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

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.

Eligibility Criteria:
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)