A Study of Subcutaneous Daratumumab Versus Active Monitoring in Participants With High-Risk Smoldering Multiple Myeloma

This study consists of 3 phases: Screening Phase (up to 35 days), an Active Monitoring Phase
or a Treatment Phase of 39 cycles or 36 months (whichever occurs first), and a Follow-up
Phase which will continue until death, lost to follow-up, consent withdrawal, or study end
(approximately 8 years after the first participant is randomized), whichever occurs first.
Active monitoring cycles and treatment cycles are 4 weeks in length. For all participants,
disease evaluations will be performed every 12 weeks until confirmed progressive disease
(PD). After PD, survival is to be followed at least every 6 months, until the end of the
study. Participants will undergo tumor assessments, pharmacokinetics, biomarkers and safety
evaluations (adverse events, laboratory tests, vital sign measurements, physical
examinations, Eastern Cooperative Oncology Group [ECOG] performance status) over the time.

Inclusion Criteria:

- Diagnosis of high risk smoldering multiple myeloma (SMM) (per International Myeloma
Working Group [IMWG] criteria) for less than or equal to (<=) 5 years with measurable
disease at the time of randomization, defined as serum M protein greater than or equal
to (>=) 10 gram per liter (g/L) or urine M protein >= 200 milligram per 24 hours
(mg/24 hours) or involved serum free light chain (FLC) >=100 milligram per liter
(mg/L) and abnormal serum FLC ratio

- Clonal bone marrow plasma cells (BMPCs) >= 10 percentage (%); and at least 1 of the
following risk factors; Serum M protein >= 30 g/L, immunoglobulin (Ig)A SMM,
immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only IgA, IgM,
and IgG should be considered in determination for immunoparesis; IgD and IgE are not
considered in this assessment), serum involved: uninvolved FLC ratio >= 8 and less
than (<) 100, or clonal BMPCs greater than (>) 50% to <60% with measurable disease

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

- Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse or to use highly effective method of contraception

- A woman of childbearing potential must have a negative serum or urine pregnancy test
at screening within 14 days prior to randomization

- During the study and for 3 months after receiving the last dose of daratumumab, a
woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction

Exclusion Criteria:

- Multiple myeloma (MM), requiring treatment, defined by any of the following:

1. Bone lesions (1 or more osteolytic lesions on low-dose whole body computed
tomography [LDCT], positron-emission tomography with computed tomography [PET-CT]
or CT). Participants who have benign/post-traumatic bone lesions visible on
screening images as well as previous imaging, may be considered for inclusion.
Details (diagnosis, location, duration) on benign/post-traumatic pre-existing
bone lesions that can be seen on the screening images (example [eg.], old
fractures) and were also present on previous imaging are to be reported in the
case report form (CRF)

2. 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]). Participants who have clinically stable hypercalcemia
attributable to a disease other than multiple myeloma (eg, hyperparathyroidism)
may be considered for inclusion after a case by case review by the medical
monitor

3. Renal insufficiency, preferably determined by creatinine clearance less than
(<)40 milliliter per minute (mL/min) measured or estimated using the Modification
of Diet in Renal Disease (MDRD), or serum creatinine >177 micromole per liter
(μmol/L). Participants who have clinically stable renal insufficiency
attributable to a disease other than multiple myeloma (eg, glomerulonephritis)
may be considered for inclusion after a case by case review by the medical
monitor

4. Anemia, defined as hemoglobin <10 gram per deciliter (g/dL) or >2 g/dL below
lower limit of normal or both; transfusion support or concurrent treatment with
erythropoietin stimulating agents is not permitted. Participants who have
clinically stable anemia attributable to a disease other than multiple myeloma
(eg, thalassemia, vitamin B12 deficiency, iron deficiency) may be considered for
inclusion after a case by case review by the medical monitor

5. Clonal BMPC percentage >=60%

6. Serum FLC ratio (involved:uninvolved) >=100 (the involved FLC must be >=100 mg/L)

7. More than 1 focal lesion >=5 millimeter (mm) in diameter by magnetic resonance
imaging (MRI)

- Primary systemic amyloid light-chain (AL) (immunoglobulin light chain) amyloidosis

- Exposure to any of the following:

1. Prior exposure to daratumumab or prior exposure to other anti-Cluster of
Differentiation 38 (anti-CD38) therapies

2. Prior exposure to approved or investigational treatments for SMM or MM (including
but not limited to conventional chemotherapies, immunomodulatory agent [IMiDs],
or proteasome inhibitor [PIs]). Stable standard dosing of bisphosphonate and
denosumab as indicated for osteoporosis is acceptable

3. Exposure to investigational drug (including investigational vaccines) or invasive
investigational medical device for any indication within 4 weeks or 5 half-lives,
whichever is longer, before Cycle 1, Day 1

4. Ongoing treatment with corticosteroids with a dose >10 milligram (mg) prednisone
or equivalent per day at the time of randomization; or >280 mg cumulative
prednisone dose or equivalent for any 4-week period in the year prior to
randomization

5. Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab),
immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine) or
other treatments that are likely to interfere with the study procedures or
results

- Received treatment (chemotherapy, surgery, et cetera [etc]) for a malignancy (other
than SMM) within 3 years before the date of randomization (exceptions are squamous and
basal cell carcinomas of the skin, carcinoma in situ of the cervix or breast, or other
non-invasive lesion), which is considered cured with minimal risk of recurrence within
3 years

- Medical or psychiatric condition or disease (for example, active systemic disease
[including presence of auto-antibodies], uncontrolled diabetes) that is likely to
interfere with the study procedures or results, or that in the opinion of the
investigator, would constitute a hazard for participating in this study

- Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
antibodies, hyaluronidase, or other human proteins, or their excipients, or known
sensitivity to mammalian-derived products (including dairy allergy)