Trial Outcomes & Findings for Study of Bortezomib and Dexamethasone With or Without Elotuzumab to Treat Relapsed or Refractory Multiple Myeloma (NCT NCT01478048)

Last Updated: 2018-05-21

Results Overview

PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified International Myeloma Working Group (IMWG) criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

185 participants

Primary outcome timeframe

Randomization until 111 events (disease progression or death), up to May 2014, approximately 2 years

Results posted on

2018-05-21

Participant Flow

185 participants were enrolled, 152 participants were randomized. Reasons not randomized: 23 no longer met study criteria, 5 withdrew consent, 2 died, 3 had poor/non-compliance. 150 were treated with study drug. 2 participants were not treated: 1 withdrawal by subject and 1 physician decision.

Participant milestones

Participant milestones
Measure	Elotuzumab + Bortezomib + Dexamethasone Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Overall Study STARTED	77	75
Overall Study Received Treatment	76	74
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	77	75

Reasons for withdrawal

Reasons for withdrawal
Measure	Elotuzumab + Bortezomib + Dexamethasone Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Overall Study Disease Progression	52	35
Overall Study study drug toxicity	11	14
Overall Study Adverse Event	2	11
Overall Study subject request to discontinue treatment	3	5
Overall Study Withdrawal by Subject	2	5
Overall Study non-specified	6	4
Overall Study poor/non-compliance	0	1
Overall Study no longer meets study criteria	1	0

Baseline Characteristics

Study of Bortezomib and Dexamethasone With or Without Elotuzumab to Treat Relapsed or Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Elotuzumab + Bortezomib + Dexamethasone n=77 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug	Total n=152 Participants Total of all reporting groups
Age, Continuous	65.4 years STANDARD_DEVIATION 9.48 • n=5 Participants	65.1 years STANDARD_DEVIATION 10.34 • n=7 Participants	65.3 years STANDARD_DEVIATION 9.88 • n=5 Participants
Age, Customized < 65 years	34 Participants n=5 Participants	33 Participants n=7 Participants	67 Participants n=5 Participants
Age, Customized ≥65 and <75 years	28 Participants n=5 Participants	28 Participants n=7 Participants	56 Participants n=5 Participants
Age, Customized >= 75 years	15 Participants n=5 Participants	14 Participants n=7 Participants	29 Participants n=5 Participants
Sex: Female, Male Female	35 Participants n=5 Participants	38 Participants n=7 Participants	73 Participants n=5 Participants
Sex: Female, Male Male	42 Participants n=5 Participants	37 Participants n=7 Participants	79 Participants n=5 Participants
Region of Enrollment United States	25 Participants n=5 Participants	23 Participants n=7 Participants	48 Participants n=5 Participants
Region of Enrollment Italy	34 Participants n=5 Participants	32 Participants n=7 Participants	66 Participants n=5 Participants
Region of Enrollment France	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment Spain	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Prior Protease Inhibitor Use Yes	38 Participants n=5 Participants	37 Participants n=7 Participants	75 Participants n=5 Participants
Prior Protease Inhibitor Use No	39 Participants n=5 Participants	38 Participants n=7 Participants	77 Participants n=5 Participants
Presence of At Least 1 FcγRIIIa V allele Yes	55 Participants n=5 Participants	54 Participants n=7 Participants	109 Participants n=5 Participants
Presence of At Least 1 FcγRIIIa V allele No	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Number of Prior Lines of Therapy 1 line of prior therapy	55 Participants n=5 Participants	51 Participants n=7 Participants	106 Participants n=5 Participants
Number of Prior Lines of Therapy 2 or 3 lines of prior therapy	22 Participants n=5 Participants	24 Participants n=7 Participants	46 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization until 111 events (disease progression or death), up to May 2014, approximately 2 years

Population: Intent to treat (ITT), all randomized participants were analyzed.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=77 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Median Investigator-Assessed Progression-free Survival (PFS) Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause - Randomized Participants	9.7 Months Interval 7.4 to 12.2	6.9 Months Interval 5.1 to 10.2

PRIMARY outcome

Timeframe: Randomization until 111 events, up to May 2014, approximately 2 years

Population: Intent to treat (ITT), all randomized participants were analyzed.

