Trial Outcomes & Findings for S1304, Carfilzomib and Dexamethasone for Treating Patients With Relapsed or Refractory Myeloma (NCT NCT01903811)

NCT ID: NCT01903811

Last Updated: 2024-12-20

Results Overview

Assessed in each arm using the method of Kaplan Meier and compared between arms using the stratified long-rank test. Progression is defined using the International Uniform Response Criteria for Multiple Myeloma as new or increase in size of existing bone lesions or soft tissue plasmacytomas; or development of hypercalcemia attributable solely to MM; or ≥ 25% increase from baseline or lowest response level of either serum M protein, urine M protein, difference in involved \& uninvolved serum free light chain level or bone marrow plasma cell percentage.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

143 participants

Primary outcome timeframe

From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 2 years

Results posted on

2024-12-20

Participant Flow

Participant milestones

Participant milestones
Measure	Arm I (Dexamethasone, Low-dose Carfilzomib) Patients receive dexamethasone IV and low-dose carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with progression cross-over to Arm II. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Overall Study STARTED	72	71
Overall Study Crossover to Arm II	16	0
Overall Study COMPLETED	64	57
Overall Study NOT COMPLETED	8	14

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Dexamethasone, Low-dose Carfilzomib) Patients receive dexamethasone IV and low-dose carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with progression cross-over to Arm II. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Overall Study No measurable disease	1	1
Overall Study Incomplete/discontinued prior therapy	1	1
Overall Study Baseline lab missing/incomplete/untimely	6	11
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Due to missing/not done labs, number analyzed in row differs from overall.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Dexamethasone, Low-dose Carfilzomib) n=64 Participants Patients receive dexamethasone IV and low-dose carfilzomib IV over 2-10 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients with progression cross-over to Arm II. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) n=57 Participants Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Total n=121 Participants Total of all reporting groups
Age, Customized Age >= 65	31 Participants n=64 Participants	32 Participants n=57 Participants	63 Participants n=121 Participants
Age, Customized Age < 65	33 Participants n=64 Participants	25 Participants n=57 Participants	58 Participants n=121 Participants
Sex: Female, Male Female	31 Participants n=64 Participants	24 Participants n=57 Participants	55 Participants n=121 Participants
Sex: Female, Male Male	33 Participants n=64 Participants	33 Participants n=57 Participants	66 Participants n=121 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=64 Participants	0 Participants n=57 Participants	1 Participants n=121 Participants
Race (NIH/OMB) Asian	1 Participants n=64 Participants	4 Participants n=57 Participants	5 Participants n=121 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=64 Participants	0 Participants n=57 Participants	0 Participants n=121 Participants
Race (NIH/OMB) Black or African American	11 Participants n=64 Participants	8 Participants n=57 Participants	19 Participants n=121 Participants
Race (NIH/OMB) White	51 Participants n=64 Participants	41 Participants n=57 Participants	92 Participants n=121 Participants
Race (NIH/OMB) More than one race	0 Participants n=64 Participants	1 Participants n=57 Participants	1 Participants n=121 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=64 Participants	3 Participants n=57 Participants	3 Participants n=121 Participants
Zubrod performance status > 1	2 Participants n=64 Participants	3 Participants n=57 Participants	5 Participants n=121 Participants
Beta-2-microglobulin >=3.5 mg/L	36 Participants n=64 Participants	31 Participants n=57 Participants	67 Participants n=121 Participants
CRP >= 8 mg/L	6 Participants n=33 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	6 Participants n=23 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	12 Participants n=56 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Creatinine >= 2 mg/dl	1 Participants n=64 Participants	0 Participants n=57 Participants	1 Participants n=121 Participants
Creatinine clearance < 60 ml/min	23 Participants n=64 Participants	18 Participants n=57 Participants	41 Participants n=121 Participants
LDH >= 190 U/L	31 Participants n=63 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	26 Participants n=56 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	57 Participants n=119 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Albumin < 3.5 g/dl	16 Participants n=64 Participants	14 Participants n=57 Participants	30 Participants n=121 Participants
ISS disease stage: Stage 1	20 Participants n=64 Participants	22 Participants n=57 Participants	42 Participants n=121 Participants
ISS disease stage: Stage 2	30 Participants n=64 Participants	19 Participants n=57 Participants	49 Participants n=121 Participants
ISS disease stage: Stage 3	14 Participants n=64 Participants	16 Participants n=57 Participants	30 Participants n=121 Participants
Hemoglobin <10 g/dL	15 Participants n=64 Participants	6 Participants n=57 Participants	21 Participants n=121 Participants
Platelet count < 150 x 10^9/L	1 Participants n=64 Participants	1 Participants n=57 Participants	2 Participants n=121 Participants
4-6 Prior lines of therapy	14 Participants n=64 Participants	15 Participants n=57 Participants	29 Participants n=121 Participants
Refractory to Bortezomib	32 Participants n=64 Participants	28 Participants n=57 Participants	60 Participants n=121 Participants
Serum M spike >3 g/dL	13 Participants n=64 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	6 Participants n=56 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	19 Participants n=120 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Bone marrow plasma cells > 60%	14 Participants n=63 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	11 Participants n=56 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	25 Participants n=119 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
sLFC Ratio >=100	24 Participants n=60 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	19 Participants n=51 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	43 Participants n=111 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Myeloma isotype: IgG	36 Participants n=61 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	24 Participants n=54 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	60 Participants n=115 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Myeloma isotype: IgA	5 Participants n=61 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	12 Participants n=54 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	17 Participants n=115 Participants • Due to missing/not done labs, number analyzed in row differs from overall.
Myeloma isotype: light chain only	9 Participants n=61 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	8 Participants n=54 Participants • Due to missing/not done labs, number analyzed in row differs from overall.	17 Participants n=115 Participants • Due to missing/not done labs, number analyzed in row differs from overall.

