Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Daratumumab, JNJ-54767414, Lenalidomide, Dexamethasone
Brief summary
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
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.
Interventions
DRUGDaratumumab IV
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).
DRUGLenalidomide
Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle.
DRUGDexamethasone
Dexamethasone 40 mg orally or intravenously once in a week.
DRUGDaratumumab SC
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization (Day -3) 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) | PFS was defined as time from date of randomization to either progressive disease (PD) or death, whichever occurred first based on computerized algorithm as per IMWG criteria. PD was 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 could be attributed solely to Plasma cell (PC) proliferative disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Very Good Partial Response (VGPR) or Better | From randomization (Day -3) up to 6.6 years | VGPR or better rate was defined as the percentage of participants who achieved VGPR or better (VGPR, CR or sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level less than (\<) 100 milligram (mg) per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \< 5% plasms cells (PCs) in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. |
| Percentage of Participants With Negative Minimal Residual Disease (MRD) | From randomization (Day -3) up to 6.6 years | MRD negativity rate is defined as the percentage of participants who had negative MRD at any time point after the date of randomization and prior to subsequent antimyeloma therapy. MRD was assessed in participants who achieved CR or better. |
| Percentage of Participants With Stringent Complete Response (sCR) | From randomization (Day -3) up to 6.6 years | sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal PCs by IHC, immunofluorescence or 2- to 4-color FC. CR: Negative immunofixation on the serum and urine; Disappearance of any soft tissue plasmacytomas; \<5% PCs in bone marrow. |
| Overall Response Rate (ORR) | From randomization (Day -3) up to 6.6 years | ORR was 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: \>=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 were not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. If present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was 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, Disappearance of any soft tissue plasmacytomas and \< 5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. |
| Overall Survival (OS) | From randomization (Day -3) up to 8.7 years | OS was measured from the date of randomization to the date of the death. Median OS was estimated by using the Kaplan-Meier method. |
| Time to Disease Progression (TTP) | From randomization (Day -3) up to 6.6 years | TTP was defined as the time from the date of randomization to date of first documented evidence of PD or death due to PD, whichever occurred first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. |
| Time to Response | From randomization (Day -3) up to 6.6 years | Time to first response, time to VGPR or better, time to CR or better and time to best response was reported for this endpoint. Time to response: time from date of randomization to first efficacy evaluation that met criteria for PR/better as their best response (PR, CR, or better) based on 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 serum and urine M-protein were not measurable, a decrease of \>=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. Based on computerized algorithm, according to IMWG response criteria, VGPR or better: proportion of participants with a response of VGPR or better (i.e., VGPR, CR or sCR), CR or better: proportion of participants with a response of CR or better (i.e., CR or sCR). |
| Percentage of Participants With Complete Response (CR) or Better | From randomization (Day -3) up to 6.6 years | Percentage of participants with a CR or better (CR or stringent complete response \[sCR\]) based on computerized algorithm as per IMWG criteria was reported. CR was 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 was required. sCR was defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescence, 2-4 color flow cytometry (FC). |
| Time to Subsequent Anti-myeloma Treatment | From randomization (Day -3) up to 8.7 years | Time to subsequent anti-myeloma treatment was defined as the time from randomization to the start of subsequent anti-myeloma treatment. Kaplan-Meier method was used for the analysis. |
| Progression-free Survival on Next Line of Therapy (PFS2) | From randomization (Day -3) up to 6.6 years | PFS2 was defined as the time from randomization to progression on next line of therapy or death, whichever comes first. Disease progression on next line of treatment was based on investigator judgment. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days) | EORTC QLQ-C30 was 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 included 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 were transformed to 0 to 100 scale, with higher scores represented better GHS and functioning, and more symptoms. Negative change from baseline values showed deterioration in quality of life or functioning and reduction in symptom and positive values indicated improvement and worsening of symptoms. |
| Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days) | EQ-5D-5L was 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 was 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. |
| Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days) | EQ-5D-5L was standardized, participant-reported questionnaire to assess health-related quality of life. EQ-5D-5L included 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L VAS. EQ-5D-5L descriptive system provided a profile of participant's health state 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflected increasing levels of difficulty. Participants indicated their health state by selecting the most appropriate level in each of the 5D. Responses to the 5D 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 scoring algorithm). Higher score indicated better health state. |
| Sub-group Analysis: Progression-free Survival (PFS) | From randomization (Day -3) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 6.6 years). | PFS for participants with cytogenic high risk was reported. PFS was time from date of randomization to either PD or death, whichever occurred first based on computerized algorithm as per IMWG criteria. PD: an increase of 25% from lowest response value in one of following: serum and urine M-component (absolute increase must be \>=0.5 g/dL and \>=200 mg/24h respectively); Only in participants without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute \>10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that could be attributed solely to PC proliferative disorder. High risk was defined as positive for any of del17p, t(14;16) or t(4;14) by (corrected serum calcium \>11.5 mg/dL) Fluorescence In Situ Hybridization (FISH)/Karyotype. |
| Sub-group Analysis: Overall Response Rate (ORR) | From randomization (Day -3) up to 6.6 years | ORR for participants with cytogenic high risk was reported. ORR: percentage of participants who achieved PR/better per IMWG criteria. PR: \>=50% reduction of serum M-protein, reduction in 24h urinary M-protein by \>=90% or \<200mg/24h. If serum/urine M-protein were not measurable, decrease of \>=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. If present at baseline, \>=50% reduction in size of soft tissue plasmacytomas was required. VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum and urine M-protein \<100mg/24h. CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, \<5% PCs in bone marrow; sCR: CR in addition to normal FLC ratio, absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. High risk: positive for any of del17p, t(14;16) or t(4;14) by FISH/Karyotype. |
| Duration of Response (DoR) | From randomization (Day -3) up to 6.6 years | DoR was defined for participants with confirmed response (PR or better) as time between first documentation of response and disease progression per IMWG response criteria, or death due to PD, whichever occurs first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. |
Countries
Australia, Austria, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Netherlands, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide + Dexamethasone (Rd) Participants received Lenalidomide 25 milligrams (mg) capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously (IV) once a week (QW) until disease progression or unacceptable toxicity up to 77.5 months. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group \[IMWG\] criteria). | 369 |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) Participants received Daratumumab 16 milligrams per kilograms (mg/kg) IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days), Lenalidomide 25 mg capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or IV QW until disease progression or unacceptable toxicity up to 77.3 months. After implementation of Amendment 8, participants who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab subcutaneous (SC) injection on Day 1 of any cycle, as per investigator's discretion. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria). | 368 |
| Total | 737 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 218 | 175 |
| Overall Study | End of data collection | 122 | 170 |
| Overall Study | Lost to Follow-up | 9 | 6 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Site closure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 20 | 15 |
Baseline characteristics
| Characteristic | Total | Lenalidomide + Dexamethasone (Rd) | Daratumumab + Lenalidomide + Dexamethasone (DRd) |
|---|---|---|---|
| Age, Continuous | 74.1 Years STANDARD_DEVIATION 5.55 | 74.2 Years STANDARD_DEVIATION 5.66 | 74.0 Years STANDARD_DEVIATION 5.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 23 Participants | 12 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 699 Participants | 352 Participants | 347 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 16 Participants | 12 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 13 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 6 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 675 Participants | 339 Participants | 336 Participants |
