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

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 daratumumab in combination with lenalidomide and
dexamethasone (DRd) or lenalidomide and dexamethasone (Rd). 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. Participants in Arm B (Rd) who had discontinued
treatment with Rd at 24 months may re-start treatment. Participants in lenalidomide and
dexamethasone (Rd) Arm 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.

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 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)