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    Clinical Trial Results:
    Randomized, Open Label, Multicenter Study Assessing The Clinical Benefit Of Isatuximab Combined With Carfilzomib (Kyprolis®) And Dexamethasone Versus Carfilzomib With Dexamethasone In Patients With Relapse And/Or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines

    Summary
    EudraCT number
    		 2017-001940-37
    Trial protocol
    		 GB   CZ   HU   ES   FR   GR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 May 2024
    First version publication date
    11 May 2023
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Results are updated and aligned with ClinicalTrials.gov

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15246
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03275285
    WHO universal trial number (UTN)
    		 U1111-1195-5957
    Other trial identifiers
    		 IND Number: 103217
    Sponsors
    Sponsor organisation name
    Sanofi Aventis Recherche & Développement
    Sponsor organisation address
    82, avenue Raspail, GENTILLY Cedex, France, 94255
    Public contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.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
    Interim
    Date of interim/final analysis
    14 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2022
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the benefit of isatuximab in combination with carfilzomib and dexamethasone in the prolongation of progression free survival (PFS) using International Myeloma Working Group (IMWG) as compared to carfilzomib and dexamethasone in subjects with relapsed and/or refractory multiple myeloma (MM) previously treated with 1 to 3 lines of therapy.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial, as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Türkiye: 14
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czechia: 34
    Country: Number of subjects enrolled
    France: 39
    Worldwide total number of subjects
    302
    EEA total number of subjects
    136
    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)
    154
    From 65 to 84 years
    146
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study conducted at 69 active centers in 16 countries. 341 subjects screened between 25 Oct 2017 & 21 Mar 2019, 39 subjects were screen failure - not met eligibility criteria. Randomisation stratified by number of prior lines (1 vs >1) & revised international staging system (R-ISS) I/II vs III vs not classified. 302 subjects enrolled & randomised.

    Pre-assignment
    Screening details
    		 Study ongoing, data cut-off date for result analysis reported 07Feb2020: efficacy outcomes; 14Jan2022: CR, MRD, PFS2. PFS data reported 7Feb2020 & 14Jan2022. Primary analysis of PFS refers to interim analysis conducted at 103 events (7Feb20); final analysis of PFS conducted at 159 events (14Jan22).Data cut-off for results analysis of OS is 7Feb2023

    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
    		 Carfilzomib + Dexamethasone (Kd)
    Arm description
    		 Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carfilzomib 20 mg/m^2, was administered as an IV infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and then on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycle along with dexamethasone 20 mg, PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone 20 mg was administered PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle along with Carfilzomib.

    Arm title
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Arm description
    		 Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carfilzomib 20 (mg/m^2, was administered as an IV infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and then on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycle along in combination with carfilzomib and dexamethasone.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone 20 mg was administered PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycle along with carfilzomib and isatuximab.

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isatuximab 10 mg/kg, was administered as an IV infusion on Days 1, 8, 15 and 22 in Cycle 1, and then on Days 1 and 15 of each 28-day treatment cycle in combination with carfilzomib and dexamethasone.

    Number of subjects in period 1
    		Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Started
    123
    179
    Treated
    122
    177
    Completed
    78
    110
    Not completed
    45
    69
         Ongoing
    45
    69

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carfilzomib + Dexamethasone (Kd)
    Reporting group description
    		 Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.

    Reporting group title
    Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Reporting group description
    		 Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.

    Reporting group values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd) Total
    Number of subjects
    		 123 179
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.9 ( 10.0 ) 63.3 ( 9.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 55 78 133
        Male
    		 68 101 169
    Race
    Units: Subjects
        White
    		 83 131 214
        Black or African American
    		 4 5 9
        Asian
    		 24 26 50
        Missing/Not reported
    		 12 14 26
        Multiple
    		 0 3 3

    End points

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    End points reporting groups
    Reporting group title
    Carfilzomib + Dexamethasone (Kd)
    Reporting group description
    		 Subjects received carfilzomib 20 milligrams per meter square (mg/m^2), intravenous (IV) infusion on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles plus dexamethasone 20 milligrams (mg), orally (PO) or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.

    Reporting group title
    Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Reporting group description
    		 Subjects received isatuximab 10 mg/kg, IV infusion on Days 1, 8, 15 and 22 in Cycle 1, then on Day 1 and Day 15 of each 28-day treatment cycles plus carfilzomib 20 mg/m^2, IV on Days 1, and 2 in Cycle 1, and then escalated to 56 mg/m^2 on Days 8, 9, 15 and 16 of Cycle 1 and on Days 1, 2, 8, 9, 15 and 16 of each subsequent 28-day treatment cycles and dexamethasone 20 mg, PO or IV on Day 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day treatment cycles until disease progression or unacceptable adverse event or subject’s decision to discontinue the study treatment or any other reason, whichever comes first.

    Primary: Progression Free Survival as Determined by Independent Response Committee: (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Primary Analysis

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    End point title
    		 Progression Free Survival as Determined by Independent Response Committee: (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Primary Analysis
    End point description
    Time from randomisation to date of 1st PD documentation/death, whichever 1st. If PD & death not observed before cut-off date/date of further anti-myeloma treatment, PFS censored at date of last disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever 1st. Progression/death occurring >8 week after last disease assessment censored at earliest date of last disease assessment without evidence of progression before initiation of anti-myeloma treatment & cut-off date. PD:meeting any 1: Inc >=25% in Serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment; and/or inc >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameter of existing soft tissue extramedullary disease lesion. ITT population. Kaplan-Meier method. 99999=value could not be calculated as <50% subjects had PFS events.
    End point type
    Primary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    20.27 (15.770 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 PFS: Event Censored: Primary Analysis
    Statistical analysis description
    Statistical analysis for comparison of PFS between the Kd and IKd arm based on primary analysis.
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0016 [2]
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.548
    Confidence interval
         level
    		 99.2%
         sides
    2-sided
         lower limit
    		 0.317
         upper limit
    		 0.948
    Notes
    [1] - The 1-sided nominal significance level to declare overwhelming efficacy at primary analysis was 0.004. Because the median PFS was not reached at the primary analysis, it was described at the final analysis.
    [2] - One-sided p-value based on Stratified log-rank test. Threshold for statistical significance at 0.004. Stratified on number of prior lines of therapy (1 vs >1) & revised international staging system stage (I/II vs III vs not classified) as per IRT.

    Primary: Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis

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    End point title
    		 Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis
    End point description
    Time from randomisation to date of 1st documentation of progressive disease (PD)/date of death, whichever 1st. If PD & death not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever 1st. PD:any 1 of following: increase(inc) >=25% serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL and/or inc >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameter of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% increase in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. ITT population. Kaplan-Meier method.99999=value could not be calculated as <50% subjects had PFS events.
    End point type
    Primary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    19.15 (15.770 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 PFS per IRC: Primary Analysis
    Statistical analysis description
    Statistical analysis for comparison of PFS between the Kd and IKd arms based on primary analysis.
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0007 [4]
    Method
    		 Stratified Log-Rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.531
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.318
         upper limit
    		 0.889
    Notes
    [3] - For PFS, the nominal significance levels at primary analysis was determined using alpha-spending function in order to control overall 1-sided type 1 error at 2.5%. The 1-sided nominal significance level to declare overwhelming efficacy at primary analysis (103 PFS events) was 0.005. Because the median PFS was not reached at the primary analysis, it was described at the final analysis.
    [4] - One-sided p-value based on Stratified log-rank test. Threshold for significance=0.005. Stratified on number of prior lines of therapy(1 vs >1) & revised international staging system (I/II vs III vs not classified) per interactive response technology.

