Trial Outcomes & Findings for A Study of Siltuximab (Anti- IL 6 Monoclonal Antibody) in Patients With High-risk Smoldering Multiple Myeloma (NCT NCT01484275)

Last Updated: 2020-01-27

Results Overview

One-year PFS rate is defined as the percentage (%) of participants surviving 1 year after randomization without progression to multiple myeloma or death estimated by the Kaplan-Meier method and based on the International Myeloma Working Group (IMWG) calcium, renal, anemia, and bone lesions (CRAB) criteria. Progressive disease (PD) is defined as presence of an M- component in serum plus clonal plasma cells in the bone marrow plus 1 or more of the following: Calcium elevation (greater than \[\>\] 11.5 milligram per deciliter \[mg/dL\] \[\> 2.88 millimoles per liter {mmol/L}\]); Renal insufficiency (creatinine \> 2 mg/dL \[177 micromoles per liter or more\]; Anemia (hemoglobin less than \[\<\] 10 gram per deciliter \[g/dL\] or 2 g/dL lower than lower limit of normal \[LLN\] \[hemoglobin \< 6.5 mmol/L or 1.25 mmol/L lower than LLN\]); Bone disease (lytic lesions or osteopenia).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

85 participants

Primary outcome timeframe

Up to 1 Year

Results posted on

2020-01-27

Participant Flow

Participant milestones

Participant milestones
Measure	Siltuximab Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Overall Study STARTED	43	42
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	43	42

Reasons for withdrawal

Reasons for withdrawal
Measure	Siltuximab Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Overall Study Study terminated by sponsor	28	32
Overall Study Other	10	0
Overall Study Death	3	4
Overall Study Withdrawal by Subject	1	5
Overall Study Lost to Follow-up	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Total n=85 Participants Total of all reporting groups
Age, Continuous	63.2 years STANDARD_DEVIATION 10.95 • n=5 Participants	59.5 years STANDARD_DEVIATION 12.03 • n=7 Participants	61.4 years STANDARD_DEVIATION 11.57 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	20 Participants n=7 Participants	37 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants	22 Participants n=7 Participants	48 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	35 Participants n=5 Participants	37 Participants n=7 Participants	72 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment Australia	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment Belgium	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment France	5 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment Germany	5 Participants n=5 Participants	14 Participants n=7 Participants	19 Participants n=5 Participants
Region of Enrollment Israel	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment Korea, Republic Of	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment Spain	9 Participants n=5 Participants	6 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment United Kingdom	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment United States	5 Participants n=5 Participants	9 Participants n=7 Participants	14 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 1 Year

Population: Intent-to-treat (ITT) population included participants who were randomly assigned to siltuximab or placebo treatment group based on an integrated voice response system (IVRS).

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
One-Year Progression-Free Survival (PFS) Rate	84.5 Percentage of participants Interval 68.6 to 92.8	74.4 Percentage of participants Interval 57.3 to 85.5

SECONDARY outcome

Timeframe: At 6 Months

Population: Response evaluable population included participants who had a diagnosis of high-risk smoldering multiple myeloma (SMM) and received at least 1 dose of siltuximab/placebo treatment. In addition, participants were to have at least 1 post-baseline disease assessment.

PDIR is defined as percentage of participants who meet any of following criteria occurring within 6 months of start of treatment. a) CRAB criteria: true progression events, b) Serum M-protein: increase by 25 % compared with baseline at 2 consecutive assessments, c) Magnetic resonance imaging: unequivocal increase in focal bone lesions, d) Immunoparesis: decrease by 25% compared with baseline of 2 other non-affected immunoglobulin (Ig) (IgG, IgM, IgA) at 2 consecutive assessments, e) Hemoglobin: decrease of 1.5 g/dL (with at least 1 read below LLN) at 2 consecutive assessments, with no other identifiable cause. PD is defined as presence of M-component in serum plus clonal plasma cells in bone marrow plus 1 or more of following: Calcium elevation (\> 11.5 mg/dL \[\> 2.88 mmol/L\]); Renal insufficiency (creatinine \>2 mg/dL \[177 micro mol/L or more\]); Anemia (hemoglobin \<10 or 2 g/dL lower than LLN) \[hemoglobin \< 6.5 or 1.25 mmol/L lower than LLN\]); Bone disease (lytic lesions or osteopenia).

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Progressive Disease Indicator Rate (PDIR) at 6 Months	30.2 Percentage of participants Interval 17.2 to 46.1	42.9 Percentage of participants Interval 27.7 to 59.0

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: ITT population included participants who were randomly assigned to siltuximab or placebo treatment group based on an IVRS.

