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

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01484275
• Collaborator: (none)
• Enrollment: 85
• Locations: 40
• Arms: 2
• Actual Duration (Months): 89.7
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
High-risk Smoldering Multiple Myeloma	Drug: Siltuximab; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Blinded, Placebo-controlled, Multicenter Study of Siltuximab (Anti IL 6 Monoclonal Antibody) in Subjects With High-risk Smoldering Multiple Myeloma
• Actual Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: May 12, 2015
• Actual Study Completion Date: Aug 21, 2019

Arms and Interventions

Arm	Intervention/Treatment
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.	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.
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.	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.

Outcome Measures

Primary Outcome Measures

1. One-Year Progression-Free Survival (PFS) Rate [Up to 1 Year]

   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).

Secondary Outcome Measures

1. Progressive Disease Indicator Rate (PDIR) at 6 Months [At 6 Months]

   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).

2. Progression-Free Survival [Up to 4.7 Years]

   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).

3. Percentage of Participants With Serum M-protein Response [Up to 4.7 Years]

   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.

4. Time to Worsening in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scale Score [Up to 4.7 Years]

   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.

5. Time to Worsening in the Brief Pain Inventory (BPI) Worst Item Scores [Up to 4.7 Years]

   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.

6. Number of Participants With Symptomatic Multiple Myeloma With Adverse Prognostic Features [Up to 4.7 Years]

   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.

7. Number of Participants With Best Response to First Subsequent Multiple Myeloma Treatment [Up to 4.7 Years]

   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.

8. Overall Survival (OS) [Up to 4.7 Years]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chicago	Illinois	United States
2		Rockville	Maryland	United States
3		Detroit	Michigan	United States
4		New York	New York	United States
5		Kittanning	Pennsylvania	United States
6		Philadelphia	Pennsylvania	United States
7		Greenville	South Carolina	United States
8		Dallas	Texas	United States
9		Camperdown		Australia
10		East Melbourne		Australia
11		Randwick		Australia
12		Antwerpen		Belgium
13		Brussels		Belgium
14		Gent		Belgium
15		Dijon		France
16		Nantes Cedex 1		France
17		Tours		France
18		Villejuif		France
19		Berlin		Germany
20		Hamburg		Germany
21		Heidelberg		Germany
22		Athens		Greece
23		Ashkelon		Israel
24		Jerusalem		Israel
25		Nahariya		Israel
26		Netanya		Israel
27		Petach Tikva		Israel
28		Tel Aviv		Israel
29		Daejeon		Korea, Republic of
30		Seoul		Korea, Republic of
31		Barcelona		Spain
32		Barcleona		Spain
33		Madrid		Spain
34		Salamanca		Spain
35		Valencia		Spain
36		Göteborg		Sweden
37		Linkoping		Sweden
38		Stockholm		Sweden
39		London		United Kingdom
40		Manchester		United Kingdom

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01484275
• Other Study ID Numbers: CR100755; CNTO328SMM2001; 2011-001735-22; NCT01563666
• First Posted: Dec 2, 2011
• Last Update Posted: Jan 27, 2020
• Last Verified: Jan 1, 2020

• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janssen Research & Development, LLC: High-risk smoldering multiple myeloma; Multiple myeloma; Siltuximab
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Smoldering Multiple Myeloma; Siltuximab

Study Results

Participant Flow

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Period Title: Overall Study
STARTED	43	42
COMPLETED	0	0
NOT COMPLETED	43	42

Baseline Characteristics

Arm/Group Title	Siltuximab	Placebo	Total
Arm/Group Description	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).	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 of all reporting groups
Overall Participants	43	42	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (10.95)	59.5 (12.03)	61.4 (11.57)
Sex: Female, Male (Count of Participants)
Female	17 39.5%	20 47.6%	37 43.5%
Male	26 60.5%	22 52.4%	48 56.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	4 9.3%	2 4.8%	6 7.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.3%	2 4.8%	3 3.5%
White	35 81.4%	37 88.1%	72 84.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 7%	1 2.4%	4 4.7%
Region of Enrollment (Count of Participants)
Australia	4 9.3%	4 9.5%	8 9.4%
Belgium	1 2.3%	1 2.4%	2 2.4%
France	5 11.6%	1 2.4%	6 7.1%
Germany	5 11.6%	14 33.3%	19 22.4%
Israel	7 16.3%	3 7.1%	10 11.8%
Korea, Republic Of	3 7%	2 4.8%	5 5.9%
Spain	9 20.9%	6 14.3%	15 17.6%
United Kingdom	4 9.3%	2 4.8%	6 7.1%
United States	5 11.6%	9 21.4%	14 16.5%

