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 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 ]
• 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 ]

The purpose of this study is to evaluate the safety and efficacy of siltuximab compared with placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial) in patients with high-risk smoldering multiple myeloma (SMM).

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 100 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.

• 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