    Primary: Progression Free Survival as Determined by Independent Response Committee: Final Analysis

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    End point title
    		 Progression Free Survival as Determined by Independent Response Committee: Final Analysis
    End point description
    PFS: time (in months) from randomisation to date of first documentation of PD or date of death from any cause, whichever comes first. If PD and death was not observed before analysis cut-off date or date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment or analysis cut-off date, whichever comes first. PD as per IMWG criteria: any 1 of following: Inc of >=25% in Serum M-component from nadir; serum M component increase >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% inc in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. Analysis was performed on ITT population and estimated by Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 January 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    19.15 (15.770 to 25.035)
    35.65 (25.758 to 43.959)
    Statistical analysis title
    		 PFS per IRC: Final Analysis
    Statistical analysis description
    Statistical Analysis Progression Free Survival: Final Analysis between Carfilzomib - Dexamethasone (Kd) and Isatuximab, Carfilzomib and Dexamethasone (IKd) arms.
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.576
    Confidence interval
         level
    		 95.4%
         sides
    2-sided
         lower limit
    		 0.418
         upper limit
    		 0.792
    Notes
    [5] - Hazard Ratio was stratified on number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Primary: Progression Free Survival as Determined by Independent Response Committee (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Final Analysis

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    End point title
    		 Progression Free Survival as Determined by Independent Response Committee (Event Censored if Occurred >8 Weeks From Last Disease Assessment): Final Analysis
    End point description
    Time from randomisation to date of 1st documentation of PD/date of death any cause, whichever come 1st. If PD & death not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS censored at date of last valid disease assessment not showing PD/cut-off date, whichever is 1st. Progressions/deaths occurring >8 weeks after last disease assessment censored at earliest date of last valid disease assessment not showing PD before initiation of further anti-myeloma treatment & cut-off date. PD: meeting any 1 criteria: Inc of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion. ITT population. Kaplan-Meier method. 99999=value could not be calculated as <50% subjects had PFS events.
    End point type
    Primary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    20.76 (16.164 to 28.189)
    41.66 (27.138 to 99999)
    Statistical analysis title
    		 PFS: Event Censored: Final Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.594
    Confidence interval
         level
    		 95.4%
         sides
    2-sided
         lower limit
    		 0.424
         upper limit
    		 0.832
    Notes
    [6] - Hazard Ratio was stratified on number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Percentage of Subjects With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis

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    End point title
    		 Percentage of Subjects With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis
    End point description
    OR: subjects with sCR, CR, VGPR & partial response (PR) as best overall response assessed using IMWG response criteria (from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/cutoff date, whichever is 1st). sCR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in bone marrow aspirate (BMA) + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in BMA. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein + urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in plasmacytoma. PR:>=50% reduction of serum M-protein & decrease in 24h urinary M-protein by >=90%/<200mg/24h, if present at baseline,>=50% decrease in SPD of soft tissue plasmacytoma. Analysis on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    82.9
    86.6
    Statistical analysis title
    		 Percentage of Subjects with OR
    Statistical analysis description
    Statistical analysis for comparison of Overall Response between the Kd and IKd arms based on primary analysis.
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.193 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - A closed test procedure was used to control the Type I error rate from the primary efficacy endpoints sequentially through the secondary efficacy endpoints. No further testing would be performed unless the significance level had been reached on PFS and testing on subsequent endpoints were continued only if the null hypothesis for the previously tested endpoint was rejected.
    [8] - One-sided p-value based on Stratified Cochran-Mantel-Haenszel test. One sided p-value was stratified based on randomisation factors according to IRT. Threshold for statistical significance level at 0.025.

    Secondary: Percentage of Subjects With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis

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    End point title
    		 Percentage of Subjects With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis
    End point description
    VGPR or better: defined as subjects with sCR, CR and VGPR as the best overall response (defined as best response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date whichever occurs first) as per IRC. As per IMWG response criteria: sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal free light chain (FLC) ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. ITT population: subjects who gave their informed consent & for whom there was confirmed randomisation number by IRT.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    56.1
    72.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With VGPR or Better with Minimal Residual Disease (MRD) Negativity: Primary Analysis

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    End point title
    		 Percentage of Subjects With VGPR or Better with Minimal Residual Disease (MRD) Negativity: Primary Analysis
    End point description
    Percentage of subjects with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in bone marrow aspiration samples from subjects who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of subjects with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    13.0
    29.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Complete Response With MRD Negativity: Final Analysis

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    End point title
    		 Percentage of Subjects With Complete Response With MRD Negativity: Final Analysis
    End point description
    MRD negativity: percentage of subjects for whom MRD was negative by next-generation sequencing at any timepoint after 1st dose of study treatment. Threshold for negativity is 10^-5. MRD status in a subject was negative if at least 1 result of assessment was negative in subject otherwise MRD was considered as positive (MRD status reported as positive, missing or unevaluable). CR: subjects with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at time of the final analysis was assessed with Hydrashift isatuximab IFE assay, which separated IgG isatuximab from IgG M protein. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    12.2
    26.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Complete Response (CR) as per Independent Response Committee: Final Analysis

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    End point title
    		 Percentage of Subjects with Complete Response (CR) as per Independent Response Committee: Final Analysis
    End point description
    Complete response was defined as the subjects with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with hydrashift isatuximab immunofixation electrophoresis (IFE) assay, which separated immunoglobulin G (IgG) isatuximab from IgG M protein. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    28.5
    44.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis

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    End point title
    		 Percentage of Subjects With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis
    End point description
    Percentage of subjects with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in BM aspiration samples from subjects who achieve VGPR/better, to determine depth of response at molecular level. VGPR or better: percentage of subjects with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio, absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: percentage of subjects
        number (not applicable)
    13.8
    33.5
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP): Primary Analysis

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    End point title
    		 Time to Progression (TTP): Primary Analysis
    End point description
    Time from randomisation to date of 1st documentation of PD. If progression not observed before analysis cut-off date/date of initiation of further anti-myeloma treatment, TTP censored at date of last valid disease assessment not showing disease progression performed prior to initiation of a further anti-myeloma treatment (if any)/analysis cut-off date, whichever 1st. As per IMWG criteria, PD was defined for subjects with inc of >= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if the lowest M component was >=5 g/dL; urine M-component (the absolute inc must be >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of a previous lesion >1 centimeter in short axis. Analysis performed on ITT population using Kaplan-Meier method. 99999 = value not calculated due to less number of subjects with progression events.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    20.27 (16.986 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis TTP: Primary Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.495
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.324
         upper limit
    		 0.757
    Notes
    [9] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Duration of Response (DOR): Primary Analysis

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    End point title
    		 Duration of Response (DOR): Primary Analysis
    End point description
    Time from date of 1st IRC determined response for subject achieving PR/better to date of 1st documented PD determined by IRC/death, whichever is 1st. If disease progression/death before analysis cut-off date not observed, DOR censored at date of last valid disease assessment performed prior to initiation of further anti-myeloma treatment/data cut-off date, whichever 1st. PD:inc >=25% from lowest confirmed value in any 1 of following criteria:serum M-protein (absolute inc >=0.5 g/dL), serum M-protein inc >=1g/dL if lowest M component >=5g/dL; urine M-component (absolute inc >=200mg/24 hour),appearance of new lesion, >=50% inc from nadir in SPD of >1 lesion, >=50% inc in longest diameter of previous lesion >1 cm in short axis. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M-protein by >=90%/<200mg/24 h. Analysis on subset of subjects with PR/better in ITT population by Kaplan Meier method. 99999=value not calculated as <50% subject reaching PR/better with PFS event.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    102
    155
    Units: months
        median (confidence interval 95%)
    99999 (14.752 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis for DOR: Primary Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.425
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.269
         upper limit
    		 0.672
    Notes
    [10] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Overall Survival (OS): Final Analysis

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    End point title
    		 Overall Survival (OS): Final Analysis
    End point description
    Overall survival, defined as the time from the date of randomization to death from any cause. The data reported is based on cut-off date of 7 Feb 2023. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 7 Feb 2023 (the median duration of follow-up was 56.61 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123 [11]
    179 [12]
    Units: months
        median (confidence interval 95%)
    50.60 (38.932 to 99999)
    99999 (52.172 to 99999)
    Notes
    [11] - 9999: upper limit of confidence interval could not be reached due to less number of subjects
    [12] - 9999: median, upper & lower limits of confidence interval not calculated due to less 50% of subjects
    No statistical analyses for this end point

    Secondary: Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 14 Jan 2022

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    End point title
    		 Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 14 Jan 2022
    End point description
    Time from date of randomisation to date of 1st documentation of PD (assessed by investigator) after initiation of further anti-myeloma treatment /death (any cause), whichever 1st. Subjects alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date, PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment/analysis cut-off date, whichever 1st. Per IMWG,PD: defined for subjects with increase (inc) of >= 25% from lowest confirmed value in any 1 of criteria: serum M-protein (absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute inc >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in longest diameter of previous lesion >1 centimeter short axis. ITT population, Kaplan-Meier method, 99999=value not calculated as not enough subjects with PFS2 events.
    End point type
    Secondary
    End point timeframe
    From randomisation until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    35.58 (24.049 to 40.509)
    47.18 (38.111 to 99999)
    Statistical analysis title
    		 Statistical Analysis for PFS2: Final Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.683
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.496
         upper limit
    		 0.941
    Notes
    [13] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Time to First Response (TFR): Primary Analysis

