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

Janssen Research & Development, LLC737 enrolled

Overview

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).

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

Daratumumab IVDRUG

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).

LenalidomideDRUG

Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle.

DexamethasoneDRUG

Dexamethasone 40 mg orally or intravenously once in a week.

Daratumumab SCDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Locations (206)

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Mobile, Alabama, United States

Unnamed facility

Glendale, Arizona, United States

Unnamed facility

Berkeley, California, United States

Unnamed facility

Beverly Hills, California, United States

Unnamed facility

Outcomes

Primary Outcomes

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)

Secondary Outcomes

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

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

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

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

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

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

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

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

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

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

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

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)

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)

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)

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.

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

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

Overview

Conditions

Interventions

Eligibility

Locations (206)

Outcomes

Primary Outcomes

Secondary Outcomes