PE planned for after at least 103 events (progression/death); analyzed at 111 events. Those who neither progressed nor died were censored on the date of last adequate tumor assessment (ATA), which requires both serum and urine M-protein tests. If no post-baseline tumor assessments/no death, then censored on randomization day. Response assessed: Day 1 (± 7 days) each cycle; 30 and 60 days post treatment. Modified IMWG criteria used. Progression: Any of following: Increase of 25% in serum and/or urine M-component; if no measurable serum, urine M-protein levels, then difference between involved and uninvolved free light chain (FLC) levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). New bone lesions or soft tissue plasmacytomas or increase in size of existing lesions, plasmacytomas. Development of hypercalcemia attributed solely to plasma cell proliferative disorder. First dose occurs within 3 days of randomization.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=77 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Number of Investigator-Assessed Progression-free Survival Events From Randomization to Date of First Tumor Progression or Death Due to Any Cause - All Randomized Participants	52 Events (progression or death)	59 Events (progression or death)

PRIMARY outcome

Timeframe: Year 1 after last participant was randomized

Population: All randomized participants were analyzed.

PFS rate=Percentage probability of participants experiencing no progression or death up to 1 year, estimated using the Kaplan-Meier method. Response assessed by the investigator: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using ATA (ie, serum and urine M-protein tests performed within 14 days of each other; imaging done if baseline measurable extramedullary plasmacytoma existed). Progression: Any of the following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L) ; Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=77 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
1 Year Progression-Free Survival Rate - Randomized Participants	0.39 percentage probability Interval 0.28 to 0.5	0.33 percentage probability Interval 0.22 to 0.44

SECONDARY outcome

Timeframe: Randomization until 111 events, up to May 2014, approximately 2 years

Population: All randomized participants who had at least one FcγRIIIa V allele were analyzed.

PE was planned for after at least 103 events; it was analyzed after 111 events. Response was assessed: Day 1 (± 7 days) of each cycle per modified IMWG criteria; assessed using adequate tumor assessment (ATA) (ie, serum and urine M-protein tests performed within 14 days of each other; imaging if baseline measurable extramedullary plasmacytoma existed). Progression: Any of following: Increase of 25% from lowest response in 1 or more: serum and/or urine M-component; in those without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute increase \> 100 mg/L); Bone marrow plasma cell percentage (≥10%). Definite new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas. Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=55 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=54 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Median Progression-free Survival Time (Months) From Randomization to Date of First Tumor Progression or Death Due to Any Cause, in Randomized Participants With at Least One FcγRIIIa V Allele	9.9 Months Interval 6.1 to 13.9	8.1 Months Interval 5.0 to 11.1

SECONDARY outcome

Timeframe: Randomization until 111 events, up to May 2014, approximately 2 years

Population: All randomized participants were analyzed.

ORR was calculated for participants with a best overall response (BOR) of partial response (PR) or better, including stringent complete response (sCR), complete response (CR), and very good partial response (VGPR). BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=77 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Investigator-Assessed Objective Response Rate (ORR) - All Randomized Participants	64.9 percentage of participants Interval 53.2 to 75.5	62.7 percentage of participants Interval 50.7 to 73.6

SECONDARY outcome

Timeframe: Randomization until 111 events, up to May 2014, approximately 2 years

Population: All randomized participants who had at least one FcγRIIIa V allele at randomization were analyzed.

ORR was calculated for participants with a BOR of PR or better, sCR, CR, and VGPR. BOR was determined by the investigator based on myeloma tumor assessments using IMWG criteria: CR=Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas, and \< 5% plasma cells in bone marrow; sCR= CR + normal FLC ratio and absence of clonal cells in bone marrow; VGPR=Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein level + urine M-protein level \< 100 mg per 24 hour; PR= ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hour. ORR= number of participants responding divided by total number of participants randomized, measured as a percentage. Randomized participants with at least 1 FcγRIIIa V allele were a sub-set of all randomized participants.

Outcome measures

Outcome measures
Measure	Elotuzumab + Bortezomib + Dexamethasone n=55 Participants Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=54 Participants Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Investigator-Assessed Objective Response Rate in Randomized Participants With at Least One FcγRIIIa V Allele	60.0 percentage of participants Interval 45.9 to 73.0	61.1 percentage of participants Interval 46.9 to 74.1