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    End point title
    		 Time to First Response (TFR): Primary Analysis
    End point description
    Time to first response was defined as the time (in months) from randomisation to the date of first IRC determined response (PR or better) that is subsequently confirmed. In the absence of response, subjects were censored at the earliest of the date of the last valid disease assessment before disease progression or death, the date of the last valid disease assessment before initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. PR per IMWG criteria was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to the above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. Analysis was performed on ITT population. Analysis was performed by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    1.12 (1.051 to 1.183)
    1.08 (1.051 to 1.117)
    Statistical analysis title
    		 Statistical Analysis for TFR: Primary Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    1.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.888
         upper limit
    		 1.471
    Notes
    [14] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Time to Best Response (TBR): Primary Analysis

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    End point title
    		 Time to Best Response (TBR): Primary Analysis
    End point description
    Time to best response: time (in months) from randomisation to date of 1st occurrence of IRC determined as best overall response (PR/better) that is subsequently confirmed. In absence of response, subjects were censored at earliest date of last valid disease assessment before disease progression/death, date of last valid disease assessment before initiation of further anti-myeloma treatment (if any)/ analysis cut-off date, whichever was 1st. PR (IMWG criteria) was defined as >=50% reduction of serum M-protein & reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. Additionally, if present at baseline, a >=50% reduction in size (SPD) of soft tissue plasmacytomas was also required. Best Overall Response defined as best response, using IRC’s assessment of response, from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date, whichever occurs 1st. Analysis was performed on ITT population using Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From randomisation until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    3.78 (2.858 to 4.172)
    4.60 (3.811 to 5.257)
    Statistical analysis title
    		 Stat Analysis for TBR: Primary Analysis
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.955
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.233
    Notes
    [15] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 07 Feb 2023

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    End point title
    		 Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 07 Feb 2023
    End point description
    PFS2 defined as time (in months) from date of randomization to date of 1st documentation of PD (as assessed by investigator) after initiation of further anti-myeloma treatment/death from any cause, whichever comes 1st.Participants alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date,PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment /analysis cut-off date,whichever comes 1st.As per IMWG criteria, PD:defined for participants with increase of >= 25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute increase must be >= 0.5 g/dL), serum M-protein increase >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute increase must be >=200 mg/24hour), appearance of new lesion(s), >=50% increase from nadir in SPD of >1 lesion, or >=50% increase in longest diameter of previous lesion >1 centimeter short axis.
    End point type
    Secondary
    End point timeframe
    From randomization until the final analysis data cut-off date of 07 Feb 2023 (the median duration of follow-up was 56.61 months)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: months
        median (confidence interval 95%)
    32.36 (23.129 to 40.016)
    47.18 (38.965 to 57.922)
    Statistical analysis title
    		 Statistical Analysis PFS2: Final Analysis 07Feb23
    Statistical analysis description
    Analysis was performed on ITT population. Analysis was performed by Kaplan-Meier method.
    Comparison groups
    Carfilzomib + Dexamethasone (Kd) v Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.663
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.491
         upper limit
    		 0.895
    Notes
    [16] - Stratification was done on the number of prior lines of therapy (1 vs. >1) and R-ISS stage (I or II vs. III vs. not classified) according to IRT.

    Secondary: Health Related Quality of Life (HRQL): Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints

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    End point title
    		 Health Related Quality of Life (HRQL): Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints
    End point description
    EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items & provides multidimensional assessment of HRQL. EORTC QLQ-C30 includes global health status/quality of life (GHS/QOL), functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 are 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale & are 7-point scale (1/Very Poor to 7/Excellent). GHS total score is calculated as ([{Q29+Q30}/2]-1)/6*100. Answers are converted into grading scale, with values between 0 (worse outcome) to100 (best outcome). High score represents a favorable outcome with best quality of life for subject. Results reported for primary analysis with data cut-off date 7-Feb-2020. Analysis was performed on ITT population. 'n' signifies subjects with available data for each category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=99,151)
    1.52 ( 21.11 )
    -1.60 ( 20.06 )
        Cycle 3 Day 1 (n=100,154)
    4.17 ( 22.92 )
    0.05 ( 20.29 )
        Cycle 4 Day 1 (n=100, 150)
    3.58 ( 21.20 )
    -1.89 ( 23.71 )
        Cycle 5 Day 1 (n=95, 149)
    3.60 ( 21.80 )
    -1.23 ( 23.12 )
        Cycle 6 Day 1 (n=88, 145)
    3.13 ( 20.50 )
    -1.44 ( 22.12 )
        Cycle 7 Day 1 (n=85, 141)
    4.22 ( 22.55 )
    -1.77 ( 22.38 )
        Cycle 8 Day 1 (n=83, 134)
    3.82 ( 21.71 )
    -1.06 ( 20.78 )
        Cycle 9 Day 1 (n=77, 128)
    6.60 ( 19.28 )
    -0.78 ( 22.17 )
        Cycle 10 Day 1 (n=73, 124)
    4.91 ( 21.55 )
    -1.21 ( 20.35 )
        Cycle 11 Day 1 (n=71, 121)
    4.34 ( 20.06 )
    -1.10 ( 20.18 )
        Cycle 12 Day 1 (n=64, 119)
    8.59 ( 22.37 )
    0.84 ( 22.40 )
        Cycle 13 Day 1 (n=60, 112)
    7.08 ( 19.76 )
    -1.26 ( 20.63 )
        Cycle 14 Day 1 (n=59, 111)
    9.75 ( 21.62 )
    -0.98 ( 21.43 )
        Cycle 15 Day 1 (n=57, 103)
    5.26 ( 22.14 )
    0.16 ( 20.51 )
        Cycle 16 Day 1 (n=50, 101)
    6.33 ( 20.73 )
    -1.07 ( 20.94 )
        Cycle 17 Day 1 (n=47, 99)
    7.27 ( 21.04 )
    0.00 ( 22.18 )
        Cycle 18 Day 1 (n=45, 92)
    8.70 ( 23.16 )
    -0.36 ( 20.56 )
        Cycle 19 Day 1 (n=41, 88)
    12.40 ( 21.42 )
    -1.23 ( 20.12 )
        Cycle 20 Day 1 (n=34, 87)
    10.78 ( 20.97 )
    -1.05 ( 20.40 )
        Cycle 21 Day 1 (n=28, 72)
    12.50 ( 21.81 )
    -1.85 ( 21.54 )
        Cycle 22 Day 1 (n=19, 53)
    17.98 ( 22.27 )
    0.31 ( 21.24 )
        Cycle 23 Day 1 (n=15, 37)
    15.56 ( 22.02 )
    3.15 ( 20.73 )
        Cycle 24 Day 1 (n=9, 22)
    14.81 ( 26.28 )
    0.38 ( 14.88 )
        Cycle 25 Day 1 (n=5, 16)
    15.00 ( 28.50 )
    3.13 ( 17.18 )
        End of Treatment (n=57,56)
    -6.14 ( 22.90 )
    -11.90 ( 25.86 )
    No statistical analyses for this end point

    Secondary: HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. Disease symptoms domain is one of the four domain scores. Disease symptoms domain consist of 6 questions and the score uses 4-point scale (1 'Not at All' to 4 'Very Much'). Disease Symptoms Domain Score is calculated as ([{Q31+Q32+Q33+Q34+Q35+Q36}/6]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more symptoms and lower HRQL. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    123
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=103,157)
    -5.34 ( 15.75 )
    -3.40 ( 19.58 )
        Cycle 3 Day 1 (n=102, 158)
    -8.28 ( 15.33 )
    -7.42 ( 18.15 )
        Cycle 4 Day 1 (n=102, 152)
    -5.45 ( 17.48 )
    -7.46 ( 17.99 )
        Cycle 5 Day 1 (n=97, 150)
    -5.78 ( 17.01 )
    -6.37 ( 18.32 )
        Cycle 6 Day 1 (n=91, 146)
    -6.11 ( 18.07 )
    -6.16 ( 19.88 )
        Cycle 7 Day 1 (n=87, 143)
    -6.64 ( 17.44 )
    -4.78 ( 20.77 )
        Cycle 8 Day 1 (n=84, 136)
    -6.94 ( 17.76 )
    -5.47 ( 19.96 )
        Cycle 9 Day 1 (n=79, 131)
    -5.65 ( 18.00 )
    -5.51 ( 17.86 )
        Cycle 10 Day 1 (n=74, 125)
    -5.56 ( 18.48 )
    -4.98 ( 17.24 )
        Cycle 11 Day 1 (n=72, 122)
    -3.24 ( 17.78 )
    -7.10 ( 17.57 )
        Cycle 12 Day 1 (n=65, 121)
    -5.30 ( 16.27 )
    -6.89 ( 17.58 )
        Cycle 13 Day 1 (n=60, 114)
    -7.69 ( 17.06 )
    -5.95 ( 16.44 )
        Cycle 14 Day 1 (n=59, 113)
    -8.66 ( 16.35 )
    -7.08 ( 17.98 )
        Cycle 15 Day 1 (n=57, 105)
    -5.56 ( 17.69 )
    -5.19 ( 17.84 )
        Cycle 16 Day 1 (n=51, 102)
    -8.06 ( 18.27 )
    -5.77 ( 18.66 )
        Cycle 17 Day 1 (n=47, 101)
    -7.57 ( 19.01 )
    -4.29 ( 19.73 )
        Cycle 18 Day 1 (n=45, 94)
    -7.16 ( 17.67 )
    -3.78 ( 17.93 )
        Cycle 19 Day 1 (n=41, 90)
    -7.18 ( 19.57 )
    -3.64 ( 16.70 )
        Cycle 20 Day 1 (n=34, 88)
    -11.93 ( 17.09 )
    -3.54 ( 21.63 )
        Cycle 21 Day 1 (n=28, 73)
    -9.72 ( 16.74 )
    -3.81 ( 19.70 )
        Cycle 22 Day 1 (n=19, 54)
    -9.94 ( 18.76 )
    -5.35 ( 22.48 )
        Cycle 23 Day 1 (n=15, 37)
    -5.56 ( 25.11 )
    -6.01 ( 19.53 )
        Cycle 24 Day 1 (n=9, 22)
    -6.17 ( 29.97 )
    -9.60 ( 18.16 )
        Cycle 25 Day 1 (n=5, 16)
    -12.22 ( 28.97 )
    -14.58 ( 21.65 )
        End of Treatment (n=59, 57)
    2.35 ( 23.10 )
    1.75 ( 23.48 )
    No statistical analyses for this end point