| Region of Enrollment Australia | 35 Participants | 18 Participants | 17 Participants |
| Region of Enrollment Austria | 14 Participants | 11 Participants | 3 Participants |
| Region of Enrollment Belgium | 7 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Canada | 52 Participants | 28 Participants | 24 Participants |
| Region of Enrollment Denmark | 16 Participants | 6 Participants | 10 Participants |
| Region of Enrollment France | 312 Participants | 155 Participants | 157 Participants |
| Region of Enrollment Germany | 35 Participants | 16 Participants | 19 Participants |
| Region of Enrollment Ireland | 7 Participants | 3 Participants | 4 Participants |
| Region of Enrollment Israel | 8 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Italy | 6 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Netherlands | 5 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Sweden | 22 Participants | 12 Participants | 10 Participants |
| Region of Enrollment United Kingdom | 67 Participants | 34 Participants | 33 Participants |
| Region of Enrollment United States | 151 Participants | 74 Participants | 77 Participants |
| Sex: Female, Male Female | 353 Participants | 174 Participants | 179 Participants |
| Sex: Female, Male Male | 384 Participants | 195 Participants | 189 Participants |
| Stage of Disease (ISS) Stage I | 201 Participants | 103 Participants | 98 Participants |
| Stage of Disease (ISS) Stage II | 319 Participants | 156 Participants | 163 Participants |
| Stage of Disease (ISS) Stage III | 217 Participants | 110 Participants | 107 Participants |
| Time from Multiple Myeloma (MM) diagnosis | 1.3 Months STANDARD_DEVIATION 1.5 | 1.3 Months STANDARD_DEVIATION 1.4 | 1.4 Months STANDARD_DEVIATION 1.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 259 / 369 | 287 / 368 |
| other Total, other adverse events | 358 / 365 | 362 / 364 |
| serious Total, serious adverse events | 262 / 365 | 289 / 364 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as time from date of randomization to either progressive disease (PD) or death, whichever occurred first based on computerized algorithm as per IMWG criteria. PD was 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 could be attributed solely to Plasma cell (PC) proliferative disorder.
Time frame: From randomization (Day -3) 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)
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Progression-free Survival (PFS) | 31.87 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Progression-free Survival (PFS) | NA Months |
p-value: <0.000195% CI: [0.43, 0.73]Log Rank
Secondary
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score
EORTC QLQ-C30 was 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 included 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 were transformed to 0 to 100 scale, with higher scores represented better GHS and functioning, and more symptoms. Negative change from baseline values showed deterioration in quality of life or functioning and reduction in symptom and positive values indicated improvement and worsening of symptoms.
Time frame: Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
Population: ITT population included all randomized participants. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure; 'n' (number analyzed) signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 9 Day 1 | 5.7 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 36 Day 1 | 5 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 18 Day 1 | 4.7 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 42 Day 1 | 3.8 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 6 Day 1 | 4.8 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 48 Day 1 | 3.4 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 24 Day 1 | 4.7 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 54 Day 1 | 6.1 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 12 Day 1 | 4.5 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 60 Day 1 | 4.9 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 30 Day 1 | 4.5 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 66 Day 1 | 7.1 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 3 Day 1 | 1.4 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 66 Day 1 | 7.7 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 3 Day 1 | 3.8 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 6 Day 1 | 6.3 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 9 Day 1 | 7.5 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 12 Day 1 | 7.8 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 18 Day 1 | 6.4 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 24 Day 1 | 6.3 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 30 Day 1 | 5.5 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 36 Day 1 | 7.7 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 42 Day 1 | 5.6 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 48 Day 1 | 4.2 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 54 Day 1 | 4.8 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status Score | Cycle 60 Day 1 | 4.1 Score on scale |
