>Drug: Bortezomib<br>* Bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 4, 8, and 11 during Cycles 1-6.<br>Drug: Dexamethasone<br>* Dexamethasone 40 mg orally every week (20 mg on Days 1, 2, 8, 9, 15, and 16).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Stringent Complete Response (sCR) | Percentage of participants who had achieved sCR as determined by the validated computer algorithm according to the International Myeloma Working Group (IMWG) criteria, by the end of post-autologous stem cell transplantation (post-ASCT) consolidation treatment were reported. Complete response (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. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry. | From randomization to post-ASCT consolidation (after Cycle 6) before maintenance treatment (up to 10 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) or Better | CR or better rate is defined as the percentage of participants who achieve CR or sCR, according to the IMWG criteria. CR is negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5% PCs in bone marrow. sCR is defined as in addition to CR a normal FLC ratio, and absence of clonal plasma cells (PCs) by immunohistochemistry or immunofluorescence or 2 to 4-color flow cytometry. For 2 participants (1 in each randomized treatment group), data were updated by the study sites which resulted in their inclusion to the response-evaluable analysis set after the primary analysis. | From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and at the end of maintenance period of 24 months (overall duration up to 34 months) | 
| Percentage of Participants With Overall Stringent Complete Response (sCR) | Overall sCR rate is defined as the percentage of participants who achieved sCR, according to the IMWG criteria. CR is defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and < 5 % PCs in bone marrow. 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 end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and at the end of maintenance treatment of 24 months (overall duration up to 34 months) | 
| Percentage of Participants With Overall Response Rate (ORR) | ORR- percentage of participants who achieved partial response (PR) or better (PR, Very Good Partial Response [VGPR], CR or sCR) based on computerized algorithm as per IMWG criteria. PR -greater than or equal to (>=) 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg//24 hours. If 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; 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; CR-negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR- 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 end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and at the end of maintenance treatment of 24 months (overall duration up to 34 months) | 
| Percentage of Participants Who Achieved Very Good Partial Response (VGPR) or Better | VGPR or better rate is defined as the percentage of participants who achieved VGPR or better, according to the 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. | From randomization to end of following: induction treatment, ASCT, post-ASCT consolidation (after Cycle 6) and at the end of maintenance period of 24 months (overall duration up to 34 months) | 
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | Minimal residual disease negative rate is defined as the percentage of participants who achieve MRD negative status by the respective time point. Minimal residual disease was evaluated in participants who achieved CR or sCR (including participants with VGPR or better and suspected daratumumab interference) using next-generation sequencing which utilizes multiple myeloma cell DNA from bone marrow aspirates at a threshold of less than (<) 10^5. | From randomization to end of following: induction treatment, post-ASCT consolidation (after Cycle 6) (up to 4.5 months), and at the end of maintenance period of 24 months (overall duration up to 34 months) | 
| Duration of Complete Response or Better | Duration of CR or better is the duration from the date of initial documentation of a CR or sCR response, according to the IMWG criteria, to the date of first documented evidence of progressive disease (PR), or relapse from CR. PD is defined as an increase of 25 % 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 milligrams [mg]/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 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 cells (PCs) proliferative disorder. | From randomization to the date of first documented evidence of progressive disease or relapse from CR (up to 5 years) | 
| Duration of Stringent Complete Response (sCR) | Duration of sCR is the duration from the date of initial documentation of a sCR response, according to the IMWG criteria, to the date of first documented evidence of progressive disease, or relapse from sCR. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 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 PC proliferative disorder. | From randomization to the date of first documented evidence of progressive disease or relapse from sCR (up to 5 years) | 
| Time to Stringent Complete Response (sCR) | Time to sCR is the duration from the date of randomization to the date of initial documentation of sCR, which was confirmed by a repeated measurement as required by the IMWG criteria. | From randomization to the date of initial documentation of sCR (up to 5 years) | 
| Time to Complete Response or Better | Time to CR or better is the duration from the date of randomization to the date of initial documentation of CR or better, which was confirmed by a repeated measurement as required by the IMWG criteria. | From randomization to the date of initial documentation of CR (up to 5 years) | 
| Time to Very Good Partial Response (VGPR) or Better | Time to VGPR or better is the duration from the date of randomization to the date of initial documentation of VGPR or better, which was confirmed by a repeated measurement as required by the IMWG criteria. | From randomization to the date of initial documentation of VGPR or better (up to 5 years) | 
| Time to Partial Response (PR) or Better | Time to PR or better is the duration from the date of randomization to the date of initial documentation of PR or better, which was confirmed by a repeated measurement as required by the IMWG criteria. | From randomization to the date of initial documentation of PR or better (up to 5 years) | 
| Progression-free Survival (PFS) | PFS is defined as the duration from the date of randomization to the date of first documented evidence of progressive disease or death, whichever comes first. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 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 PC proliferative disorder. | From randomization to the date of first documented evidence of progressive disease or death (up to 5 years) | 
| Overall Survival (OS) | OS is measured from the date of randomization to the date of the participant's death. | From randomization to the date of initial documentation of participant's death (up to 5 years) | 
| Time to Progression (TTP) | TTP is defined as the duration from the date of randomization to the date of first documented evidence of progressive disease according to the IMWG criteria. | From randomization to the date of first documented evidence of progressive disease (up to 5 years) | 
| Duration of Response | Duration of response is defined as the duration from the date of initial documentation of a response (PR or better) according to the IMWG criteria to the date of first documented evidence of progressive disease according to the IMWG criteria. PD is defined as an increase of 25 % from the lowest response value in one of the following: serum and urine M-component (absolute increase must be >= 0.5 g/dL and >=200 mg/24 hours respectively); Only in participants without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (absolute increase must be > 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 PC proliferative disorder. | From the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive (up to 5 years) |