    Secondary: HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. Side effects of treatment domain is one of the four domain scores. Side effects of treatment domain consists of 10 questions and the score uses a 4-point scale (1 'Not at All' to 4 'Very Much'). Side Effects of Treatment Score (MYSE) is calculated as ([{Q37+Q38+Q39+Q40+Q41+Q42+Q43+Q44+Q45+Q46}/10]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more side effects and lower HRQL and lower scores = less side effects and better HRQL. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=103,157)
    1.23 ( 11.56 )
    1.41 ( 11.71 )
        Cycle 3 Day 1 (n=102, 158)
    0.44 ( 10.11 )
    0.84 ( 12.00 )
        Cycle 4 Day 1 (n=102, 152)
    0.83 ( 11.38 )
    0.99 ( 11.89 )
        Cycle 5 Day 1 (n=97, 150)
    1.91 ( 11.36 )
    2.36 ( 11.94 )
        Cycle 6 Day 1 (n=91, 146)
    2.08 ( 11.81 )
    1.61 ( 12.32 )
        Cycle 7 Day 1 (n=87, 143)
    1.47 ( 12.14 )
    2.14 ( 10.76 )
        Cycle 8 Day 1 (n=84, 136)
    1.53 ( 12.07 )
    2.86 ( 12.77 )
        Cycle 9 Day 1 (n=79, 131)
    1.68 ( 11.57 )
    1.49 ( 11.96 )
        Cycle 10 Day 1 (n=74, 125)
    2.07 ( 11.62 )
    2.68 ( 12.51 )
        Cycle 11 Day 1 (n=72, 122)
    3.38 ( 12.00 )
    2.03 ( 12.16 )
        Cycle 12 Day 1 (n=65, 121)
    1.20 ( 10.52 )
    3.04 ( 12.72 )
        Cycle 13 Day 1 (n=60, 114)
    0.82 ( 10.22 )
    2.12 ( 12.33 )
        Cycle 14 Day 1 (n=59, 113)
    1.08 ( 10.56 )
    1.71 ( 12.58 )
        Cycle 15 Day 1 (n=57, 105)
    1.85 ( 11.45 )
    1.87 ( 11.80 )
        Cycle 16 Day 1 (n=51, 102)
    0.99 ( 10.54 )
    2.58 ( 11.88 )
        Cycle 17 Day 1 (n=47, 101)
    2.74 ( 10.03 )
    4.10 ( 12.77 )
        Cycle 18 Day 1 (n=45, 94)
    2.37 ( 10.51 )
    2.95 ( 13.38 )
        Cycle 19 Day 1 (n=41, 90)
    2.76 ( 11.41 )
    2.16 ( 11.56 )
        Cycle 20 Day 1 (n=34, 88)
    -0.17 ( 10.62 )
    2.05 ( 13.03 )
        Cycle 21 Day 1 (n=28, 73)
    3.17 ( 10.61 )
    2.74 ( 12.87 )
        Cycle 22 Day 1 (n=19, 54)
    3.55 ( 6.46 )
    1.51 ( 12.51 )
        Cycle 23 Day 1 (n=15, 37)
    7.85 ( 9.93 )
    -1.39 ( 12.02 )
        Cycle 24 Day 1 (n=9, 22)
    12.35 ( 7.17 )
    -2.54 ( 11.33 )
        Cycle 25 Day 1 (n=5, 16)
    11.85 ( 4.06 )
    -3.50 ( 12.83 )
        End of Treatment (n=59, 57)
    4.63 ( 13.01 )
    5.56 ( 16.22 )
    No statistical analyses for this end point

    Secondary: HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of one question and scores are based on the 4-point Likert scale ranging from 'Not at all' to 'Very much'. Body image score is calculated as: (1 – [Q47-1]/3)*100. Scores are averaged, and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=103,157)
    -1.29 ( 23.76 )
    -1.27 ( 21.31 )
        Cycle 3 Day 1 (n=101, 158)
    1.98 ( 23.01 )
    1.27 ( 26.84 )
        Cycle 4 Day 1 (n=101, 152)
    -1.65 ( 25.55 )
    -1.10 ( 28.04 )
        Cycle 5 Day 1 (n=97, 150)
    -0.69 ( 26.34 )
    -2.89 ( 27.29 )
        Cycle 6 Day 1 (n=91, 146)
    -1.83 ( 24.02 )
    -1.60 ( 26.93 )
        Cycle 7 Day 1 (n=87, 143)
    -0.77 ( 27.83 )
    -3.03 ( 24.36 )
        Cycle 8 Day 1 (n=84, 136)
    -5.16 ( 25.08 )
    -0.25 ( 24.84 )
        Cycle 9 Day 1 (n=78, 131)
    -2.14 ( 24.82 )
    -1.02 ( 25.80 )
        Cycle 10 Day 1 (n=74, 125)
    -1.80 ( 25.22 )
    -1.33 ( 25.54 )
        Cycle 11 Day 1 (n=72, 122)
    -1.85 ( 29.01 )
    -0.55 ( 23.47 )
        Cycle 12 Day 1 (n=65, 121)
    -2.05 ( 25.60 )
    -0.55 ( 25.09 )
        Cycle 13 Day 1 (n=60, 114)
    -3.89 ( 26.10 )
    -2.63 ( 21.79 )
        Cycle 14 Day 1 (n=59, 113)
    -4.52 ( 26.59 )
    -3.24 ( 25.57 )
        Cycle 15 Day 1 (n=57, 105)
    0.00 ( 25.20 )
    -2.22 ( 24.58 )
        Cycle 16 Day 1 (n=51, 102)
    -1.31 ( 27.46 )
    -2.94 ( 22.55 )
        Cycle 17 Day 1 (n=47, 101)
    -1.42 ( 28.62 )
    -1.98 ( 26.17 )
        Cycle 18 Day 1 (n=45, 94)
    1.48 ( 30.11 )
    -1.77 ( 24.62 )
        Cycle 19 Day 1 (n=41, 90)
    0.00 ( 31.62 )
    -3.70 ( 26.18 )
        Cycle 20 Day 1 (n=34, 88)
    0.00 ( 27.22 )
    -0.76 ( 24.75 )
        Cycle 21 Day 1 (n=28, 73)
    -4.76 ( 34.80 )
    -3.20 ( 26.74 )
        Cycle 22 Day 1 (n=19, 54)
    -8.77 ( 36.59 )
    -1.85 ( 27.02 )
        Cycle 23 Day 1 (n=15, 37)
    -13.33 ( 30.34 )
    -5.41 ( 24.23 )
        Cycle 24 Day 1 (n=9, 22)
    -25.93 ( 36.43 )
    -3.03 ( 25.01 )
        Cycle 25 Day 1 (n=5, 16)
    -53.33 ( 18.26 )
    -8.33 ( 25.82 )
        End of Treatment (n=59, 57)
    -5.65 ( 21.58 )
    -9.36 ( 27.28 )
    No statistical analyses for this end point

