A Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

This is a randomized (participants will be assigned by chance to study treatments),
open-label (all participants and study personnel will know the identity of the study
treatments), active-controlled (none of the study treatments are placebo), parallel-group
(both treatment arms will run at the same time), multicenter study. In this study,
daratumumab, lenalidomide, and low-dose dexamethasone (DRd) will be compared with
lenalidomide and low dose dexamethasone (Rd) in participants with relapsed or refractory
multiple myeloma. Participants will be randomized in a 1:1 ratio to receive either DRd or Rd.
The study will include a Screening Phase, a Treatment Phase (involving treatment cycles of
approximately 28 days in length), and a Follow-up Phase. The Treatment Phase will extend from
the administration of the first dose of study medication until disease progression or
unacceptable toxicity. Participants will also discontinue study treatment if: they become
pregnant; have their dose held for more than 28 days (or if 3 consecutive planned doses of
daratumumab are missed for reasons other than toxicity); or for safety reasons (for example,
adverse event). The Follow-up Phase will begin at the end of treatment and will continue
until death, loss to follow-up, consent withdrawal for study participation, or study end,
whichever occurs first. Eligible participants from Rd group who have had sponsor-confirmed
disease progression will be offered the option for treatment with daratumumab monotherapy (of
28 days cycle). The primary endpoint will be progression-free survival (PFS). Analysis of the
primary endpoint is anticipated to be performed at approximately 18 months after
participant's first dose. Study end is anticipated at approximately 6 years after the last
participant is randomized. Blood and urine samples will be obtained at time points during the
study, together with bone marrow aspirates/biopsies and skeletal surveys. Participant safety
will be assessed throughout the study.

Inclusion Criteria:

- Must have documented multiple myeloma and measurable disease

- Must have received at least 1 prior line of therapy for multiple myeloma and achieved
a response (partial response or better) to at least one prior regimen

- Must have documented evidence of progressive disease as defined by the International
Myeloma Working Group criteria on or after their last regimen

- Must have an Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2

- If a participant has received subsequent anticancer therapy (salvage therapy), the
participant must have a "wash-out period" defined as 2 weeks or 5 pharmacokinetic
half-lives of the treatment, whichever is longer, before the planned start date of
daratumumab monotherapy. The only exception is the emergency use of a short course of
corticosteroids (equivalent of dexamethasone 40 milligram per day for a maximum of 4
days) before Daratumumab monotherapy

Exclusion Criteria:

- Has received any of the following therapies: daratumumab or other anti-CD38 therapies

- Has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of
the treatment

- Disease shows evidence of refractoriness or intolerance to lenalidomide or if
previously treated with a lenalidomide-containing regimen the participant is excluded
if he or she discontinued due to any adverse event related to prior lenalidomide
treatment

- Has received autologous stem cell transplantation within 12 weeks before the date of
randomization, or previously received an allogenic stem cell transplant (regardless of
timing), or planning to undergo a stem cell transplant prior to progression of disease

- History of malignancy (other than multiple myeloma) within 5 years before the first
dose of daratumumab monotherapy (exceptions are squamous and basal cell carcinomas of
the skin and carcinoma in situ of the cervix, or breast, or other non-invasive lesion,
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)