PRIMARY outcome

Timeframe: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 2 years

Population: Group of participants that were eligible and analyzable per protocol.

Outcome measures

Outcome measures
Measure	Arm III (Crossover Group) n=64 Participants Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 additional courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) n=57 Participants Patients receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose of 20 mg/m\^2 over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Progression-free Survival	5 months Interval 4.0 to 11.0	8 months Interval 6.0 to 12.0

SECONDARY outcome

Timeframe: From date of registration to date of death due to any cause, assessed up to 3 years

Population: Participants that were eligible and analyzable per protocol.

Assessed in each arm using the method of Kaplan Meier and compared between arms using the stratified log-rank test.

Outcome measures

Outcome measures
Measure	Arm III (Crossover Group) n=64 Participants Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 additional courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) n=57 Participants Patients receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose of 20 mg/m\^2 over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Overall Survival	26 months Interval 16.0 to The upper limit for this 95% confidence interval for the median is not calculable.	22 months Interval 18.0 to 29.0

SECONDARY outcome

Timeframe: From date of registration to date of best response while on study treatment

Population: This population includes eligible and analyzable patients who had a follow-up response assessment.

Per International Uniform Response Criteria for Multiple Myeloma PR- ≥ 50% reduction in size of soft tissue plasmacytomas \& plasma cells; ≥ 50% decrease in serum \& reduction in urine M protein ≥ 90% or to \< 200 mg/24hr or ≥ 50% decrease in difference in uninvolved \& involved serum free light chain levels; VGPR- PR + Serum and urine M proteins detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M protein \& urine M protein \< 100 mg/24 hrs; uPR- 1 objective status of PR, but confirmation studies are not done, or do not meet the requirements necessary to confirm response; SD- does not meet criteria for sCR, CR, VGPR, PR or PROG; PROG- new or increase in size of existing bone lesions or soft tissue plasmacytomas/ development of hypercalcemia attributable solely to MM/ ≥ 25% increase from baseline/ lowest response level of either serum or Urine M protein, difference in involved \& uninvolved serum free light chain level or bone marrow plasma cell percentage.

Outcome measures

Outcome measures
Measure	Arm III (Crossover Group) n=59 Participants Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 additional courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) n=53 Participants Patients receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose of 20 mg/m\^2 over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Best Overall Response - Partial Response (PR), Very Good Partial Response (VGPR), Unconfirmed PR (uPR), Stable Disease (SD) Progression (PROG) Very Good Partial Response (VGPR)	5 Participants	14 Participants
Best Overall Response - Partial Response (PR), Very Good Partial Response (VGPR), Unconfirmed PR (uPR), Stable Disease (SD) Progression (PROG) Partial Response (PR)	18 Participants	11 Participants
Best Overall Response - Partial Response (PR), Very Good Partial Response (VGPR), Unconfirmed PR (uPR), Stable Disease (SD) Progression (PROG) Unconfirmed Partial Response (uPR)	0 Participants	2 Participants
Best Overall Response - Partial Response (PR), Very Good Partial Response (VGPR), Unconfirmed PR (uPR), Stable Disease (SD) Progression (PROG) Stable Disease (SD)	24 Participants	19 Participants
Best Overall Response - Partial Response (PR), Very Good Partial Response (VGPR), Unconfirmed PR (uPR), Stable Disease (SD) Progression (PROG) Progressive Disease	12 Participants	7 Participants

