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    Clinical Trial Results:
    A Randomized, Open-label, Phase 3 Study in Subjects With Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination With Dexamethasone, Comparing Once-weekly Versus Twice-weekly Carfilzomib Dosing

    Summary
    EudraCT number
    		 2014-005325-12
    Trial protocol
    		 GB   DE   IT   HU   BE   DK   ES   PL   GR   SE   FI   RO  
    Global end of trial date
    07 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Dec 2019
    First version publication date
    28 Dec 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CFZ014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02412878
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Amgen Study ID: 20140355
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to the PFS of twice-weekly carfilzomib dosing in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma who have received prior treatment with a proteasome inhibitor and an immunomodulatory agent.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH), Good Clinical Practice (GCP) regulations/guidelines. The protocol, protocol amendments, and proposed informed consent form were submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for written approval. A copy of the written approval of the protocol, amendments, and informed consent form was received by the sponsor before recruitment of subjects into the study and shipment of investigational product. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Sep 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 19 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Greece: 46
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Italy: 65
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Canada: 31
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    478
    EEA total number of subjects
    395
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    208
    From 65 to 84 years
    269
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from September 2015 to August 2016 at 118 sites in Australia, New Zealand, Japan, North America, and Europe.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio to receive a regimen consisting of either once-weekly or twice weekly carfilzomib in combination with dexamethasone. Randomization was stratified by International Staging System (ISS) stage (stage 1 vs stages 2 or 3), refractory to bortezomib treatment (yes vs no), and age (< 65 vs ≥ 65 years).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Arm description
    		 Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carfilzomib was administered as an IV infusion 20/27 mg/m² twice-weekly

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Solution for infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    40 mg dexamethasone IV or orally.

    Arm title
    		 Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Arm description
    		 Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carfilzomib was administered as an IV infusion 20/27 mg/m² once-weekly

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Solution for infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    40 mg dexamethasone IV or orally.

    Number of subjects in period 1
    		Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Started
    238
    240
    Received Carfilzomib
    235
    238
    Completed
    217
    227
    Not completed
    21
    13
         Consent withdrawn by subject
    19
    10
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Reporting group title
    Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Reporting group values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Total
    Number of subjects
    		 238 240 478
    Age, Customized
    Units: Subjects
        18 - 64 years
    		 104 104 208
        65 - 74 years
    		 102 90 192
        75 - 84 years
    		 32 45 77
        ≥ 85 years
    		 0 1 1
    Age Continuous
    Units: years
        median (full range (min-max))
    		 66.0 (35 to 83) 66.0 (39 to 85) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 110 108 218
        Male
    		 128 132 260
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 15 30 45
        Black or African American
    		 2 3 5
        White
    		 202 200 402
        Other
    		 9 4 13
        Missing
    		 10 3 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 2 7
        Not Hispanic or Latino
    		 226 235 461
        Unknown or Not Reported
    		 7 3 10
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        0 (Fully active)
    		 118 118 236
        1 (Restrictive but ambulatory)
    		 120 121 241
        2 (Ambulatory but unable to work)
    		 0 1 1
    Stratification Factor: International Staging System (ISS) stage
    The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group: • Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL • Stage II: β2M < 3.5 mg/L and albumin < 3.5 g/dL; or β2M 3.5 mg/L - 5.5 mg/L irrespective of the serum albumin • Stage III: β2M ≥ 5.5 mg/L
    Units: Subjects
        Stage 1
    		 100 100 200
        Stage 2 or 3
    		 138 140 278
    Stratification Factor: Refractory to Bortezomib Treatment
    Participants were classified as refractory to bortezomib in prior regimens if the data collected on prior multiple myeloma therapy indicated that any of the following criteria were met: a. Best Response to any regimen containing bortezomib was stable disease or progressive disease. b. Reason bortezomib was stopped was progression in any regimen. c. Date of relapse/progression was after start date and within 60 days after stop date of bortezomib in any regimen.
    Units: Subjects
        Yes
    		 88 88 176
        No
    		 150 152 302

