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    Clinical Trial Results:
    A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma Following Autologous Stem Cell Transplant

    Summary
    EudraCT number
    		 2013-002076-41
    Trial protocol
    		 BE   CZ   SE   DK   IT   PT   ES   AT   HU   DE   NL   GR   PL   NO  
    Global end of trial date
    08 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Sep 2024
    First version publication date
    22 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C16019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02181413
    WHO universal trial number (UTN)
    		 U1111-1155-8695
    Other trial identifiers
    		 Israel MOH: C16019CTIL, CCMO: NL.47795.029.14, HC-CTD: 173116, TCTIN: 1036024001, SNCTP: SNCTP000001745
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, United States, MA 02421
    Public contact
    Study Director, Takeda, N/A N/A, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, N/A N/A, TrialDisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to determine the effect of ixazomib maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with newly diagnosed multiple myeloma (NDMM) who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT).
    Protection of trial subjects
    Each participant signed an informed consent form (ICF) before participating in the study.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    16 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 83 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Japan: 22
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czechia: 42
    Country: Number of subjects enrolled
    Denmark: 31
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 76
    Country: Number of subjects enrolled
    Greece: 60
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Israel: 22
    Country: Number of subjects enrolled
    Italy: 50
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Norway: 19
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Türkiye: 20
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    656
    EEA total number of subjects
    428
    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)
    525
    From 65 to 84 years
    131
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants enrolled at 167 sites globally to take part in this study from 16 July 2014 to 8 September 2023.

    Pre-assignment
    Screening details
    		 Participants with newly diagnosed multiple myeloma (NDMM) who underwent induction therapy according to regional standard of care (SoC), followed by high-dose melphalan (200 milligrams per meter square [mg/m^2]) and Autologous Stem Cell Transplant (ASCT) were enrolled in a 3:2 ratio to receive ixazomib citrate or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    On Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.

    Arm title
    		 Ixazomib Citrate
    Arm description
    		 Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib citrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib citrate 3 mg, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons

    Number of subjects in period 1
    		Placebo Ixazomib Citrate
    Started
    261
    395
    Intent-to-Treat (ITT) Population
    261
    395
    Safety Population
    259
    394
    Per Protocol (PP) Population
    256
    387
    Completed
    206
    322
    Not completed
    55
    73
         Consent withdrawn by subject
    45
    61
         Reason Not Specified
    2
    5
         Lost to follow-up
    8
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.

    Reporting group title
    Ixazomib Citrate
    Reporting group description
    		 Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.

    Reporting group values
    		 Placebo Ixazomib Citrate Total
    Number of subjects
    		 261 395
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.2 ( 7.92 ) 56.8 ( 8.17 ) -
    Gender categorical
    Units: Subjects
        Male
    		 162 252 414
        Female
    		 99 143 242
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    		 11 14 25
        Not Hispanic or Latino
    		 240 362 602
        Unknown or Not Reported
    		 10 19 29
    Race/Ethnicity
    Units: Subjects
        White
    		 213 315 528
        Black or African American
    		 3 7 10
        Asian
    		 36 59 95
        Other
    		 1 2 3
        Not Reported
    		 8 12 20
    Region of Enrollment
    Units: Subjects
        Australia
    		 11 17 28
        Japan
    		 9 13 22
        Korea, Republic of
    		 17 23 40
        Singapore
    		 4 8 12
        Taiwan
    		 3 10 13
        Thailand
    		 1 5 6
        Austria
    		 2 2 4
        Belgium
    		 5 5 10
        Czech Republic
    		 12 30 42
        Denmark
    		 11 20 31
        France
    		 7 11 18
        Germany
    		 26 50 76
        Greece
    		 22 38 60
        Hungary
    		 9 16 25
        Israel
    		 12 10 22
        Italy
    		 26 24 50
        Netherlands
    		 11 8 19
        Norway
    		 6 13 19
        Poland
    		 5 10 15
        Portugal
    		 2 8 10
        South Africa
    		 4 3 7
        Spain
    		 19 19 38
        Sweden
    		 4 7 11
        Switzerland
    		 3 0 3
        Turkey
    		 10 10 20
        Ukraine
    		 2 1 3
        United Kingdom
    		 14 21 35
        Argentina
    		 0 3 3
        Brazil
    		 3 5 8
        United States
    		 1 5 6
    Height
    Number analysed is the number of participants with available height data.
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Body Surface Area (BSA)
    Number analysed is the number of participants with available BSA data.
    Units: meter per square (m^2)
        arithmetic mean (standard deviation)
    		 ( ) ( ) -
    Weight
    Number analysed is the number of participants with available weight data.
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 75.18 ( 14.648 ) 75.93 ( 15.989 ) -
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.