    Secondary: HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in subjects with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of three questions and the scores are based on the 4-point Likert scale ranging from 'Not at all' to 'Very much'. Future Perspective score is calculated as (1 - ([{Q48+Q49+Q50}/3] -1)/3)*100. Scores are averaged and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=103,157)
    0.54 ( 19.33 )
    7.57 ( 26.48 )
        Cycle 3 Day 1 (n=101, 158)
    4.84 ( 22.08 )
    9.70 ( 24.76 )
        Cycle 4 Day 1 (n=101, 152)
    6.60 ( 20.44 )
    8.55 ( 26.62 )
        Cycle 5 Day 1 (n=97, 150)
    7.67 ( 22.64 )
    7.56 ( 26.98 )
        Cycle 6 Day 1 (n=91, 146)
    8.42 ( 21.81 )
    9.97 ( 25.70 )
        Cycle 7 Day 1 (n=87, 143)
    8.17 ( 21.93 )
    8.47 ( 24.74 )
        Cycle 8 Day 1 (n=84, 136)
    7.41 ( 22.51 )
    10.54 ( 24.50 )
        Cycle 9 Day 1 (n=78, 131)
    7.26 ( 21.10 )
    8.57 ( 28.26 )
        Cycle 10 Day 1 (n=74, 125)
    8.56 ( 22.79 )
    11.56 ( 24.82 )
        Cycle 11 Day 1 (n=72, 122)
    8.02 ( 21.69 )
    12.02 ( 24.23 )
        Cycle 12 Day 1 (n=65, 121)
    6.84 ( 24.51 )
    11.48 ( 22.90 )
        Cycle 13 Day 1 (n=60, 114)
    11.11 ( 20.04 )
    10.72 ( 23.18 )
        Cycle 14 Day 1 (n=59, 113)
    8.85 ( 22.86 )
    11.31 ( 23.29 )
        Cycle 15 Day 1 (n=57, 105)
    9.55 ( 24.16 )
    12.28 ( 22.27 )
        Cycle 16 Day 1 (n=51, 102)
    12.42 ( 24.51 )
    11.76 ( 25.20 )
        Cycle 17 Day 1 (n=47, 101)
    12.29 ( 21.64 )
    10.89 ( 25.29 )
        Cycle 18 Day 1 (n=45, 94)
    11.36 ( 22.41 )
    7.33 ( 23.25 )
        Cycle 19 Day 1 (n=41, 90)
    9.21 ( 24.96 )
    8.40 ( 25.50 )
        Cycle 20 Day 1 (n=34, 88)
    10.13 ( 24.67 )
    9.60 ( 25.34 )
        Cycle 21 Day 1 (n=28, 73)
    10.32 ( 22.41 )
    10.65 ( 26.15 )
        Cycle 22 Day 1 (n=19, 54)
    8.77 ( 25.28 )
    12.14 ( 22.35 )
        Cycle 23 Day 1 (n=15, 37)
    9.63 ( 27.81 )
    12.61 ( 20.48 )
        Cycle 24 Day 1 (n=9, 22)
    1.23 ( 24.50 )
    16.16 ( 18.70 )
        Cycle 25 Day 1 (n=5, 16)
    -4.44 ( 24.34 )
    15.28 ( 16.67 )
        End of Treatment (n=59, 57)
    -3.95 ( 22.86 )
    -3.70 ( 31.45 )
    No statistical analyses for this end point

    Secondary: HRQL: Change from Baseline in European Quality of Life Group Questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change from Baseline in European Quality of Life Group Questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis
    End point description
    The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=99,151)
    0.05 ( 0.17 )
    0.04 ( 0.19 )
        Cycle 3 Day 1 (n=98, 150)
    0.06 ( 0.21 )
    0.05 ( 0.22 )
        Cycle 4 Day 1 (n=99, 147)
    0.02 ( 0.21 )
    0.05 ( 0.21 )
        Cycle 5 Day 1 (n=95, 144)
    0.04 ( 0.20 )
    0.04 ( 0.20 )
        Cycle 6 Day 1 (n=88, 141)
    0.03 ( 0.19 )
    0.05 ( 0.23 )
        Cycle 7 Day 1 (n=85, 139)
    0.06 ( 0.19 )
    0.04 ( 0.21 )
        Cycle 8 Day 1 (n=81, 132)
    0.06 ( 0.19 )
    0.05 ( 0.22 )
        Cycle 9 Day 1 (n=77, 124)
    0.05 ( 0.20 )
    0.04 ( 0.19 )
        Cycle 10 Day 1 (n=71, 120)
    0.06 ( 0.22 )
    0.03 ( 0.22 )
        Cycle 11 Day 1 (n=69, 118)
    0.04 ( 0.23 )
    0.05 ( 0.20 )
        Cycle 12 Day 1 (n=63, 115)
    0.03 ( 0.16 )
    0.02 ( 0.20 )
        Cycle 13 Day 1 (n=59, 109)
    0.06 ( 0.16 )
    0.03 ( 0.19 )
        Cycle 14 Day 1 (n=58, 109)
    0.06 ( 0.24 )
    0.04 ( 0.19 )
        Cycle 15 Day 1 (n=57, 101)
    0.05 ( 0.18 )
    0.05 ( 0.18 )
        Cycle 16 Day 1 (n=50, 98)
    0.06 ( 0.16 )
    0.04 ( 0.19 )
        Cycle 17 Day 1 (n=46, 97)
    0.05 ( 0.15 )
    0.03 ( 0.20 )
        Cycle 18 Day 1 (n=45, 90)
    0.02 ( 0.15 )
    0.04 ( 0.17 )
        Cycle 19 Day 1 (n=41, 86)
    0.03 ( 0.20 )
    0.03 ( 0.18 )
        Cycle 20 Day 1 (n=34, 85)
    0.06 ( 0.17 )
    0.03 ( 0.23 )
        Cycle 21 Day 1 (n=28, 70)
    0.03 ( 0.15 )
    0.02 ( 0.22 )
        Cycle 22 Day 1 (n=19, 52)
    0.05 ( 0.19 )
    0.02 ( 0.22 )
        Cycle 23 Day 1 (n=15, 36)
    0.05 ( 0.18 )
    0.00 ( 0.27 )
        Cycle 24 Day 1 (n=9, 22)
    0.04 ( 0.24 )
    0.03 ( 0.20 )
        Cycle 25 Day 1 (n=5, 16)
    0.05 ( 0.38 )
    0.04 ( 0.22 )
        End of Treatment (n=57, 56)
    -0.03 ( 0.25 )
    -0.08 ( 0.27 )
    No statistical analyses for this end point

    Secondary: HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis

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    End point title
    		 HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis
    End point description
    The EQ-5D-5L is a standardised measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent’s self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents. Analysis was performed on ITT population. Here, ‘n’ signifies subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    123
    179
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n=99,151)
    2.42 ( 17.04 )
    0.60 ( 15.23 )
        Cycle 3 Day 1 (n=98, 150)
    4.70 ( 16.13 )
    3.47 ( 17.80 )
        Cycle 4 Day 1 (n=99, 147)
    6.03 ( 16.73 )
    2.29 ( 18.69 )
        Cycle 5 Day 1 (n=94, 144)
    3.40 ( 16.89 )
    2.35 ( 19.73 )
        Cycle 6 Day 1 (n=88, 141)
    2.80 ( 18.56 )
    1.24 ( 19.11 )
        Cycle 7 Day 1 (n=84, 139)
    0.64 ( 21.69 )
    2.24 ( 18.85 )
        Cycle 8 Day 1 (n=81, 132)
    1.48 ( 17.11 )
    2.40 ( 18.87 )
        Cycle 9 Day 1 (n=77, 124)
    -0.14 ( 17.46 )
    2.93 ( 19.04 )
        Cycle 10 Day 1 (n=71, 120)
    2.76 ( 17.41 )
    2.82 ( 18.35 )
        Cycle 11 Day 1 (n=69, 118)
    3.86 ( 20.07 )
    3.77 ( 18.51 )
        Cycle 12 Day 1 (n=63, 115)
    5.29 ( 18.51 )
    3.63 ( 19.34 )
        Cycle 13 Day 1 (n=59, 109)
    6.81 ( 19.57 )
    4.94 ( 18.41 )
        Cycle 14 Day 1 (n=58, 109)
    7.95 ( 18.12 )
    4.72 ( 4.72 )
        Cycle 15 Day 1 (n=57, 101)
    4.96 ( 18.92 )
    3.23 ( 18.87 )
        Cycle 16 Day 1 (n=50, 98)
    3.94 ( 18.78 )
    4.56 ( 18.88 )
        Cycle 17 Day 1 (n=46, 97)
    5.04 ( 17.93 )
    4.97 ( 18.55 )
        Cycle 18 Day 1 (n=45, 90)
    3.71 ( 19.08 )
    3.83 ( 18.46 )
        Cycle 19 Day 1 (n=41, 86)
    7.44 ( 18.73 )
    3.69 ( 18.37 )
        Cycle 20 Day 1 (n=34, 85)
    6.18 ( 18.43 )
    4.20 ( 17.20 )
        Cycle 21 Day 1 (n=28, 70)
    7.25 ( 23.46 )
    3.26 ( 18.97 )
        Cycle 22 Day 1 (n=19, 52)
    5.58 ( 24.06 )
    2.35 ( 18.62 )
        Cycle 23 Day 1 (n=15, 36)
    6.33 ( 18.73 )
    6.44 ( 18.34 )
        Cycle 24 Day 1 (n=9, 22)
    5.11 ( 17.93 )
    4.50 ( 18.31 )
        Cycle 25 Day 1 (n=5, 16)
    9.20 ( 21.48 )
    5.00 ( 18.83 )
        End of Treatment (n=57, 56)
    -4.40 ( 18.66 )
    -7.80 ( 21.08 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Plasma concentration of Isatuximab at Ctrough: Primary Analysis