    End points

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    End points reporting groups
    Reporting group title
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Reporting group title
    Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group—Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
    End point type
    Primary
    End point timeframe
    From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively.
    End point values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects analysed
    238
    240
    Units: months
        median (confidence interval 95%)
    7.6 (5.8 to 9.2)
    11.2 (8.6 to 13.0)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The inferential comparison between the 2 treatment groups used the 1-sided log-rank test stratified by the randomization stratification factors. A 1-sided p-value was compared against the prespecified adjusted alpha value of 0.011 to determine significance. The hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated from a stratified Cox proportional hazards model.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0014 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.693
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.544
         upper limit
    		 0.883
    Notes
    [1] - To ensure proper control of type I error, analysis of PFS was performed under a group sequential design framework with stopping boundaries constructed using the Lan-DeMets spending function with an O'Brien-Fleming approach. Progression-free survival, overall response rate, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
    [2] - One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
    Statistical analysis title
    		 Unstratified Analysis
    Statistical analysis description
    The hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0033 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.567
         upper limit
    		 0.913
    Notes
    [3] - One-sided unstratified log-rank test

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively.
    End point values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects analysed
    238
    240
    Units: percentage of participants
        number (confidence interval 95%)
    40.8 (34.5 to 47.3)
    62.9 (56.5 to 69.0)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The inferential comparison of ORR between treatment groups was performed using the Cochran-Mantel-Haenszel test stratified by the randomization stratification factors. A 1-sided p-value from the test was compared against the prespecified alpha value of 0.021 to determine the significance. The odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method stratified by the randomization stratification factors.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.485
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.716
         upper limit
    		 3.598
    Notes
    [4] - Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
    [5] - One-sided p-value from CMH test stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
    Statistical analysis title
    		 Unstratified Analysis
    Statistical analysis description
    The odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.466
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.707
         upper limit
    		 3.563

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive. "99999" indicates values that could not be estimated due to the low number of events at the time of the analysis.
    End point type
    Secondary
    End point timeframe
    From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively.
    End point values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects analysed
    238
    240
    Units: months
        median (confidence interval 95%)
    99999 (18.1 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The inferential comparison between the 2 treatment groups for OS used the 1-sided log-rank test stratified by the randomization stratification factors. A 1-sided p-value was compared against the prespecified adjusted alpha value of 0.018 to determine significance. The hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using a Cox proportional hazards model stratified by the randomization stratification factors.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.107 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.563
         upper limit
    		 1.138
    Notes
    [6] - Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
    [7] - One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
    Statistical analysis title
    		 Unstratified Analysis
    Statistical analysis description
    The hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.
    Comparison groups
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone v Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1326 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.578
         upper limit
    		 1.164
    Notes
    [8] - One-sided unstratified log-rank test

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship. The safety population included all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
    End point values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects analysed
    235
    238
    Units: participants
        Adverse events (AEs)
    230
    233
        Adverse events Grade ≥ 3
    152
    181
        Serious adverse events
    102
    118
        AEs leading to discontinuation of carfilzomib
    29
    35
        AEs leading to discontinuation of dexamethasone
    31
    40
        Fatal adverse events
    20
    21
        Treatment-related adverse events (TRAEs)
    176
    180
        Treatment-related adverse events Grade ≥ 3
    82
    108
        Serious treatment-related adverse events
    31
    57
        TRAE leading to discontinuation of carfilzomib
    11
    23
        TRAEs leading to discontinuation of dexamethasone
    13
    29
        Fatal treatment-related adverse events
    3
    5
    No statistical analyses for this end point

    Secondary: Plasma Carfilzomib Concentration During Cycle 2

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    End point title
    		 Plasma Carfilzomib Concentration During Cycle 2
    End point description
    Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL. "99999" indicates not applicable since participants in the twice weekly group received carfilzomib IV infusion for only 10 minutes.
    End point type
    Secondary
    End point timeframe
    Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion
    End point values
    		 Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Number of subjects analysed
    36 [9]
    55
    Units: ng/mL
    arithmetic mean (standard deviation)
        Predose
    36.2 ( 162 )
    203 ( 1380 )
        15 minutes after start of infusion*
    99999 ( 99999 )
    1370 ( 1410 )
        End of infusion
    1640 ( 1900 )
    1130 ( 928 )
        30 minutes after end of infusion
    104 ( 293 )
    480 ( 2300 )
    Notes
    [9] - *Participants in twice weekly Carfilzomib received IV for 10 minutes
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from the first dose of study drug up to 30 days after last dose; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
    Adverse event reporting additional description
    Deaths are reported from first dose of study drug until the end of study; median (minimum, maximum) follow-up time was 30.7 (0, 39) and 31.2 (0, 38) months in each treatment group respectively. Three participants who died after randomization but before receiving any study treatment are not include in the table below.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Reporting group title
    Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Reporting group description
    		 Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.