    Subject analysis set title
    Ixazomib citrate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.

    Subject analysis sets values
    		 Placebo Ixazomib citrate
    Number of subjects
    256
    388
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Male
    0
    0
        Female
    0
    0
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    0
    0
        Not Hispanic or Latino
    0
    0
        Unknown or Not Reported
    0
    0
    Race/Ethnicity
    Units: Subjects
        White
    0
    0
        Black or African American
    0
    0
        Asian
    0
    0
        Other
    0
    0
        Not Reported
    0
    0
    Region of Enrollment
    Units: Subjects
        Australia
    0
    0
        Japan
    0
    0
        Korea, Republic of
    0
    0
        Singapore
    0
    0
        Taiwan
    0
    0
        Thailand
    0
    0
        Austria
    0
    0
        Belgium
    0
    0
        Czech Republic
    0
    0
        Denmark
    0
    0
        France
    0
    0
        Germany
    0
    0
        Greece
    0
    0
        Hungary
    0
    0
        Israel
    0
    0
        Italy
    0
    0
        Netherlands
    0
    0
        Norway
    0
    0
        Poland
    0
    0
        Portugal
    0
    0
        South Africa
    0
    0
        Spain
    0
    0
        Sweden
    0
    0
        Switzerland
    0
    0
        Turkey
    0
    0
        Ukraine
    0
    0
        United Kingdom
    0
    0
        Argentina
    0
    0
        Brazil
    0
    0
        United States
    0
    0
    Height
    Number analysed is the number of participants with available height data.
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    168.73 ( 10.347 )
    169.71 ( 10.004 )
    Body Surface Area (BSA)
    Number analysed is the number of participants with available BSA data.
    Units: meter per square (m^2)
        arithmetic mean (standard deviation)
    1.87 ( 0.221 )
    1.88 ( 0.235 )
    Weight
    Number analysed is the number of participants with available weight data.
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.

    Reporting group title
    Ixazomib Citrate
    Reporting group description
    		 Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until progressive disease (PD), unacceptable toxicity, or discontinuation for alternate reasons.

    Subject analysis set title
    Ixazomib citrate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to adverse events (AEs) were not dose escalated.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomisation to the date of first documentation of PD, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be >10 milligrams per deciliter (mg/dL); participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development. Intent-to-Treat (ITT) Population was defined as all participants who were randomised and had post randomisation data.
    End point type
    Primary
    End point timeframe
    Randomisation up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks until progression of disease or death (up to 4 years)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    21.3 (17.97 to 24.67)
    26.5 (23.69 to 33.81)
    Statistical analysis title
    		 Progression Free Survival (PFS)
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.582
         upper limit
    		 0.89
    Notes
    [1] - P-value was based on log-rank test stratified by pre-induction regimen, International Staging System (ISS) stage and response after transplantation.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was measured as the time from the date of randomisation to the date of death. '99999' indicates median and upper limit of 95% confidence interval (CI) were not estimable due to low number of participants with events. ITT Population was defined as all participants who were randomised and had post randomisation data.  
    End point type
    Secondary
    End point timeframe
    Randomisation up to end of follow up period (up to 107 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    99999 (96.95 to 99999)
    99999 (104.97 to 99999)
    Statistical analysis title
    		 Overall Survival (OS)
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.789
         upper limit
    		 1.332
    Notes
    [2] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy

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    End point title
    		 Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy
    End point description
    Response was assessed according to IMWG criteria. Best response includes partial response (PR), very good partial response (VGPR) and complete response (CR). PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to less than (<)200 milligrams (mg) per 24 hours. VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. CR is negative immunofixation of serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent CR (sCR) is CR and normal FLC ratio and absence of clonal plasma cells (PCs) by immunohistochemistry or 2 to 4-color flow cytometry. ITT Population was defined as all participants who were randomised and had post randomisation data.
    End point type
    Secondary
    End point timeframe
    Randomisation up to EOT (up to 24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: percentage of participants
    number (not applicable)
        PR
    14
    11
        VGPR
    11
    11
        CR
    6
    5
    Statistical analysis title
    		 CR
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.732
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.365
         upper limit
    		 1.466
    Notes
    [3] - P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by pre-induction regimen, pre-induction international staging system (ISS), and response after transplantation at screening

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    TTP is defined as the time from the date of randomisation to the date of first documentation of PD, using IMWG criteria. PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. Participants without documentation of PD at the time of analysis were censored at the date of last response assessment that is stable disease or better. ITT Population was defined as all participants who were randomised and had post randomisation data.
    End point type
    Secondary
    End point timeframe
    Randomisation up to PD (up to 107 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    21.4 (18.10 to 24.67)
    26.6 (23.69 to 33.81)
    Statistical analysis title
    		 Time to Progression (TTP)
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.716
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.579
         upper limit
    		 0.886
    Notes
    [4] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Second Progression Free Survival (PFS2)

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    End point title
    		 Second Progression Free Survival (PFS2)
    End point description
    PFS2 is defined as the time from the date of randomisation to the date of objective disease progression on next line treatment or death from any cause (whichever occurs first). PD is defined as ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. '99999' indicates upper limit of 95% CI was not estimable due to low number of participants with events. ITT Population was defined as all participants who were randomised and had post randomisation data.  
    End point type
    Secondary
    End point timeframe
    Randomisation up to EOT (up to 24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to 107 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    80.4 (68.7 to 99999)
    84.0 (67.22 to 99999)
    Statistical analysis title
    		 Second Progression Free Survival (PFS2)
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.902 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.795
         upper limit
    		 1.298
    Notes
    [5] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Time to Start of the Next Line of Therapy

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    End point title
    		 Time to Start of the Next Line of Therapy
    End point description
    Time to start of the next line of therapy was defined as the time from the date of randomisation to the date of initiation dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurs first. Participants who never took antineoplastic therapy were censored at the date of last contact or death. ITT Population was defined as all participants who were randomised and had post randomisation data.
    End point type
    Secondary
    End point timeframe
    Randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    27.6 (24.48 to 31.61)
    33.1 (29.14 to 36.34)
    Statistical analysis title
    		 Time to Start of the Next Line of Therapy
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.833
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.005
    Notes
    [6] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Time to End of the Next Line of Therapy

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    End point title
    		 Time to End of the Next Line of Therapy
    End point description
    Time to end of the next line of therapy was defined as the time from the date of randomisation to the date of last dose of the next line of antineoplastic therapy following study treatment or death due to any cause, whichever occurred first or date of last contact for participants who never took antineoplastic therapy. ITT Population was defined as all participants who were randomised and had post randomisation data.
    End point type
    Secondary
    End point timeframe
    Randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    261
    395
    Units: months
        median (confidence interval 95%)
    50.4 (42.84 to 61.01)
    55.9 (49.61 to 61.86)
    Statistical analysis title
    		 Time to End of the Next Line of Therapy
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.431 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.922
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.753
         upper limit
    		 1.129
    Notes
    [7] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Duration of the Next Line of Therapy