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    End point title
    		 Pharmacokinetics: Plasma concentration of Isatuximab at Ctrough: Primary Analysis [17]
    End point description
    Ctrough was the plasma concentration observed just before treatment administration during repeated dosing. Analysis was performed on PK population. Here, ‘n’ signifies number of subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Cycle 1 Day 1, Day 8, Day 15 and Day 22, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and Cycle 10 Day 1
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    172
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=166)
    3.66 ( 34.40 )
        Cycle 1 Day 8 (n=152)
    82.14 ( 43.87 )
        Cycle 1 Day 15 (n=144)
    180.02 ( 71.83 )
        Cycle 1 Day 22 (n=147)
    252.63 ( 100.16 )
        Cycle 2 Day 1 (n=130)
    324.28 ( 132.98 )
        Cycle 3 Day 1 (n=145)
    295.78 ( 146.11 )
        Cycle 4 Day 1 (n=137)
    342.48 ( 140.94 )
        Cycle 5 Day 1 (n=135)
    389.25 ( 172.11 )
        Cycle 6 Day 1 (n=130)
    427.16 ( 188.51 )
        Cycle 7 Day 1 (n=123)
    433.22 ( 177.11 )
        Cycle 8 Day 1 (n=118)
    490.51 ( 198.17 )
        Cycle 9 Day 1 (n=113)
    486.07 ( 181.34 )
        Cycle 10 Day 1 (n=100)
    490.08 ( 206.53 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Plasma Concentration at End of infusion (Ceoi) of Isatuximab: Primary Analysis

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    End point title
    		 Pharmacokinetics: Plasma Concentration at End of infusion (Ceoi) of Isatuximab: Primary Analysis [18]
    End point description
    Ceoi is the plasma concentration observed at the end of intravenous infusion. Analysis was performed on pharmacokinetic (PK) population which included subjects who received at least 1 dose of Isatuximab, with data for at least 1 PK parameter available. Here, ‘n' signifies number of subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    End of infusion on Cycle 1 Day 1 and Cycle 1 Day 15; Cycle 2 Day 1
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    172
    Units: microgram/milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=169)
    274.01 ( 183.67 )
        Cycle 1 Day 15 (n=27)
    380.28 ( 85.70 )
        Cycle 2 Day 1 (n=161)
    522.74 ( 204.11 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area under the Plasma concentration time curve from time 0 to last quantifiable concentration (AUClast) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Area under the Plasma concentration time curve from time 0 to last quantifiable concentration (AUClast) of Carfilzomib: Primary Analysis [19]
    End point description
    AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration. AUClast was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    779 ( 505 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: tmax of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: tmax of Carfilzomib: Primary Analysis [20]
    End point description
    Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: hours
        median (full range (min-max))
    0.54 (0.35 to 0.75)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: tlast of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: tlast of Carfilzomib: Primary Analysis [21]
    End point description
    Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: hours
        median (full range (min-max))
    4.50 (2.52 to 4.75)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Clast of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Clast of Carfilzomib: Primary Analysis [22]
    End point description
    Clast was defined as the last concentration observed above the lower limit of quantification. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: ng/mL
        arithmetic mean (standard deviation)
    3.00 ( 5.11 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis [23]
    End point description
    Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 minutes (min), 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: nanogram/milliliter (ng/mL)
        arithmetic mean (standard deviation)
    2090 ( 1360 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis [24]
    End point description
    T1/2 was defined as the time required for the concentration of the drug to reach half of its original value, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: hours
        median (full range (min-max))
    0.860 (0.450 to 1.89)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis [25]
    End point description
    Volume of Distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: liters
        arithmetic mean (standard deviation)
    453 ( 1570 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis [26]
    End point description
    AUC was defined as area under the plasma concentration-time curve extrapolated to infinity according to the equation: AUC= AUClast + Clast/λz. AUC was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: nanograms*hour/milliliter(ng*h/mL)
        arithmetic mean (standard deviation)
    784 ( 509 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Drug Antibodies (ADA): Primary Analysis

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    End point title
    		 Number of Subjects with Anti-Drug Antibodies (ADA): Primary Analysis [27]
    End point description
    ADA were categorised as: pre-existing, treatment induced, and treatment boosted response. Pre-existing ADA was defined as ADA that were present in samples drawn during the pretreatment period (i.e., before the first isatuximab administration). Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in subjects without pre-existing ADA, including subjects without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA with an increase in titer during the ADA on-study observation period. Analysis was performed on ADA evaluable population which included subjects who received at least one dose of study drug from the IKd arm with at least one ADA assessment during the ADA on-study observation period with a reportable result.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 111 weeks)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    168
    Units: subjects
        Pre-existing ADA
    0
        Treatment induced ADA
    0
        Treatment boosted ADA
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Percentage of extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Percentage of extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis [28]
    End point description
    AUCext was defined as the percentage of the extrapolation of AUC, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: percentage of AUC
        geometric mean (geometric coefficient of variation)
    0 ( 172 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis

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    End point title
    		 Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis [29]
    End point description
    CLss was defined as a quantitative measure of the rate at which a drug substance is removed from the body at steady state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab. Analysis was performed on PK population. Here, ‘number of subjects analysed’ = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was not planned to be collected and analysed for Kd arm.
    End point values
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    16
    Units: Liters/hour (L/h)
        arithmetic mean (standard deviation)
    466 ( 1190 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): Final Analysis

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): Final Analysis
    End point description
    Adverse Event (AE) was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment period (time from the first dose of study treatments up to 30 days after last dose of study treatments). An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalization, resulted in persistent or significant disability / incapacity, was a congenital anomaly/birth defect, was a medically important event. Analysis was performed on safety population which included all subjects who gave their informed consent and for whom there was confirmation of successful allocation of a randomisation number by the IRT and received at least one dose or a part of a dose of the study treatments.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 265 weeks for Kd arm and 268 weeks for IKd arm)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    122
    177
    Units: subjects
        Any TEAE
    119
    175
        Any treatment emergent SAE
    74
    126
    No statistical analyses for this end point

    Secondary: Number of Subjects with Renal Response (RR): Primary Analysis

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    End point title
    		 Number of Subjects with Renal Response (RR): Primary Analysis
    End point description
    RR comprises of complete RR (CR renal), partial RR (PR renal) & minor RR (MR renal). CR renal: improvement in estimated glomerular filtration rate (eGFR) from <50 mL/min/1.73m^2 at Baseline to >=60 mL/min/1.73m^2 in at least 1 assessment during treatment period (time from 1st dose of study treatment [ST] up to 30 days after last dose of ST); PR renal: improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in range of 30 to 60 mL/min/1.73m^2 during on treatment-period (OTP) & MR renal: improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in range of 15-30 mL/min/1.73m^2 during OTP/from 15-30 mL/min/1.73m^2 at Baseline to at least 1 assessment in range of 30 to 60 mL/min/1.73m^2 during OTP. Analysis on ITT population. 'Number of subjects analysed' = subjects with available data for the endpoint & ‘n’ = subjects with available data for each category. 99999 signifies no subjects available for assessment at specified timepoint.
    End point type
    Secondary
    End point timeframe
    From the first dose of study treatment to 30 days following the last administration of study treatment (maximum duration: up to 114 weeks)
    End point values
    		 Carfilzomib + Dexamethasone (Kd) Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Number of subjects analysed
    13
    25
    Units: number of subjects
        CR Renal (n=13,25)
    4
    13
        PR Renal (n=0,0)
    99999
    99999
        MR Renal (n=3,4)
    1
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE data was collected from the time of first dose of study treatment to 30 days following the last administration of study treatment (up to 265 weeks for Kd arm and 268 weeks for IKd arm)
    Adverse event reporting additional description
    Reported AEs & deaths are TEAEs that developed, worsened or became serious during the treatment period (from the 1st dose of study treatments up to 30 days after last dose of study treatment). All-Cause Mortality data collected during the study was assessed for all randomized participants. Serious & other AEs collected for safety population only
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Isatuximab + Carfilzomib + Dexamethasone (IKd)
    Reporting group description
    		 -