PFS is defined as the time between randomization and initial documented PD according to the CRAB - International Myeloma Working Group (IMWG) criteria or date of death, whichever occurs first. PD is defined as presence of an M-component in serum plus clonal plasma cells in the bone marrow plus 1 or more of the following: Calcium elevation (\> 11.5 mg/dL \[\> 2.88 mmol/L\]); Renal insufficiency (creatinine \> 2 mg/dL \[177 \[micro mol/L or more\]); Anemia (\<10 g/dL or 2 g/dL) lower than LLN) \[hemoglobin \< 6.5 mmol/L or 1.25 mmol/L lower than LLN\]); Bone disease (lytic lesions or osteopenia).

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Progression-Free Survival	NA Days Interval 703.0 to Here, NA signifies that median and upper limit of confidence interval (CI) was not estimable due to less number of events.	715.0 Days Interval 490.0 to 1232.0

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: ITT population included participants who were randomly assigned to siltuximab or placebo treatment group based on an IVRS.

Serum M-protein response is defined as a decrease of greater than or equal to (\>=) 50% in serum M-protein compared with baseline at 2 consecutive assessments.

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Percentage of Participants With Serum M-protein Response	2.3 Percentage of participants Interval 0.1 to 12.3	0.0 Percentage of participants Interval 0.0 to 8.4

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: ITT population included participants who were randomly assigned to siltuximab or placebo treatment group based on an IVRS who had 10 points decrease from baseline in the physical function scale.

Time to worsening in EORTC-QLQ-C30 (physical function scale) is defined as time between randomization and first documentation of a worsening in EORTC-QLQ-C-30. Worsening in the EORTC-QLQ-C30 is defined as 10 points decrease from baseline. It comprises module with 30 items. Questionnaire includes 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea/vomiting), a global health and quality of life scale, and a number of single items assessing symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhoea). Instrument contains 28 items using a Likert scale with 4 response options: "Not at All," "A Little," "Quite a Bit," "Very Much" (scored 1-4). Two additional items use response options (1-7): 1=Very Poor, to 7=Excellent. All scale and item scores were linearly transformed to be in range from 0-100. A higher score represents a higher (better) level of functioning, or a higher (worse) level of symptoms.

Outcome measures

Outcome measures
Measure	Siltuximab n=22 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=21 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Time to Worsening in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scale Score	125.50 Days Interval 56.0 to 1021.0	118.00 Days Interval 56.0 to 565.0

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: ITT population included participants who were randomly assigned to siltuximab or placebo treatment group based on an IVRS.

Time to worsening in the BPI worst item is defined as the time between randomization and the first documentation of a worsening in the BPI worst item. It has 2 domains reflecting pain severity and pain interference with domains of functioning and well-being. The selected item refers to the "worst" pain the patient has experienced over the past 24 hours. This item has been found to be most responsive to interference with key domains of functioning and well-being and may be used as a single item. Responses are provided on an 11-point numeric rating scale ranging from 0 "no pain" to 10 "pain as bad as you can imagine". Responses are described as mild (1 to 4), moderate (5 to 6) and severe (7 to 10). Worsening in the BPI worst item is defined as 2 points increase from baseline.

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Time to Worsening in the Brief Pain Inventory (BPI) Worst Item Scores	652.0 Days Interval 226.0 to Here, NA signifies that upper limit of CI was not estimable due to an insufficient number of events.	453.0 Days Interval 277.0 to Here, NA signifies that upper limit of CI was not estimable due to an insufficient number of events.

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: The data was not collected and analyzed for this outcome measure as per the change in planned analysis.

Number of participants who progressed to symptomatic multiple myeloma with stage III of International Staging System (ISS) or abnormal cytogenetic findings were assessed. The ISS system consists of stage I: beta2-microglobulin \< 3.5 milligram per liter (mg/L) and albumin \>= 3.5 gram (g)/100 ml; stage II: neither stage I nor stage III and stage III: beta2-microglobulin \>= 5.5 mg/L.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: The data was not collected and analyzed for this outcome measure as per the change in planned analysis.

Best response to first subsequent anti-myeloma therapy was assessed by physician report at 6-month intervals and classified as: complete response (CR) (negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasms cells (PCs) in bone marrow); stringent CR (CR plus a normal FLC ratio, absence of clonal cells in bone marrow); near CR (\< 5% PCs in a bone marrow aspirate, no increase in lytic bone lesions); very good partial response (VGPR) (serum and urine component detectable by immunofixation but not on electrophoresis, or \>= 90% reduction in serum M-protein plus urine M-protein level \<100 mg per 24 hour); partial response (PR): \>= 50 reduction of serum M-protein, reduction in 24-hour urinary M-protein by \>=90 % or to \< 200 mg/24 hours); minimal response (\>=25% but \<= 49% reduction of serum M-protein and reduction in urine M-protein by 50%-89%); stable disease (not meeting criteria for CR, VGPR, PR, or PD); PD; not evaluable and unknown.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 4.7 Years

Population: ITT population included participants who were randomly assigned to siltuximab or placebo treatment group based on an IVRS.

