A Study of Siltuximab (Anti- IL 6 Monoclonal Antibody) in Patients With High-risk Smoldering Multiple Myeloma

This is a randomized (treatment assigned by chance), double-blind (neither patient nor
investigator know which treatment is given), multicenter study to evaluate the safety and
efficacy of siltuximab compared with placebo in patients with high-risk SMM (defined as bone
marrow plasma cells >=10% and either serum monoclonal protein >=3 g/dL, or abnormal free
light chain ratio <0.126 or >8 and serum M-protein <3 g/dL but >=1 g/dL). Approximately 74
patients will receive either siltuximab or placebo by intravenous (IV, injection into a vein)
infusion every 4 weeks until progression to symptomatic multiple myeloma, unacceptable
toxicity, withdrawal of consent, or the end of the study (approximately 4 years after
randomization of the last patient). Efficacy, pharmacokinetics, immunogenicity, and potential
biomarkers will be assessed at time points defined in the protocol. Patient reported outcomes
(European Organization for Research and Treatment of Cancer, Quality of Life
Questionnaire-Core 30, Brief Pain Inventory [worst pain], Non-Chemotherapy Anemia Symptom
Scale) will be administered before any procedure or treatment at each visit. Patient safety
will be monitored throughout the study.

Inclusion Criteria:

- Diagnosis of smoldering multiple myeloma (SMM) for <4 years

- Diagnosis of high-risk SMM (defined as bone marrow plasma cells >=10% and either serum
monoclonal protein >=3 g/dL, or abnormal free light chain ratio <0.126 or >8 and serum
M-protein <3 g/dL but >=1 g/dL)

- Patients must be within certain limits for protocol-specified laboratory tests

- Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1

- Women not of childbearing potential must be postmenopausal, permanently sterilized, or
otherwise incapable of pregnancy

- Women of childbearing potential must agree to use adequate birth control measures and
agree to not donate eggs for the purpose of assisted reproduction during the study and
for 3 months after receiving the last dose of study agent, and must have a negative
pregnancy test at screening

- Men must agree to use a double-barrier method of birth control and to not donate sperm
during the study and for 3 months after receiving the last dose of study agent

Exclusion Criteria:

- Having symptomatic multiple myeloma, defined by any of the following (if due to
myeloma): lytic bone lesions, severe osteopenia (low bone density), pathologic
fractures, hypercalcemia (too much calcium in the blood), kidney insufficiency;
symptomatic hyperviscosity of the blood, or recurrent serious bacterial infections
such as pneumonia

- Primary systemic amyloid light (AL) chain amyloidosis (a build-up of amyloid light
chain proteins in the blood)

- Prior or concurrent exposure to approved or investigational multiple myeloma
treatments (concurrent treatment with bone-protecting agents (eg, bisphosphonates,
denosumab), or steroids (not exceeding 10 mg prednisone per day or equivalent) are
only allowed if given in a stable dose and for a nonmalignant condition; concurrent
treatment with erythropoietin-stimulating agents (ESAs) are not allowed.)

- Prior exposure to agents targeting interleukin 6 (IL 6) or the IL 6 receptor

- Other malignancy within the past 3 years, except for the following, if treated and not
active: basal cell or nonmetastatic (non-spreading) squamous cell carcinoma of the
skin, cervical carcinoma or International Federation of Gynecology and Obstetrics
Stage 1 carcinoma of the cervix