    Serious adverse events
    		 Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    118 / 238 (49.58%)
    102 / 235 (43.40%)
         number of deaths (all causes)
    117
    126
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell leukaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    4 / 238 (1.68%)
    7 / 235 (2.98%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 4
    1 / 7
    Plasmacytoma
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral neoplasm
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 238 (0.00%)
    4 / 235 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site vesicles
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Critical illness
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Disease progression
         subjects affected / exposed
    2 / 238 (0.84%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    3 / 238 (1.26%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 238 (1.68%)
    5 / 235 (2.13%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Homicide
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 238 (2.52%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Bradyphrenia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    2 / 238 (0.84%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    3 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoclonal immunoglobulin present
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 238 (0.84%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    3 / 238 (1.26%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 238 (1.68%)
    8 / 235 (3.40%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Anaemia folate deficiency
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia vitamin B12 deficiency
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic uraemic syndrome
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    2 / 238 (0.84%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 238 (0.42%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal haematoma
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    12 / 238 (5.04%)
    8 / 235 (3.40%)
         occurrences causally related to treatment / all
    4 / 15
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 238 (0.42%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    3 / 238 (1.26%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 238 (0.42%)
    4 / 235 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 238 (0.42%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    4 / 238 (1.68%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 238 (1.68%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 238 (1.26%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    23 / 238 (9.66%)
    22 / 235 (9.36%)
         occurrences causally related to treatment / all
    9 / 27
    10 / 24
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pneumonia bacterial
         subjects affected / exposed
    3 / 238 (1.26%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 238 (0.00%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 238 (1.26%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 238 (2.52%)
    3 / 235 (1.28%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 2
    Septic shock
         subjects affected / exposed
    5 / 238 (2.10%)
    2 / 235 (0.85%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Spinal cord infection
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 238 (0.42%)
    4 / 235 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 238 (0.84%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 238 (0.84%)
    4 / 235 (1.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 238 (0.00%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 238 (0.42%)
    0 / 235 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    4 / 238 (1.68%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    217 / 238 (91.18%)
    204 / 235 (86.81%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    58 / 238 (24.37%)
    49 / 235 (20.85%)
         occurrences all number
    85
    79
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 238 (12.18%)
    29 / 235 (12.34%)
         occurrences all number
    44
    38
    Fatigue
         subjects affected / exposed
    50 / 238 (21.01%)
    47 / 235 (20.00%)
         occurrences all number
    65
    66
    Oedema peripheral
         subjects affected / exposed
    23 / 238 (9.66%)
    26 / 235 (11.06%)
         occurrences all number
    29
    36
    Pyrexia
         subjects affected / exposed
    55 / 238 (23.11%)
    38 / 235 (16.17%)
         occurrences all number
    76
    55
    Chest pain
         subjects affected / exposed
    12 / 238 (5.04%)
    4 / 235 (1.70%)
         occurrences all number
    17
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    44 / 238 (18.49%)
    33 / 235 (14.04%)
         occurrences all number
    73
    50
    Dyspnoea
         subjects affected / exposed
    27 / 238 (11.34%)
    21 / 235 (8.94%)
         occurrences all number
    46
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    39 / 238 (16.39%)
    49 / 235 (20.85%)
         occurrences all number
    47
    62
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    14 / 238 (5.88%)
    8 / 235 (3.40%)
         occurrences all number
    27
    9
    Neutrophil count decreased
         subjects affected / exposed
    12 / 238 (5.04%)
    5 / 235 (2.13%)
         occurrences all number
    31
    18
    Platelet count decreased
         subjects affected / exposed
    27 / 238 (11.34%)
    21 / 235 (8.94%)
         occurrences all number
    162
    59
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 238 (11.76%)
    25 / 235 (10.64%)
         occurrences all number
    40
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    69 / 238 (28.99%)
    73 / 235 (31.06%)
         occurrences all number
    141
    168
    Neutropenia
