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

• Progression-free survival (PFS) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  Based on CRAB criteria.
• Progressive Disease (PD) indicator rate [ Time Frame: 6 months after 74th participant is randomized ] [ Designated as safety issue: No ]
  Novel composite endpoint, built from potential early signs of progression to multiple myeloma.
• European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  The questionnaire includes 9 scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), 6 single-item scales (dyspnea, insomnia, anorexia, constipation, diarrhea and financial impact) and single-item global health and quality of life scales.
• Brief Pain Inventory (worst pain item) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  Refers to the "worst" pain the patient has experienced over the past 24 hours.
• Changes in clinical laboratory values [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: Yes ]
• Number of participants experiencing adverse events [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: Yes ]
• Overall survival [ Time Frame: Approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]

• Progression-free survival (PFS) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  Based on CRAB criteria.
• Progressive Disease (PD) indicator rate [ Time Frame: 6 months after randomization of last patient ] [ Designated as safety issue: No ]
  Novel composite endpoint, built from potential early signs of progression to multiple myeloma.
• European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  The questionnaire includes 9 scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, nausea and vomiting, and pain), 6 single-item scales (dyspnea, insomnia, anorexia, constipation, diarrhea and financial impact) and single-item global health and quality of life scales.
• Brief Pain Inventory (worst pain item) [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]
  Refers to the "worst" pain the patient has experienced over the past 24 hours.
• Changes in clinical laboratory values [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: Yes ]
• Adverse events [ Time Frame: Up to approximately 4 years after randomization of last patient ] [ Designated as safety issue: Yes ]
• Overall survival [ Time Frame: Approximately 4 years after randomization of last patient ] [ Designated as safety issue: No ]

• Drug: Siltuximab
  Type=exact, unit=mg/kg, number=15, form=intravenous infusion, route=intravenous use, every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study.
• Drug: Placebo
  Form=intravenous infusion, route=intravenous use route=intravenous, use every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study.

• Experimental: Siltuximab
  Type=exact, unit=mg/kg, number=15, form=intravenous infusion, route=intravenous use, every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study.
  Intervention: Drug: Siltuximab
• Placebo Comparator: Placebo
  Form=intravenous infusion, route=intravenous use route=intravenous, use every 4 weeks until progression to symptomatic multiple myeloma, unacceptable toxicity, withdrawal of consent, or the end of the study.
  Intervention: Drug: Placebo

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