A Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) With VELCADE, Lenalidomide, and Dexamethasone (VRd) in Participants With Untreated Multiple Myeloma and for Whom Hematopoietic Stem Cell Transplant is Not Planned as Initial Therapy

This study will evaluate participants with newly diagnosed multiple myeloma (MM) for whom
hematopoietic stem cell transplant is not planned as initial therapy. The data available from
other available studies suggests that addition of daratumumab with Velcade (bortezomib),
lenalidomide, and dexamethasone [VRd] is anticipated to improve the response rates and the
depth of response and may lead to improved long-term outcomes in newly diagnosed participants
with MM. Daratumumab targets CD38, a protein expressed on the surface of MM cells and other
hematopoietic cells. Bortezomib is a proteasome inhibitor, which plays a critical role in the
pathogenesis of MM. Lenalidomide has cytotoxic effects on myeloma cells and is capable of
inducing apoptosis, or programmed cell death and dexamethasone induces apoptosis in MM cells.
The rationale for the study is to utilize the subcutaneous (SC) formulation of daratumumab
instead of the intravenous (IV) formulation, which is expected to provide similar exposure
and is expected to limit additional toxicity to participants, treated with this quadruplet
regimen. The study will consist of 3 phases: Screening (up to 28 days before randomization),
Treatment phase (from Cycle 1 [21 days] Day 1 and continues until disease progression) and
Follow up (Postintervention). Efficacy evaluations will include measurements of tumor
burden/residual disease, myeloma proteins, bone marrow examinations, skeletal surveys,
extramedullary plasmacytomas, and serum calcium corrected for albumin. Participants will
undergo procedures like electrocardiogram (ECG), chest x-rays or full dose chest CT scans,
Pulmonary function test (PFT), spirometry etc. during the course of study. Participants will
also be monitored closely for adverse events (AEs), laboratory abnormalities, and clinical
response. The duration of the study will be approximately 6.5 years.

Inclusion Criteria:

- Diagnosis of multiple myeloma as documented per International Myeloma Working Group
(IMWG) criteria Monoclonal plasma cells in the bone marrow greater than or equal to (>=)10
percentage (%) or presence of a biopsy proven plasmacytoma and documented multiple myeloma
satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers
of malignancy criteria. CRAB criteria: Hypercalcemia: serum calcium greater than (>) 0.25
millimoles per liter (mmol/L) (>1 milligram per deciliter [mg/dL]) higher than upper limit
of normal (ULN) or >2.75 mmol/L (>11 mg/dL); Renal insufficiency: creatinine clearance less
than (<) 40 milliliter per minute (mL/min) or serum creatinine >177 micro millimoles per
liter (umol/L) (>2 mg/dL); Anemia: hemoglobin >2 g/dL below the lower limit of normal or
hemoglobin <10 g/dL; Bone lesions: one or more osteolytic lesions on skeletal radiography,
computed tomography (CT), or positron emission tomography (PET)-CT.

Biomarkers of Malignancy: Clonal bone marrow plasma cell percentage >=60%; Involved:
uninvolved serum free light chain (FLC) ratio >=100; >1 focal lesion on magnetic resonance
imaging (MRI) studies

- Must have measurable disease, as assessed by central laboratory

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2

- A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
at Screening, first within 10 to 14 days prior to dosing and the second within 24
hours prior to dosing

- A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 3 months after receiving the last
dose of any component of the treatment regimen

Exclusion Criteria:

- Frailty index of >=2 according to Myeloma Geriatric Assessment score

- Prior therapy for multiple myeloma other than a short course of corticosteroids (not
to exceed 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days, total
of 160 mg dexamethasone or equivalent)

- Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years
of date of randomization (exceptions are adequately treated basal cell or squamous
cell carcinoma of the skin, 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
3 years)

- Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE)
Version 5

- Radiation therapy within 14 days of randomization