Comparison: Cycle 30 Day 1p-value: =0.582595% CI: [-2.6, 4.6]Mixed Models Analysis
Comparison: For Cycle 3 Day 1p-value: =0.098695% CI: [-0.4, 5.2]Mixed Models Analysis
Comparison: Cycle 6 Day 1p-value: =0.304295% CI: [-1.4, 4.4]Mixed Models Analysis
Comparison: Cycle 9 Day 1p-value: =0.233995% CI: [-1.2, 4.9]Mixed Models Analysis
Comparison: Cycle 12 Day 1p-value: =0.036595% CI: [0.2, 6.3]Mixed Models Analysis
Comparison: Cycle 18 Day 1p-value: =0.309395% CI: [-1.6, 4.9]Mixed Models Analysis
Comparison: Cycle 24 Day 1p-value: =0.348195% CI: [-1.8, 5]Mixed Models Analysis
Comparison: Cycle 36 Day 1p-value: =0.156695% CI: [-1, 6.4]Mixed Models Analysis
Comparison: Cycle 42 Day 1p-value: =0.385895% CI: [-2.2, 5.7]Mixed Models Analysis
Comparison: Cycle 48 Day 1p-value: =0.729695% CI: [-3.5, 5]Least Square Mean Difference
Comparison: Cycle 54 Day 1p-value: =0.579395% CI: [-6, 3.3]Mixed Models Analysis
Comparison: Cycle 60 Day 1p-value: =0.775695% CI: [-6.1, 4.5]Mixed Models Analysis
Comparison: Cycle 66 Day 1p-value: =0.845895% CI: [-6, 7.4]Mixed Models Analysis
Secondary
Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score
EQ-5D-5L was standardized, participant-reported questionnaire to assess health-related quality of life. EQ-5D-5L included 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L VAS. EQ-5D-5L descriptive system provided a profile of participant's health state 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflected increasing levels of difficulty. Participants indicated their health state by selecting the most appropriate level in each of the 5D. Responses to the 5D 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 scoring algorithm). Higher score indicated better health state.
Time frame: Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
Population: ITT population included all randomized participants. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure; 'n' signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 9 Day 1 | 0.113 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 36 Day 1 | 0.099 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 18 Day 1 | 0.089 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 42 Day 1 | 0.062 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 6 Day 1 | 0.111 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 48 Day 1 | 0.075 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 24 Day 1 | 0.088 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 54 Day 1 | 0.05 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 12 Day 1 | 0.103 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 60 Day 1 | 0.068 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 30 Day 1 | 0.088 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 66 Day 1 | 0.041 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 3 Day 1 | 0.081 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 66 Day 1 | 0.111 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 3 Day 1 | 0.097 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 6 Day 1 | 0.13 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 9 Day 1 | 0.124 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 12 Day 1 | 0.132 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 18 Day 1 | 0.116 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 24 Day 1 | 0.121 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 30 Day 1 | 0.102 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 36 Day 1 | 0.109 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 42 Day 1 | 0.113 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 48 Day 1 | 0.082 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 54 Day 1 | 0.087 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score | Cycle 60 Day 1 | 0.079 Score on scale |
Comparison: Cycle 3 Day 1p-value: =0.306995% CI: [-0.015, 0.046]Mixed Models Analysis
Comparison: Cycle 6 Day 1p-value: =0.247295% CI: [-0.013, 0.05]Mixed Models Analysis
Comparison: Cycle 9 Day 1p-value: =0.497295% CI: [-0.021, 0.044]Mixed Models Analysis
Comparison: Cycle 12 Day 1p-value: =0.084195% CI: [-0.004, 0.062]Mixed Models Analysis
Comparison: Cycle 18 Day 1p-value: =0.129695% CI: [-0.008, 0.062]Mixed Models Analysis
Comparison: Cycle 24 Day 1p-value: =0.076295% CI: [-0.003, 0.07]Mixed Models Analysis
Comparison: Cycle 30 Day 1p-value: =0.485995% CI: [-0.025, 0.052]Mixed Models Analysis
Comparison: Cycle 36 Day 1p-value: =0.603195% CI: [-0.029, 0.051]Mixed Models Analysis
Comparison: Cycle 42 Day 1p-value: =0.017895% CI: [0.009, 0.093]Mixed Models Analysis
Comparison: Cycle 48 Day 1p-value: =0.74695% CI: [-0.038, 0.053]Mixed Models Analysis
Comparison: Cycle 54 Day 1p-value: =0.139495% CI: [-0.012, 0.086]Mixed Models Analysis
Comparison: Cycle 60 Day 1p-value: =0.698295% CI: [-0.045, 0.068]Mixed Models Analysis
Comparison: Cycle 66 Day 1p-value: =0.054395% CI: [-0.001, 0.14]Mixed Models Analysis
Secondary
Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS)
EQ-5D-5L was 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 was 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.