OS is defined as the time between randomization and death due to any cause.

Outcome measures

Outcome measures
Measure	Siltuximab n=43 Participants Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 Participants Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Overall Survival (OS)	NA Days Here, NA signifies that median and confidence interval was not estimable due to less number of events.	NA Days Here, NA signifies that median and confidence interval was not estimable due to less number of events.

Adverse Events

Siltuximab

Serious events: 13 serious events

Other events: 41 other events

Deaths: 3 deaths

Placebo

Serious events: 13 serious events

Other events: 42 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Director

Janssen Research & Development, LLC

Phone: 844-434-4210

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	Siltuximab n=43 participants at risk Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 participants at risk Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Blood and lymphatic system disorders Anaemia	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Cardiac disorders Acute Coronary Syndrome	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Cardiac disorders Cardiac Arrest	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Ear and labyrinth disorders Eustachian Tube Disorder	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Gastric Disorder	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Asthenia	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Hepatobiliary disorders Cholecystitis Acute	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Diverticulitis	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Influenza	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Lower Respiratory Tract Infection	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Mastoiditis	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Otitis Media	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Pharyngitis	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Pneumonia	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Pneumonia Streptococcal	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Sepsis	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Sinusitis	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Urinary Tract Infection	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Injury, poisoning and procedural complications Back Injury	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Injury, poisoning and procedural complications Joint Dislocation	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Injury, poisoning and procedural complications Lower Limb Fracture	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Injury, poisoning and procedural complications Rib Fracture	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Injury, poisoning and procedural complications Spinal Fracture	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Back Pain	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Cancer	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Facial Paresis	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Transient Ischaemic Attack	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Renal and urinary disorders Acute Kidney Injury	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	4.8% 2/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Renal and urinary disorders Oliguria	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Renal and urinary disorders Renal Impairment	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Nasal Septum Deviation	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Skin and subcutaneous tissue disorders Angioedema	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Vascular disorders Ischaemia	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Vascular disorders Poor Venous Access	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).

Measure	Siltuximab n=43 participants at risk Participants received 15 milligram per kilogram (mg/kg) of siltuximab as a 1-hour intravenous (IV) infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).	Placebo n=42 participants at risk Participants received placebo as a 1-hour IV infusion every 4 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study (up to 4 years after randomization of the last participant).
Blood and lymphatic system disorders Anaemia	14.0% 6/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	14.3% 6/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Blood and lymphatic system disorders Neutropenia	18.6% 8/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Blood and lymphatic system disorders Thrombocytopenia	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Cardiac disorders Palpitations	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Abdominal Distension	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Abdominal Pain	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	14.3% 6/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Abdominal Pain Lower	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Abdominal Pain Upper	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Constipation	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	16.7% 7/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Diarrhoea	14.0% 6/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	16.7% 7/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Nausea	20.9% 9/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	23.8% 10/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Gastrointestinal disorders Stomatitis	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Asthenia	18.6% 8/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Chest Pain	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	11.9% 5/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Fatigue	14.0% 6/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	33.3% 14/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Influenza Like Illness	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	11.9% 5/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Oedema Peripheral	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
General disorders Pyrexia	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	14.3% 6/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Bronchitis	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Gastroenteritis	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Herpes Zoster	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Nasopharyngitis	20.9% 9/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	35.7% 15/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Oral Herpes	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Pneumonia	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Rhinitis	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Sinusitis	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Upper Respiratory Tract Infection	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	23.8% 10/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Infections and infestations Urinary Tract Infection	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Investigations Alanine Aminotransferase Increased	9.3% 4/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Investigations Aspartate Aminotransferase Increased	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Metabolism and nutrition disorders Decreased Appetite	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Metabolism and nutrition disorders Hypertriglyceridaemia	9.3% 4/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Arthralgia	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	26.2% 11/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Back Pain	23.3% 10/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	28.6% 12/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Muscle Spasms	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	11.9% 5/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Musculoskeletal Chest Pain	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	21.4% 9/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Myalgia	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Musculoskeletal and connective tissue disorders Pain in Extremity	11.6% 5/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	19.0% 8/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Dizziness	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	14.3% 6/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Headache	14.0% 6/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	21.4% 9/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Sciatica	9.3% 4/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	4.8% 2/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Nervous system disorders Syncope	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	2.4% 1/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Psychiatric disorders Insomnia	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Cough	18.6% 8/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	19.0% 8/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.0% 3/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	11.9% 5/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	4.7% 2/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	23.8% 10/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Skin and subcutaneous tissue disorders Night Sweats	0.00% 0/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	7.1% 3/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Skin and subcutaneous tissue disorders Rash	14.0% 6/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	0.00% 0/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Vascular disorders Hypertension	2.3% 1/43 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).	9.5% 4/42 • Up to 4.7 Years Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).