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    End point title
    		 Duration of the Next Line of Therapy
    End point description
    Duration of the next line of therapy is defined as the time from the date of the first dose of the next line of therapy to the date of the last dose of the next antineoplastic therapy following study treatment or death due to any cause, whichever occurred first. Duration of the next line of therapy was analysed on those participants who actually received and completed the next line of therapy following the study treatment and duration would be summarized using Kaplan-Meier method. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed indicates the number of participants who started next line of therapy.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    187
    278
    Units: months
        median (confidence interval 95%)
    12.3 (9.82 to 16.53)
    9.6 (7.49 to 12.06)
    Statistical analysis title
    		 Duration of the Next Line of Therapy
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.959
         upper limit
    		 1.45

    Secondary: Percentage of Participants Who Develop A New Primary Malignancy

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    End point title
    		 Percentage of Participants Who Develop A New Primary Malignancy
    End point description
    The decimal values of percentages were subjected to rounding off. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    259
    394
    Units: percentage of participants
        number (not applicable)
    8
    7
    No statistical analyses for this end point

    Secondary: Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative

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    End point title
    		 Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative
    End point description
    MRD negativity (MRD-) is defined as absence of MRD and MRD positivity (MRD+) is defined as presence of MRD. The conversion rate from MRD positive to MRD negative was assessed and reported. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed indicates the number of participants with MRD+ at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (up to 24 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    139
    225
    Units: participants
    27
    39
    Statistical analysis title
    		 Conversion to MRD-
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.814 [8]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [8] - P-value was based on Fisher’s exact test comparing conversion to MRD- at any time post study entry between treatment groups.

    Secondary: Number of Participants With Maintenance of MRD Negativity

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    End point title
    		 Number of Participants With Maintenance of MRD Negativity
    End point description
    MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD. The maintenance of MRD negativity up to the end of treatment was assessed and reported in participants converting from MRD+ at Baseline to MRD negative. Bone marrow aspirates and blood samples were sent to a central laboratory and were assessed for MRD using flow cytometry and a sequencing methodology. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed is the number of participants who converted from MRD+ at Baseline to MRD negative.
    End point type
    Secondary
    End point timeframe
    Up to EOT (up to 24 months)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    27
    39
    Units: participants
    25
    37
    Statistical analysis title
    		 Maintenance of MRD Negativity
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.805 [9]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [9] - P-value was based on Fisher’s exact test comparing conversion to MRD- at any time post study entry between treatment groups.

    Secondary: Correlation Between MRD Status and Progression Free Survival (PFS)

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    End point title
    		 Correlation Between MRD Status and Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from the date of randomisation to the date of first documentation of PD as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurred first, assessed for up to 107 months in this outcome measure. '99999' indicates upper limit of 95% CI was not estimable due to censoring. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed is the number of participants with data available for analyses. ‘n’ indicates the number of participants available for analysis in the specified category.  
    End point type
    Secondary
    End point timeframe
    From randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    214
    342
    Units: months
    median (confidence interval 95%)
        MRD- at Study Entry (n=75,117)
    32.5 (19.32 to 99999)
    38.6 (33.81 to 99999)
        MRD+ at Study Entry (n=139,225)
    18.5 (15.70 to 21.91)
    23.1 (20.24 to 25.69)
    Statistical analysis title
    		 MRD- at Study Entry
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [10]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.386
         upper limit
    		 0.969
    Notes
    [10] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.
    Statistical analysis title
    		 MRD+ at Study Entry
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.704
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.539
         upper limit
    		 0.92
    Notes
    [11] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: Correlation Between MRD Status and Overall Survival (OS)