Time frame: Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
Population: ITT population included all randomized participants. Here 'N' (overall number of participants analyzed) signifies number of participants who were evaluable for this outcome measure; 'n' signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 9 Day 1 | 7 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 36 Day 1 | 4.9 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 18 Day 1 | 5.4 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 42 Day 1 | 4.6 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 6 Day 1 | 4.8 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 48 Day 1 | 5.5 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 24 Day 1 | 4.3 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 54 Day 1 | 3.4 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 12 Day 1 | 3.6 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 60 Day 1 | 5.8 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 30 Day 1 | 4.6 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 66 Day 1 | 6.9 Score on scale |
| Lenalidomide + Dexamethasone (Rd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 3 Day 1 | 2.1 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 66 Day 1 | 5.6 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 3 Day 1 | 4.2 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 6 Day 1 | 7.6 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 9 Day 1 | 9.6 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 12 Day 1 | 9.4 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 18 Day 1 | 7.4 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 24 Day 1 | 7 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 30 Day 1 | 6.9 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 36 Day 1 | 8.1 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 42 Day 1 | 5.6 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 48 Day 1 | 6.7 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 54 Day 1 | 5.8 Score on scale |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) | Cycle 60 Day 1 | 5.2 Score on scale |
Comparison: Cycle 3 Day 1p-value: =0.117695% CI: [-0.5, 4.5]Mixed Models Analysis
Comparison: Cycle 6 Day 1p-value: =0.033695% CI: [0.2, 5.4]Mixed Models Analysis
Comparison: Cycle 9 Day 1p-value: =0.065395% CI: [-0.2, 5.3]Mixed Models Analysis
Comparison: Cycle 12 Day 1p-value: =095% CI: [3, 8.5]Mixed Models Analysis
Comparison: Cycle 18 Day 1p-value: =0.180595% CI: [-0.9, 4.8]Mixed Models Analysis
Comparison: Cycle 24 Day 1p-value: =0.078395% CI: [-0.3, 5.7]Mixed Models Analysis
Comparison: Cycle 30 Day 1p-value: =0.142295% CI: [-0.8, 5.5]Mixed Models Analysis
Comparison: Cycle 36 Day 1p-value: =0.057595% CI: [-0.1, 6.5]Least Square Mean Difference
Comparison: Cycle 42 Day 1p-value: =0.533995% CI: [-2.4, 4.5]Mixed Models Analysis
Comparison: Cycle 48 Day 1p-value: =0.501595% CI: [-2.4, 5]Mixed Models Analysis
Comparison: Cycle 54 Day 1p-value: =0.251295% CI: [-1.7, 6.3]Mixed Models Analysis
Comparison: Cycle 60 Day 1p-value: =0.824695% CI: [-5.1, 4.1]Mixed Models Analysis
Comparison: Cycle 66 Day 1p-value: =0.66495% CI: [-7, 4.5]Mixed Models Analysis
Secondary
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 per IMWG response criteria, or death due to PD, whichever occurs first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder.
Time frame: From randomization (Day -3) up to 6.6 years
Population: Response evaluable population included all participants with confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit and received at least one administration of study treatment and had adequate postbaseline disease assessments. Here, 'N' (Overall number of participants analyzed) signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Duration of Response (DoR) | 43.7 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Duration of Response (DoR) | NA Months |
Secondary
Overall Response Rate (ORR)
ORR was 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: \>=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 were not measurable, a decrease of \>=50% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. If present at baseline, a \>=50% reduction in the size of soft tissue plasmacytomas was 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, Disappearance of any soft tissue plasmacytomas and \< 5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC.
Time frame: From randomization (Day -3) up to 6.6 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Overall Response Rate (ORR) | 81.6 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Overall Response Rate (ORR) | 92.9 Percentage of participants |
p-value: <0.000195% CI: [1.85, 4.86]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
OS was measured from the date of randomization to the date of the death. Median OS was estimated by using the Kaplan-Meier method.