    Reporting group title
    Carfilzomib + Dexamethasone (Kd)
    Reporting group description
    		 -

    Serious adverse events
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd) Carfilzomib + Dexamethasone (Kd)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    126 / 177 (71.19%)
    74 / 122 (60.66%)
         number of deaths (all causes)
    12
    6
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Cancer Female
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal Cancer Stage I
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Cell Lung Cancer
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung Squamous Cell Carcinoma Stage Ii
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Plasma Cell Leukaemia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Second Primary Malignancy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Cancer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Vasculitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    3 / 177 (1.69%)
    4 / 122 (3.28%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity Necrosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous Thrombosis Limb
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (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
    Malaise
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         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 / 177 (2.26%)
    3 / 122 (2.46%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (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
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection Site Extravasation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Death
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General Physical Health Deterioration
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired Phimosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    3 / 177 (1.69%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Malfunction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Plasma Cells Increased
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grip Strength Decreased
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T Wave Inversion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Marrow Plasmacyte Count Increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (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 / 177 (0.56%)
    0 / 122 (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
    Infusion Related Reaction
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia Postoperative
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Contusion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    4 / 177 (2.26%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic Fracture
         subjects affected / exposed
    5 / 177 (2.82%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Injury
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Injuries
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Left Ventricular Failure
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    4 / 177 (2.26%)
    4 / 122 (3.28%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Stenosis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Insufficiency
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Hypertrophy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic Stroke
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial Mass
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic Cerebral Infarction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Nerve Paresis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (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 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normocytic Anaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deafness Neurosensory
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal Perforation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic Foot
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug Eruption
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic Syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute Kidney Injury
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 122 (4.10%)
         occurrences causally related to treatment / all
    1 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Calculus Urinary
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis Of Jaw
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sympathetic Posterior Cervical Syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Pneumococcal
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Covid-19 Pneumonia
         subjects affected / exposed
    3 / 177 (1.69%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Campylobacter Gastroenteritis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 177 (1.69%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus Viraemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Bacteraemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Respiratory Syncytial Viral
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Influenzal
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1n1 Influenza
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H3n2 Influenza
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma Infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 177 (1.13%)
    5 / 122 (4.10%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Abscess
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    8 / 177 (4.52%)
    6 / 122 (4.92%)
         occurrences causally related to treatment / all
    2 / 8
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection Viral
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus Pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae Virus Infection
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis Infective
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy Bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    37 / 177 (20.90%)
    17 / 122 (13.93%)
         occurrences causally related to treatment / all
    14 / 50
    8 / 19
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    Gastroenteritis Salmonella
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Legionella
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 177 (3.39%)
    2 / 122 (1.64%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visceral Leishmaniasis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Streptococcal
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Sepsis
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Bronchitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mineral Metabolism Disorder
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 122 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 122 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Isatuximab + Carfilzomib + Dexamethasone (IKd) Carfilzomib + Dexamethasone (Kd)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 177 (94.35%)
    113 / 122 (92.62%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    69 / 177 (38.98%)
    42 / 122 (34.43%)
         occurrences all number
    107
    66
    Superficial Vein Thrombosis
         subjects affected / exposed
    10 / 177 (5.65%)
    7 / 122 (5.74%)
         occurrences all number
    13
    12
    Deep Vein Thrombosis
         subjects affected / exposed
    8 / 177 (4.52%)
    8 / 122 (6.56%)
         occurrences all number
    12
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    56 / 177 (31.64%)
    25 / 122 (20.49%)
         occurrences all number
    80
    29
    Asthenia
         subjects affected / exposed
    36 / 177 (20.34%)
    21 / 122 (17.21%)
         occurrences all number
    70
    30
    Pyrexia
         subjects affected / exposed
    21 / 177 (11.86%)
    21 / 122 (17.21%)
         occurrences all number
    30
    31
    Oedema Peripheral
         subjects affected / exposed
    29 / 177 (16.38%)
    21 / 122 (17.21%)
         occurrences all number
    47
    30
    Influenza Like Illness
         subjects affected / exposed
    9 / 177 (5.08%)
    5 / 122 (4.10%)
         occurrences all number
    11
    9
    Non-Cardiac Chest Pain
         subjects affected / exposed
    12 / 177 (6.78%)
    7 / 122 (5.74%)
         occurrences all number
    12
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    54 / 177 (30.51%)
    27 / 122 (22.13%)
         occurrences all number
    75
    41
    Cough
         subjects affected / exposed
    40 / 177 (22.60%)
    18 / 122 (14.75%)
         occurrences all number
    63
    27
    Productive Cough
         subjects affected / exposed
    9 / 177 (5.08%)
    2 / 122 (1.64%)
         occurrences all number
    10
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    45 / 177 (25.42%)
    30 / 122 (24.59%)
         occurrences all number
    52
    43
    Anxiety
         subjects affected / exposed
    15 / 177 (8.47%)
    4 / 122 (3.28%)
         occurrences all number
    18
    5
    Investigations
    Weight Decreased
         subjects affected / exposed
    11 / 177 (6.21%)
    1 / 122 (0.82%)
         occurrences all number
    11
    1
    Injury, poisoning and procedural complications
    Skin Laceration
         subjects affected / exposed
    10 / 177 (5.65%)
    3 / 122 (2.46%)
         occurrences all number
    32
    7
    Accidental Overdose
         subjects affected / exposed
    17 / 177 (9.60%)
    7 / 122 (5.74%)
         occurrences all number
    41
    8
    Contusion
         subjects affected / exposed
    12 / 177 (6.78%)
    6 / 122 (4.92%)
         occurrences all number
    19
    13
    Fall
         subjects affected / exposed
    21 / 177 (11.86%)
    12 / 122 (9.84%)
         occurrences all number
    29
    23
    Infusion Related Reaction
         subjects affected / exposed
    80 / 177 (45.20%)
    4 / 122 (3.28%)
         occurrences all number
    122
    6
    Limb Injury
         subjects affected / exposed
    11 / 177 (6.21%)
    3 / 122 (2.46%)
         occurrences all number
    12
    5
    Traumatic Fracture
         subjects affected / exposed
    12 / 177 (6.78%)
    4 / 122 (3.28%)
         occurrences all number
    13
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 177 (5.08%)
    7 / 122 (5.74%)
         occurrences all number
    13
    11
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    29 / 177 (16.38%)
    16 / 122 (13.11%)
         occurrences all number
    35
    24
    Headache
         subjects affected / exposed
    30 / 177 (16.95%)
    22 / 122 (18.03%)
         occurrences all number
    43
    41
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    11 / 177 (6.21%)
    1 / 122 (0.82%)
         occurrences all number
    19
    1
    Thrombocytopenia