SECONDARY outcome

Timeframe: From date of crossover to date of subsequent documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years from randomization

Population: Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive high dose carfilzomib

Assessed in the crossover arm using the method of Kaplan Meier. Progression is defined using the International Uniform Response Criteria for Multiple Myeloma as new or increase in size of existing bone lesions or soft tissue plasmacytomas; or development of hypercalcemia attributable solely to MM; or ≥ 25% increase from baseline or lowest response level of either serum M protein, urine M protein, difference in involved \& uninvolved serum free light chain level or bone marrow plasma cell percentage.

Outcome measures

Outcome measures
Measure	Arm III (Crossover Group) n=16 Participants Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 additional courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) Patients receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose of 20 mg/m\^2 over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Progression-free Survival of Crossover Group	3 months Interval 2.0 to 6.0	—

SECONDARY outcome

Timeframe: From date of crossover to date of death due to any cause, assessed up to 3 years from randomization

Assessed in the crossover arm using the method of Kaplan Meier.

Outcome measures

Outcome measures
Measure	Arm III (Crossover Group) n=16 Participants Patients on Arm 1 that progress after the start of course 2 and prior to completion of 12 courses receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 additional courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies	Arm II (Dexamethasone, High-dose Carfilzomib) Patients receive 20 mg dexamethasone IV and high-dose (56 mg/m\^2) carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16. (Note that course 1 is given at a reduced dose of 20 mg/m\^2 over 2-10 minutes.) Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Carfilzomib: Given IV Dexamethasone: Given IV Laboratory Biomarker Analysis: Correlative studies
Overall Survival Crossover Group	15 months Interval 5.0 to 27.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 3 years

Bone marrow compared to that of an aspirate taken at the site of the EMP. Data will be log-transformed before analysis. Exploratory analyses will examine underlying distributions using boxplots, density plots, scatter plots, etc. For differential expression analysis of the two sample types t-tests will be conducted on genes. False discovery rate will be used to control the average false positive proportions among selected genes. Genes will be ranked by their q-value and pathway analysis conducted upon selected genes to determine biological plausibility and relevance to molecular functionality.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to week 45

Univariate and multivariate logistic regression will be used to determine the impact of biochemical CR on CR by PET. In the multivariate analysis adjustment for standard prognostic factors such as age, albumin, beta-2 microglobulin, serum creatinine, c-reactive protein and lactate dehydrogenase will be included.

Outcome measures

Outcome data not reported

Adverse Events

Arm I (Dexamethasone, Low-dose Carfilzomib)

Serious events: 26 serious events

Other events: 66 other events

Deaths: 38 deaths

Arm II (Dexamethasone, High-dose Carfilzomib)