Outcome Measures

1. Primary Outcome

Title	One-Year Progression-Free Survival (PFS) Rate
Description	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).
Time Frame	Up to 1 Year

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Number (95% Confidence Interval) [Percentage of participants]	84.5 196.5%	74.4 177.1%

2. Secondary Outcome

Title	Progressive Disease Indicator Rate (PDIR) at 6 Months
Description	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).
Time Frame	At 6 Months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Number (95% Confidence Interval) [Percentage of participants]	30.2 70.2%	42.9 102.1%

3. Secondary Outcome

Title	Progression-Free Survival
Description	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).
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Median (95% Confidence Interval) [Days]	NA	715.0

4. Secondary Outcome

Title	Percentage of Participants With Serum M-protein Response
Description	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.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Number (95% Confidence Interval) [Percentage of participants]	2.3 5.3%	0.0 0%

5. Secondary Outcome

Title	Time to Worsening in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) Scale Score
Description	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.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	22	21
Median (Full Range) [Days]	125.50	118.00

6. Secondary Outcome

Title	Time to Worsening in the Brief Pain Inventory (BPI) Worst Item Scores
Description	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.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Median (95% Confidence Interval) [Days]	652.0	453.0

7. Secondary Outcome

Title	Number of Participants With Symptomatic Multiple Myeloma With Adverse Prognostic Features
Description	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.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	0	0

8. Secondary Outcome

Title	Number of Participants With Best Response to First Subsequent Multiple Myeloma Treatment
Description	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.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	0	0

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time between randomization and death due to any cause.
Time Frame	Up to 4.7 Years

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	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).	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).
Measure Participants	43	42
Median (95% Confidence Interval) [Days]	NA	NA