Adverse Events

Elotuzumab + Bortezomib + Dexamethasone

Serious events: 39 serious events

Other events: 72 other events

Deaths: 37 deaths

Bortezomib + Dexamethasone

Serious events: 31 serious events

Other events: 71 other events

Deaths: 39 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Elotuzumab + Bortezomib + Dexamethasone n=75 participants at risk Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 participants at risk Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Blood and lymphatic system disorders Thrombocytopenia	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Angina pectoris	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Atrial fibrillation	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Atrial flutter	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Cardio-respiratory arrest	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Coronary artery disease	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Myocardial infarction	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Sinus tachycardia	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Tachycardia	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Eye disorders Cataract	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Eye disorders Diplopia	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Abdominal pain	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Colitis	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Constipation	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Diarrhoea	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Gastritis	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Ileus	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Ileus paralytic	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Impaired gastric emptying	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Nausea	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Oesophagitis	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Pancreatitis	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Vomiting	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Asthenia	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Gait disturbance	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders General physical health deterioration	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Non-cardiac chest pain	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Oedema peripheral	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Pyrexia	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Hepatobiliary disorders Hepatitis	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Aspergillus infection	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Bacteraemia	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Bacterial pyelonephritis	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Bronchitis	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Cellulitis	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Cytomegalovirus colitis	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Cytomegalovirus infection	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Diverticulitis	0.00% 0/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)

Other adverse events
Measure	Elotuzumab + Bortezomib + Dexamethasone n=75 participants at risk Elotuzumab: Solution; Intravenous (IV); 10 mg/kg; (Cycles 1 \& 2: Days 1, 8 \& 15; Cycles 3-8: Days 1 \& 11; Cycle 9+: Days 1 \& 15); Until participant meets criteria for discontinuation of drug Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of drug. Days of Elotuzumab infusion: Dexamethasone (8mg IV + 8mg Oral) administered. Other days Dexamethasone 20 mg Oral administered Dexamethasone: Tablets; 20 mg; (Cycles 1\& 2: once daily on Days 2, 4, 5, 8, 9, 11; Cycles 3-8: once daily on Days 2, 4, 5, 9, 12; Cycles 9+: once daily on Days 2, 8, 9, 16); Until criteria met for discontinuation. Dexamethasone: Tablets; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation of drug. Dexamethasone: Solution; IV; 8 mg; (Cycles 1\& 2: Days 1, 8, 15; Cycles 3-8: Days 1 \&11; Cycles 9+; Days 1 \& 15); Until criteria met for discontinuation	Bortezomib + Dexamethasone n=75 participants at risk Bortezomib: Solution; IV; 1.3 mg/m\^2; (Cycles 1 - 8: Days 1, 4, 8, 11; Cycles 9+: Days 1, 8, 15); Until criteria met for discontinuation of study drug. Dexamethasone: Tablets; 20 mg; (Cycles 1-8 once daily on Days 1, 2, 4, 5, 8, 9, 11, 12; Cycles 9+ once daily on Days 1, 2, 8, 9, 15, 16); Until criteria is met for discontinuation of study drug
Blood and lymphatic system disorders Anaemia	33.3% 25/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	26.7% 20/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Blood and lymphatic system disorders Lymphopenia	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Blood and lymphatic system disorders Neutropenia	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Blood and lymphatic system disorders Thrombocytopenia	17.3% 13/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	29.3% 22/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Cardiac disorders Tachycardia	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Eye disorders Cataract	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Eye disorders Vision blurred	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Abdominal distension	12.0% 9/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Abdominal pain	10.7% 8/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	10.7% 8/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Abdominal pain upper	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Constipation	37.3% 28/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	28.0% 21/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Diarrhoea	41.3% 31/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	32.0% 24/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Dyspepsia	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Gastrooesophageal reflux disease	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Nausea	25.3% 19/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	21.3% 16/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Gastrointestinal disorders Vomiting	18.7% 14/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Asthenia	26.7% 20/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	28.0% 21/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Chest pain	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Chills	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Face oedema	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Fatigue	29.3% 22/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	22.7% 17/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Influenza like illness	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Injection site erythema	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Oedema	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Oedema peripheral	28.0% 21/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	24.0% 18/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
General disorders Pyrexia	33.3% 25/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	20.0% 15/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Bronchitis	10.7% 8/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Conjunctivitis	12.0% 9/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Herpes zoster	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Influenza	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Pneumonia	1.3% 1/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Upper respiratory tract infection	13.3% 10/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Urinary tract infection	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Infections and infestations Viral upper respiratory tract infection	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Injury, poisoning and procedural complications Rib fracture	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	2.7% 2/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Investigations Blood creatinine increased	6.7% 5/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Investigations Platelet count decreased	8.0% 6/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	10.7% 8/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Investigations Weight decreased	9.3% 7/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	4.0% 3/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Investigations Weight increased	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	5.3% 4/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)
Metabolism and nutrition disorders Decreased appetite	16.0% 12/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)	12.0% 9/75 • From first dose to last dose plus 60 days (assessed up to April 2017, approximately 63 months)