         subjects affected / exposed
    20 / 238 (8.40%)
    23 / 235 (9.79%)
         occurrences all number
    47
    50
    Thrombocytopenia
         subjects affected / exposed
    30 / 238 (12.61%)
    19 / 235 (8.09%)
         occurrences all number
    78
    60
    Eye disorders
    Cataract
         subjects affected / exposed
    14 / 238 (5.88%)
    13 / 235 (5.53%)
         occurrences all number
    18
    14
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    21 / 238 (8.82%)
    22 / 235 (9.36%)
         occurrences all number
    25
    24
    Diarrhoea
         subjects affected / exposed
    53 / 238 (22.27%)
    51 / 235 (21.70%)
         occurrences all number
    73
    75
    Nausea
         subjects affected / exposed
    38 / 238 (15.97%)
    30 / 235 (12.77%)
         occurrences all number
    56
    38
    Vomiting
         subjects affected / exposed
    25 / 238 (10.50%)
    17 / 235 (7.23%)
         occurrences all number
    46
    25
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 238 (3.78%)
    13 / 235 (5.53%)
         occurrences all number
    9
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 238 (7.98%)
    15 / 235 (6.38%)
         occurrences all number
    24
    19
    Back pain
         subjects affected / exposed
    35 / 238 (14.71%)
    31 / 235 (13.19%)
         occurrences all number
    45
    37
    Bone pain
         subjects affected / exposed
    20 / 238 (8.40%)
    17 / 235 (7.23%)
         occurrences all number
    28
    21
    Muscle spasms
         subjects affected / exposed
    22 / 238 (9.24%)
    20 / 235 (8.51%)
         occurrences all number
    30
    29
    Musculoskeletal pain
         subjects affected / exposed
    14 / 238 (5.88%)
    12 / 235 (5.11%)
         occurrences all number
    16
    13
    Pain in extremity
         subjects affected / exposed
    17 / 238 (7.14%)
    19 / 235 (8.09%)
         occurrences all number
    24
    22
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    31 / 238 (13.03%)
    25 / 235 (10.64%)
         occurrences all number
    53
    35
    Respiratory tract infection
         subjects affected / exposed
    18 / 238 (7.56%)
    23 / 235 (9.79%)
         occurrences all number
    37
    34
    Upper respiratory tract infection
         subjects affected / exposed
    39 / 238 (16.39%)
    28 / 235 (11.91%)
         occurrences all number
    59
    45
    Influenza
         subjects affected / exposed
    13 / 238 (5.46%)
    9 / 235 (3.83%)
         occurrences all number
    13
    11
    Nasopharyngitis
         subjects affected / exposed
    35 / 238 (14.71%)
    30 / 235 (12.77%)
         occurrences all number
    61
    50
    Pneumonia
         subjects affected / exposed
    15 / 238 (6.30%)
    5 / 235 (2.13%)
         occurrences all number
    18
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 238 (5.88%)
    14 / 235 (5.96%)
         occurrences all number
    14
    16
    Hypokalaemia
         subjects affected / exposed
    20 / 238 (8.40%)
    10 / 235 (4.26%)
         occurrences all number
    29
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2015
    - clarified that consent was required from subjects if additional blood samples were collected for pharmacokinetic (sparse sampling) and for the intensive pharmacokinetic/ pharmacodynamics substudy - clarified dexamethasone was to be administrated orally on day 22 in cycles 1 to 9 - clarified that dexamethasone was not to be administered on day 22 after cycle 9 - clarified that events occurring before consent should have been captured as medical history information - clarified the timing of safety labs after cycle 4 - clarified the timing of patient-reported outcome questionnaires
    28 Apr 2015
    - added adverse events of pulmonary hypertension and TTP/HUS to the dose modification guidelines - clarified pharmacokinetic time points for intensive and sparse pharmacokinetic sampling.
    22 Apr 2016
    - clarified timepoints for study procedures - clarified exclusion criteria of antineoplastic therapy use to allow immunotherapy or proteasome inhibitors - added the potential use of an IRC - removed information for formulation, physical description, storage, and investigational product accountability to avoid duplication with Investigational Product Instruction Manual - clarified carfilzomib and dexamethasone dosing and procedures for dose interruption - updated text to align with current carfilzomib core safety language - revised hematologic and nonhematologic toxicities for carfilzomib, and dexamethasone-related toxicities - clarified guidance for use of concomitant medications and therapies that were excluded - clarified that cytogenetic abnormalities from prior testing should have been reported as part of multiple myeloma history - added other radiologic modalities permitted for performing skeletal assessment (eg, low-dose CT scan) - clarified requirements for the discontinuation of subjects for PD - revised definition of adverse events regarding worsening of pre-existing conditions - clarified disease response for IMWG-URC
    08 Feb 2017
    - changed PFS from a key secondary objective/endpoint to the primary objective/endpoint and ORR from the primary objective/endpoint to a key secondary objective/endpoint - revised the interim PFS analysis to monitor efficacy and allow the possibility of stopping the study early for efficacy; statistical language was aligned - updated stopping boundaries for PFS - updated carfilzomib dose modifications for nonhematologic toxicity - allowed for the possibility of long-term follow-up for overall survival - added sections for end of study, product complaints, and thromboprophylaxis - added sample forms for serious adverse event reporting and pregnancy and lactation notifications - updated background information

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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