Serious events: 27 serious events

Other events: 55 other events

Deaths: 40 deaths

Crossover Arm

Serious events: 5 serious events

Other events: 14 other events

Deaths: 12 deaths

Serious adverse events

Other adverse events

Additional Information

S1304 Statistician

SWOG Statistical Center

Phone: 2066674623

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Arm I (Dexamethasone, Low-dose Carfilzomib) n=66 participants at risk Patients receive dexamethasone and low dose carfilzomib. Includes all eligible and analyzable patients. Deaths for patients that registered Crossover arm are also counted in this arm.	Arm II (Dexamethasone, High-dose Carfilzomib) n=57 participants at risk Patients receive dexamethasone and high dose carfilzomib. Includes all eligible and analyzable patients.	Crossover Arm n=16 participants at risk Patients on Arm 1 that progress after the start of cycle 2 and prior to completion of 12 cycles receive high dose carfilzomib. Includes all eligible and analyzable patients. These patients are also included under "Arm I".
Blood and lymphatic system disorders Anemia	4.5% 3/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	10.5% 6/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Acute coronary syndrome	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Atrial flutter	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Cardiac arrest	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Chest pain - cardiac	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Heart failure	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Left ventricular systolic dysfunction	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Restrictive cardiomyopathy	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Sinus tachycardia	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Supraventricular tachycardia	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Eye disorders Blurred vision	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Eye disorders Glaucoma	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Gastroesophageal reflux disease	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Nausea	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Vomiting	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Chills	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Death NOS	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Edema limbs	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Fatigue	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Fever	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	10.5% 6/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Multi-organ failure	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Non-cardiac chest pain	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Sudden death NOS	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Hepatobiliary disorders Cholecystitis	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Endocarditis infective	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Infections and infestations-Other	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Lung infection	4.5% 3/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.3% 7/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Otitis media	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Sepsis	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Sinusitis	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Urinary tract infection	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Injury, poisoning and procedural complications Fall	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Injury, poisoning and procedural complications Fracture	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Injury, poisoning and procedural complications Injury, poison and procedural complications - Other	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Creatinine increased	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Ejection fraction decreased	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Lymphocyte count decreased	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Lymphocyte count increased	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Neutrophil count decreased	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.

Other adverse events
Measure	Arm I (Dexamethasone, Low-dose Carfilzomib) n=66 participants at risk Patients receive dexamethasone and low dose carfilzomib. Includes all eligible and analyzable patients. Deaths for patients that registered Crossover arm are also counted in this arm.	Arm II (Dexamethasone, High-dose Carfilzomib) n=57 participants at risk Patients receive dexamethasone and high dose carfilzomib. Includes all eligible and analyzable patients.	Crossover Arm n=16 participants at risk Patients on Arm 1 that progress after the start of cycle 2 and prior to completion of 12 cycles receive high dose carfilzomib. Includes all eligible and analyzable patients. These patients are also included under "Arm I".
Blood and lymphatic system disorders Anemia	59.1% 39/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	66.7% 38/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	50.0% 8/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Cardiac disorders-Other	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Chest pain - cardiac	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Sinus bradycardia	6.1% 4/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Cardiac disorders Sinus tachycardia	10.6% 7/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Ear and labyrinth disorders Hearing impaired	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Eye disorders Blurred vision	13.6% 9/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	19.3% 11/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Eye disorders Watering eyes	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Abdominal pain	9.1% 6/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	14.0% 8/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Bloating	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	7.0% 4/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Constipation	18.2% 12/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	24.6% 14/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Diarrhea	30.3% 20/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	35.1% 20/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Dry mouth	9.1% 6/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.3% 7/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Dyspepsia	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.3% 7/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Gastroesophageal reflux disease	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Mucositis oral	6.1% 4/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	7.0% 4/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Nausea	37.9% 25/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	36.8% 21/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	31.2% 5/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Stomach pain	3.0% 2/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Gastrointestinal disorders Vomiting	19.7% 13/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	15.8% 9/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Chills	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	8.8% 5/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Edema face	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Edema limbs	21.2% 14/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	15.8% 9/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Fatigue	59.1% 39/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	57.9% 33/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	37.5% 6/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Fever	13.6% 9/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	8.8% 5/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Flu like symptoms	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Non-cardiac chest pain	6.1% 4/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	7.0% 4/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
General disorders Pain	19.7% 13/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	26.3% 15/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Immune system disorders Allergic reaction	0.00% 0/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Immune system disorders Immune system disorders-Other	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Infections and infestations-Other	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	10.5% 6/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Sinusitis	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	1.8% 1/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Skin infection	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Infections and infestations Upper respiratory infection	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.3% 7/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Injury, poisoning and procedural complications Bruising	7.6% 5/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	10.5% 6/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Injury, poisoning and procedural complications Fracture	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	3.5% 2/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Alanine aminotransferase increased	1.5% 1/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	7.0% 4/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Alkaline phosphatase increased	10.6% 7/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	5.3% 3/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	6.2% 1/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Aspartate aminotransferase increased	10.6% 7/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	14.0% 8/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Blood bilirubin increased	12.1% 8/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	7.0% 4/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	0.00% 0/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.
Investigations Creatinine increased	22.7% 15/66 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	24.6% 14/57 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.	12.5% 2/16 • For the duration of treatment, up to 12 cycles and maximum follow up of 3 years post-registration. Note that denominators differ from those reported in other Results sections as the AE data tables are pulled from the live database and thus reflect more current data while other Sections are based those data reported at the time of Primary Endpoint analyses.