Time frame: From randomization (Day -3) up to 8.7 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Overall Survival (OS) | 64.07 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Overall Survival (OS) | 90.25 Months |
p-value: <0.000195% CI: [0.55, 0.82]Log Rank
Secondary
Percentage of Participants With Complete Response (CR) or Better
Percentage of participants with a CR or better (CR or stringent complete response \[sCR\]) based on computerized algorithm as per IMWG criteria was reported. CR was 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 was required. sCR was defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescence, 2-4 color flow cytometry (FC).
Time frame: From randomization (Day -3) up to 6.6 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Percentage of Participants With Complete Response (CR) or Better | 30.1 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Percentage of Participants With Complete Response (CR) or Better | 51.1 Percentage of participants |
p-value: <0.000195% CI: [1.8, 3.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Negative Minimal Residual Disease (MRD)
MRD negativity rate is defined as the percentage of participants who had negative MRD at any time point after the date of randomization and prior to subsequent antimyeloma therapy. MRD was assessed in participants who achieved CR or better.
Time frame: From randomization (Day -3) up to 6.6 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Percentage of Participants With Negative Minimal Residual Disease (MRD) | 11.1 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Percentage of Participants With Negative Minimal Residual Disease (MRD) | 32.1 Percentage of participants |
p-value: <0.000195% CI: [2.55, 5.59]Fisher Exact
Secondary
Percentage of Participants With Stringent Complete Response (sCR)
sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal PCs by IHC, immunofluorescence or 2- to 4-color FC. CR: Negative immunofixation on the serum and urine; Disappearance of any soft tissue plasmacytomas; \<5% PCs in bone marrow.
Time frame: From randomization (Day -3) up to 6.6 years
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Percentage of Participants With Stringent Complete Response (sCR) | 15.7 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Percentage of Participants With Stringent Complete Response (sCR) | 35.6 Percentage of participants |
p-value: <0.000195% CI: [2.09, 4.24]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Very Good Partial Response (VGPR) or Better
VGPR or better rate was defined as the percentage of participants who achieved VGPR or better (VGPR, CR or sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level less than (\<) 100 milligram (mg) per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and \< 5% plasms cells (PCs) in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC.
Time frame: From randomization (Day -3) up to 6.6 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Percentage of Participants With Very Good Partial Response (VGPR) or Better | 56.9 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Percentage of Participants With Very Good Partial Response (VGPR) or Better | 81.5 Percentage of participants |
p-value: <0.000195% CI: [2.42, 4.77]Cochran-Mantel-Haenszel
Secondary
Progression-free Survival on Next Line of Therapy (PFS2)
PFS2 was defined as the time from randomization to progression on next line of therapy or death, whichever comes first. Disease progression on next line of treatment was based on investigator judgment.
Time frame: From randomization (Day -3) up to 6.6 years
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Progression-free Survival on Next Line of Therapy (PFS2) | 48.89 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Progression-free Survival on Next Line of Therapy (PFS2) | 73.72 Months |
p-value: <0.000195% CI: [0.49, 0.76]Log Rank
Secondary
Sub-group Analysis: Overall Response Rate (ORR)
ORR for participants with cytogenic high risk was reported. ORR: percentage of participants who achieved PR/better per IMWG criteria. PR: \>=50% reduction of serum M-protein, reduction in 24h urinary M-protein by \>=90% or \<200mg/24h. If serum/urine M-protein were not measurable, decrease of \>=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. If present at baseline, \>=50% reduction in size of soft tissue plasmacytomas was required. VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum and urine M-protein \<100mg/24h. CR: negative immunofixation on serum/urine, disappearance of soft tissue plasmacytomas, \<5% PCs in bone marrow; sCR: CR in addition to normal FLC ratio, absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. High risk: positive for any of del17p, t(14;16) or t(4;14) by FISH/Karyotype.