Adverse Events

Time Frame	Up to 4.7 Years
Adverse Event Reporting Description	Safety analysis set included participants who have received at least 1 administration of any study agent (siltuximab or placebo).
Arm/Group Title	Siltuximab		Placebo
Arm/Group Description	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).		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).
All Cause Mortality
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/43 (7%)		4/42 (9.5%)
Serious Adverse Events
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/43 (30.2%)		13/42 (31%)
Blood and lymphatic system disorders
Anaemia	0/43 (0%)		1/42 (2.4%)
Cardiac disorders
Acute Coronary Syndrome	1/43 (2.3%)		0/42 (0%)
Cardiac Arrest	0/43 (0%)		1/42 (2.4%)
Ear and labyrinth disorders
Eustachian Tube Disorder	1/43 (2.3%)		0/42 (0%)
Gastrointestinal disorders
Gastric Disorder	1/43 (2.3%)		0/42 (0%)
General disorders
Asthenia	1/43 (2.3%)		0/42 (0%)
Hepatobiliary disorders
Cholecystitis Acute	0/43 (0%)		1/42 (2.4%)
Infections and infestations
Diverticulitis	1/43 (2.3%)		1/42 (2.4%)
Influenza	0/43 (0%)		1/42 (2.4%)
Lower Respiratory Tract Infection	0/43 (0%)		1/42 (2.4%)
Mastoiditis	1/43 (2.3%)		0/42 (0%)
Otitis Media	1/43 (2.3%)		0/42 (0%)
Pharyngitis	1/43 (2.3%)		0/42 (0%)
Pneumonia	2/43 (4.7%)		1/42 (2.4%)
Pneumonia Streptococcal	0/43 (0%)		1/42 (2.4%)
Sepsis	0/43 (0%)		1/42 (2.4%)
Sinusitis	1/43 (2.3%)		0/42 (0%)
Urinary Tract Infection	0/43 (0%)		1/42 (2.4%)
Injury, poisoning and procedural complications
Back Injury	0/43 (0%)		1/42 (2.4%)
Joint Dislocation	1/43 (2.3%)		0/42 (0%)
Lower Limb Fracture	1/43 (2.3%)		0/42 (0%)
Rib Fracture	1/43 (2.3%)		0/42 (0%)
Spinal Fracture	1/43 (2.3%)		0/42 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	0/43 (0%)		1/42 (2.4%)
Hypoglycaemia	0/43 (0%)		1/42 (2.4%)
Musculoskeletal and connective tissue disorders
Back Pain	2/43 (4.7%)		0/42 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	1/43 (2.3%)		0/42 (0%)
Nervous system disorders
Facial Paresis	0/43 (0%)		1/42 (2.4%)
Transient Ischaemic Attack	1/43 (2.3%)		0/42 (0%)
Renal and urinary disorders
Acute Kidney Injury	0/43 (0%)		2/42 (4.8%)
Oliguria	1/43 (2.3%)		0/42 (0%)
Renal Impairment	0/43 (0%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Nasal Septum Deviation	1/43 (2.3%)		0/42 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/43 (2.3%)		0/42 (0%)
Vascular disorders
Ischaemia	0/43 (0%)		1/42 (2.4%)
Poor Venous Access	0/43 (0%)		1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/43 (95.3%)		42/42 (100%)
Blood and lymphatic system disorders
Anaemia	6/43 (14%)		6/42 (14.3%)
Neutropenia	8/43 (18.6%)		1/42 (2.4%)
Thrombocytopenia	5/43 (11.6%)		0/42 (0%)
Cardiac disorders
Palpitations	1/43 (2.3%)		4/42 (9.5%)
Gastrointestinal disorders
Abdominal Distension	0/43 (0%)		4/42 (9.5%)
Abdominal Pain	3/43 (7%)		6/42 (14.3%)
Abdominal Pain Lower	1/43 (2.3%)		3/42 (7.1%)
Abdominal Pain Upper	2/43 (4.7%)		4/42 (9.5%)
Constipation	5/43 (11.6%)		7/42 (16.7%)
Diarrhoea	6/43 (14%)		7/42 (16.7%)
Nausea	9/43 (20.9%)		10/42 (23.8%)
Stomatitis	2/43 (4.7%)		3/42 (7.1%)
General disorders
Asthenia	8/43 (18.6%)		3/42 (7.1%)
Chest Pain	1/43 (2.3%)		5/42 (11.9%)
Fatigue	6/43 (14%)		14/42 (33.3%)
Influenza Like Illness	1/43 (2.3%)		5/42 (11.9%)
Oedema Peripheral	3/43 (7%)		3/42 (7.1%)
Pyrexia	3/43 (7%)		6/42 (14.3%)
Infections and infestations
Bronchitis	3/43 (7%)		3/42 (7.1%)
Gastroenteritis	3/43 (7%)		1/42 (2.4%)
Herpes Zoster	1/43 (2.3%)		3/42 (7.1%)
Nasopharyngitis	9/43 (20.9%)		15/42 (35.7%)
Oral Herpes	0/43 (0%)		4/42 (9.5%)
Pneumonia	3/43 (7%)		1/42 (2.4%)
Rhinitis	1/43 (2.3%)		4/42 (9.5%)
Sinusitis	3/43 (7%)		3/42 (7.1%)
Upper Respiratory Tract Infection	5/43 (11.6%)		10/42 (23.8%)
Urinary Tract Infection	3/43 (7%)		3/42 (7.1%)
Investigations
Alanine Aminotransferase Increased	4/43 (9.3%)		0/42 (0%)
Aspartate Aminotransferase Increased	3/43 (7%)		1/42 (2.4%)
Metabolism and nutrition disorders
Decreased Appetite	3/43 (7%)		0/42 (0%)
Hypertriglyceridaemia	4/43 (9.3%)		0/42 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/43 (11.6%)		11/42 (26.2%)
Back Pain	10/43 (23.3%)		12/42 (28.6%)
Muscle Spasms	0/43 (0%)		5/42 (11.9%)
Musculoskeletal Chest Pain	5/43 (11.6%)		9/42 (21.4%)
Myalgia	2/43 (4.7%)		3/42 (7.1%)
Pain in Extremity	5/43 (11.6%)		8/42 (19%)
Nervous system disorders
Dizziness	3/43 (7%)		6/42 (14.3%)
Headache	6/43 (14%)		9/42 (21.4%)
Sciatica	4/43 (9.3%)		2/42 (4.8%)
Syncope	3/43 (7%)		1/42 (2.4%)
Psychiatric disorders
Insomnia	0/43 (0%)		4/42 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	8/43 (18.6%)		8/42 (19%)
Dyspnoea	3/43 (7%)		3/42 (7.1%)
Epistaxis	0/43 (0%)		5/42 (11.9%)
Oropharyngeal Pain	2/43 (4.7%)		10/42 (23.8%)
Rhinorrhoea	0/43 (0%)		4/42 (9.5%)
Skin and subcutaneous tissue disorders
Night Sweats	0/43 (0%)		3/42 (7.1%)
Rash	6/43 (14%)		0/42 (0%)
Vascular disorders
Hypertension	1/43 (2.3%)		4/42 (9.5%)

Limitations/Caveats

Siltuximab demonstrated positive trending toward 1-year PFS only in high risk SMM-group. Sponsor and Steering Committee decided not to further pursue clinical development of siltuximab for SMM and terminated study, and was considered as completed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.