         subjects affected / exposed
    5 / 177 (2.82%)
    11 / 122 (9.02%)
         occurrences all number
    5
    13
    Eye disorders
    Cataract
         subjects affected / exposed
    31 / 177 (17.51%)
    11 / 122 (9.02%)
         occurrences all number
    37
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    24 / 177 (13.56%)
    13 / 122 (10.66%)
         occurrences all number
    32
    17
    Diarrhoea
         subjects affected / exposed
    69 / 177 (38.98%)
    38 / 122 (31.15%)
         occurrences all number
    128
    55
    Vomiting
         subjects affected / exposed
    28 / 177 (15.82%)
    13 / 122 (10.66%)
         occurrences all number
    43
    25
    Nausea
         subjects affected / exposed
    36 / 177 (20.34%)
    22 / 122 (18.03%)
         occurrences all number
    75
    35
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    12 / 177 (6.78%)
    5 / 122 (4.10%)
         occurrences all number
    12
    5
    Dyspepsia
         subjects affected / exposed
    17 / 177 (9.60%)
    5 / 122 (4.10%)
         occurrences all number
    25
    5
    Abdominal Pain
         subjects affected / exposed
    8 / 177 (4.52%)
    9 / 122 (7.38%)
         occurrences all number
    11
    10
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    9 / 177 (5.08%)
    2 / 122 (1.64%)
         occurrences all number
    12
    2
    Rash
         subjects affected / exposed
    13 / 177 (7.34%)
    9 / 122 (7.38%)
         occurrences all number
    15
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    42 / 177 (23.73%)
    14 / 122 (11.48%)
         occurrences all number
    63
    20
    Back Pain
         subjects affected / exposed
    43 / 177 (24.29%)
    25 / 122 (20.49%)
         occurrences all number
    60
    34
    Bone Pain
         subjects affected / exposed
    14 / 177 (7.91%)
    9 / 122 (7.38%)
         occurrences all number
    17
    12
    Muscle Spasms
         subjects affected / exposed
    28 / 177 (15.82%)
    19 / 122 (15.57%)
         occurrences all number
    41
    26
    Muscular Weakness
         subjects affected / exposed
    6 / 177 (3.39%)
    11 / 122 (9.02%)
         occurrences all number
    7
    14
    Musculoskeletal Chest Pain
         subjects affected / exposed
    10 / 177 (5.65%)
    8 / 122 (6.56%)
         occurrences all number
    11
    9
    Myalgia
         subjects affected / exposed
    11 / 177 (6.21%)
    6 / 122 (4.92%)
         occurrences all number
    11
    7
    Pain In Extremity
         subjects affected / exposed
    27 / 177 (15.25%)
    17 / 122 (13.93%)
         occurrences all number
    35
    20
    Infections and infestations
    Influenza
         subjects affected / exposed
    20 / 177 (11.30%)
    13 / 122 (10.66%)
         occurrences all number
    27
    26
    Urinary Tract Infection
         subjects affected / exposed
    18 / 177 (10.17%)
    11 / 122 (9.02%)
         occurrences all number
    30
    21
    Upper Respiratory Tract Infection
         subjects affected / exposed
    71 / 177 (40.11%)
    32 / 122 (26.23%)
         occurrences all number
    166
    51
    Sinusitis
         subjects affected / exposed
    12 / 177 (6.78%)
    5 / 122 (4.10%)
         occurrences all number
    18
    8
    Rhinitis
         subjects affected / exposed
    11 / 177 (6.21%)
    3 / 122 (2.46%)
         occurrences all number
    18
    4
    Respiratory Tract Infection
         subjects affected / exposed
    19 / 177 (10.73%)
    7 / 122 (5.74%)
         occurrences all number
    46
    10
    Pneumonia
         subjects affected / exposed
    15 / 177 (8.47%)
    13 / 122 (10.66%)
         occurrences all number
    17
    21
    Nasopharyngitis
         subjects affected / exposed
    36 / 177 (20.34%)
    16 / 122 (13.11%)
         occurrences all number
    49
    30
    Bronchitis
         subjects affected / exposed
    43 / 177 (24.29%)
    14 / 122 (11.48%)
         occurrences all number
    69
    22
    Covid-19
         subjects affected / exposed
    23 / 177 (12.99%)
    2 / 122 (1.64%)
         occurrences all number
    26
    2
    Conjunctivitis
         subjects affected / exposed
    12 / 177 (6.78%)
    9 / 122 (7.38%)
         occurrences all number
    13
    13
    Gastroenteritis
         subjects affected / exposed
    19 / 177 (10.73%)
    7 / 122 (5.74%)
         occurrences all number
    23
    7
    Lower Respiratory Tract Infection
         subjects affected / exposed
    11 / 177 (6.21%)
    8 / 122 (6.56%)
         occurrences all number
    15
    12
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    14 / 177 (7.91%)
    5 / 122 (4.10%)
         occurrences all number
    18
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2017
    Infusion time of carfilzomib changed from 10 to 30 minutes to be consistent with SMPC/PI.
    08 Feb 2018
    Added objective to evaluate rate of VGPR/better in subjects who were MRD negative, Removed local laboratory testing for response to reduce number of blood samples drawn, Added Coombs test after treatment was initiated to assess assay interference, Changed frequency of pregnancy testing & added appendix with additional pregnancy testing requirements, Allowed urine pregnancy test. Added Grade 5 IARs & symptomatic NIMP overdose as AESIs, HR estimate & corresponding 95% CI was changed to HR & corresponding (1-2α)% (α: 1-sided nominal significance level: α=0.023 at final analysis & 0.005 at PFS interim analysis), Added serologic definition of active hepatitis B & C, Clarified instructions for duration of contraceptive measures, Clarified that further anti myeloma therapies be collected until OS analysis, Clarified that hydration prior carfilzomib could be <500 mL (but >250 mL) during 2 first infusions for subjects at risk of cardiac decompensation, G-CSF use no longer limited to 1st 3 cycles, Added treatment delays for subject convenience be avoided during 1st cycles, Modified recommended actions for low ANC & platelet count, Added delay for carfilzomib infusion if Grade 3-4 IR occurred during isatuximab infusion, Added Appendix with description of low dose body CT scan, Added PFS2 be assessed by Investigator, Added when confirmatory disease assessments be repeated at 3 month intervals, Added subjects with history of hypertension had to have controlled BP before dosing, Added hydration requirements predose if TLS observed at prior infusion.
    02 Jul 2018
    BMA is an invasive procedure and study allows up to 6 BMAs. To limit the number of BMAs, wording to trigger BMA was clarified, In absence of radiological and M protein progression, if clinical and biological data together provided clear evidence of clinical progression based on IRC judgement, the IRC could consider clinical progression as a PFS event, Czech Republic added to appendix list of countries with increased pregnancy testing, For exclusion criterion 12: Clarified that only curative radiotherapy was allowed within 14 days prior to randomization, Clarified that any therapy (not just chemotherapy) for other cancer should have been completed at least 5 years prior to enrollment, Allowed oral diphenhydramine or equivalent in country where there is no longer IV formulation, Added possibility of keeping the same hydration volume and lengthening the administration time in case of cardiac decompensation risk, Clarified rules for dose modifications, Added protocol recommendations regarding antibacterial prophylaxis and thromboprophylaxis, and added caution regarding cotreatment of dexamethasone with CYP3A inhibitor.
    11 Jun 2019
    Contraception duration after end of isatuximab changed from 3 months (12 weeks) to 5 months, Change in frequency of pregnancy test per country requirement for women with childbearing potential; pregnancy test was to be performed before each cycle and then monthly during the follow-up period up to 3 months (12 weeks) in the Kd arm and up to 5 months in the IKd arm.
    11 Sep 2019
    Implemented safety monitoring measures following identification of 2 new risks related to carfilzomib - Carfilzomib may increase risk of progressive multifocal leukoencephalopathy & Carfilzomib may increase risk of hepatitis B virus reactivation.
    13 Nov 2019
    Based on Health Authority feedback, censoring rules for the primary PFS analysis were changed; PFS2 was also updated according to the change. Hepatitis B virus DNA testing by polymerase chain reaction was added for patients with a positive hepatitis B surface antigen test and/or anti-Hepatitis B core antibody test, Added that any second primary malignancies during the follow-up period will be reported, Statistical sections were updated to match Statistical Analysis Plan amendment of July 2019 and changes to the PFS definition.
    10 Aug 2020
    Instruction for collecting hospitalization report and exams reports in case of serious adverse events section was updated. Switch to the approved Isatuximab administration mode with fixed volume. Option of direct supplies of oral investigational medicinal products (IMPs) was added in case of regional or national emergency declared by a governmental agency that resulted in travel restrictions, confinement, or restricted site access.
    11 Mar 2021
    Based on the positive interim PFS data, the treatment effect of IKd was expected to be better than initially anticipated in comparison to Kd. A descriptive PFS analysis was added when approximately 180 PFS events were reached. Based on more PFS events accumulated, this additional analysis would help to better characterize the distribution of PFS in a descriptive way for the IKd arm. With approximately 180 PFS events planned, the possibility of observing the median PFS time for the IKd arm was expected to be increased. Clarification of accidental or intentional overdose of isatuximab and carfilzomib was defined by each administration and dexamethasone defined by cycle. Appendix N was added for contingency measures for a regional or national emergency declared by a governmental agency.
    14 Sep 2021
    Addition of the possibility to omit carfilzomib dosing on Days 8 and 9 if a subject asked for a more convenient schedule and Investigator agreed because she/he judges that the maximum benefit was reached. If dexamethasone dosing was maintained on Days 8 and 9 while carfilzomib on Days 8 and 9 was omitted, possibility to re-increase the dose of dexamethasone if dose previously reduced, based on Investigator judgement.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34097854
    http://www.ncbi.nlm.nih.gov/pubmed/36372355
    http://www.ncbi.nlm.nih.gov/pubmed/36239134
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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