Time frame: From randomization (Day -3) up to 6.6 years
Population: Intent-to-treat (ITT) population included all randomized participants. Here, 'N' signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Sub-group Analysis: Overall Response Rate (ORR) | 75.0 Percentage of participants |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Sub-group Analysis: Overall Response Rate (ORR) | 91.7 Percentage of participants |
Secondary
Sub-group Analysis: Progression-free Survival (PFS)
PFS for participants with cytogenic high risk was reported. PFS was time from date of randomization to either PD or death, whichever occurred first based on computerized algorithm as per IMWG criteria. PD: an increase of 25% from lowest response value in one of following: serum and urine M-component (absolute increase must be \>=0.5 g/dL and \>=200 mg/24h respectively); Only in participants without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute \>10 mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that could be attributed solely to PC proliferative disorder. High risk was defined as positive for any of del17p, t(14;16) or t(4;14) by (corrected serum calcium \>11.5 mg/dL) Fluorescence In Situ Hybridization (FISH)/Karyotype.
Time frame: From randomization (Day -3) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 6.6 years).
Population: Intent-to-treat (ITT) population included all randomized participants. Here, 'N' signifies number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Sub-group Analysis: Progression-free Survival (PFS) | 29.6 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Sub-group Analysis: Progression-free Survival (PFS) | 45.3 Months |
Secondary
Time to Disease Progression (TTP)
TTP was defined as the time from the date of randomization to date of first documented evidence of PD or death due to PD, whichever occurred first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase \>=0.5 g/dL); Urine M-component (absolute increase \>=200 mg/24 hours); Only in participants without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase \>10 milligram per deciliter \[mg/dL\]); Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL) that can be attributed solely to the PC proliferative disorder.
Time frame: From randomization (Day -3) up to 6.6 years
Population: ITT population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Time to Disease Progression (TTP) | 40.87 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Disease Progression (TTP) | NA Months |
p-value: <0.000195% CI: [0.39, 0.62]Log Rank
Secondary
Time to Response
Time to first response, time to VGPR or better, time to CR or better and time to best response was reported for this endpoint. Time to response: time from date of randomization to first efficacy evaluation that met criteria for PR/better as their best response (PR, CR, or better) based on 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 serum and urine M-protein were not measurable, a decrease of \>=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. Based on computerized algorithm, according to IMWG response criteria, VGPR or better: proportion of participants with a response of VGPR or better (i.e., VGPR, CR or sCR), CR or better: proportion of participants with a response of CR or better (i.e., CR or sCR).
Time frame: From randomization (Day -3) up to 6.6 years
Population: Response evaluable population included all participants with confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit and received at least one administration of study treatment and had adequate postbaseline disease assessments. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure. Here 'n' signifies number of participants analyzed at specified timepoints.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Time to Response | Time to VGPR or better | 4.70 Months |
| Lenalidomide + Dexamethasone (Rd) | Time to Response | Time to first response | 1.05 Months |
| Lenalidomide + Dexamethasone (Rd) | Time to Response | Time to CR or better | 13.17 Months |
| Lenalidomide + Dexamethasone (Rd) | Time to Response | Time to best response | 6.31 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Response | Time to best response | 9.97 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Response | Time to CR or better | 10.66 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Response | Time to first response | 1.05 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Response | Time to VGPR or better | 3.01 Months |
Secondary
Time to Subsequent Anti-myeloma Treatment
Time to subsequent anti-myeloma treatment was defined as the time from randomization to the start of subsequent anti-myeloma treatment. Kaplan-Meier method was used for the analysis.
Time frame: From randomization (Day -3) up to 8.7 years
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide + Dexamethasone (Rd) | Time to Subsequent Anti-myeloma Treatment | 42.4 Months |
| Daratumumab + Lenalidomide + Dexamethasone (DRd) | Time to Subsequent Anti-myeloma Treatment | NA Months |
p-value: <0.000195% CI: [0.41, 0.63]Log Rank