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    End point title
    		 Correlation Between MRD Status and Overall Survival (OS)
    End point description
    OS was measured as the time from the date of randomisation to the date of death, assessed for up to 107 months in this outcome measure. '99999' indicates median, lower limit, and upper limit of 95% CI were not estimable due to censoring. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed is the number of participants with data available for analyses. ‘n’ indicates the number of participants available for analysis in the specified category.  
    End point type
    Secondary
    End point timeframe
    From randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    214
    342
    Units: months
    median (confidence interval 95%)
        MRD- at Study Entry (n=75,117)
    99999 (84.90 to 99999)
    99999 (99999 to 99999)
        MRD+ at Study Entry (n=139,225)
    99999 (90.74 to 99999)
    105.0 (91.47 to 99999)
    Statistical analysis title
    		 MRD- at Study Entry
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.414
         upper limit
    		 1.184
    Notes
    [12] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.
    Statistical analysis title
    		 MRD+ at Study Entry
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.847 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.966
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.682
         upper limit
    		 1.368
    Notes
    [13] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: OS Benefits in a High-Risk Population

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    End point title
    		 OS Benefits in a High-Risk Population
    End point description
    High-risk population included but was not limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. OS was measured as the time from the date of randomisation to the date of death. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed is the number of participants present in the high-risk group. ‘99999’ indicates that upper limit of 95% CI was not estimable due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    54
    61
    Units: months
        median (confidence interval 95%)
    69.0 (33.25 to 92.98)
    64.2 (40.97 to 99999)
    Statistical analysis title
    		 OS Benefits in a HIgh-Risk Population
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.905 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.583
         upper limit
    		 1.613
    Notes
    [14] - P-value was based on log-rank test stratified by pre-induction regimen, ISS stage and response after transplantation.

    Secondary: PFS Benefits in a High-Risk Population

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    End point title
    		 PFS Benefits in a High-Risk Population
    End point description
    High-risk population included but not be limited to participants carrying deletion (del)17, t(4:14), t(14:16), amplification (ampl) 1q, del13, or del1p. PFS= time from date of randomisation to the date of first documentation of PD, as evaluated by an IRC according to IMWG criteria, or death due to any cause (whichever occurs first). PD= ≥25% increase from lowest value in: serum/urine M-component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels must be >10 mg/dL; participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must be ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed is the number of participants present in the high-risk group.
    End point type
    Secondary
    End point timeframe
    Randomisation up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    54
    61
    Units: months
        median (confidence interval 95%)
    16.8 (12.81 to 18.50)
    18.5 (12.06 to 31.15)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Score

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    End point title
    		 Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Score
    End point description
    ECOG performance status assesses a participant’s performance status on a 6-point scale ranging from 0=fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead. Lower scores indicate improvement. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Subjects analysed indicates the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (up to Month 24)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    252
    371
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.1 ( 0.63 )
    0.0 ( 0.54 )
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered a drug. An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital abnormality or birth defect, an important medical event. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    259
    394
    Units: participants
        TEAEs
    241
    382
        SAEs
    51
    108
    No statistical analyses for this end point

    Secondary: Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs

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    End point title
    		 Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs
    End point description
    Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A TEAE was defined as an AE that started or worsened after first study drug administration and within 30 days of last dose of study drug. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    259
    394
    Units: subjects
    36
    81
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-related Quality of Life (HRQL) Score Based on The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Domain

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    End point title
    		 Change From Baseline in Health-related Quality of Life (HRQL) Score Based on The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Domain
    End point description
    EORTC QLQ-C30 is 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), & 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= ([{Q29+Q30} /2]-1)/6*100. Answers are converted into grading scale, with values between 0 (worse outcome) to 100 (best outcome). High score represents a favorable outcome with best quality of life for participant. ITT Population was defined as all participants who were randomised and had post randomisation data. Subjects analysed indicates the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOT (up to Month 24)
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    237
    349
    Units: score on a scale
        least squares mean (standard error)
    -1.7 ( 1.57 )
    -4.1 ( 1.43 )
    Statistical analysis title
    		 Change From Baseline in HRQL Score
    Comparison groups
    Placebo v Ixazomib Citrate
    Number of subjects included in analysis
    586
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.074 [15]
    Method
    		 Logrank
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 0.2
    Notes
    [15] - P-value was from the significance test for the coefficient of the interaction between treatment and visit.

    Secondary: Plasma Concentration of Ixazomib

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    End point title
    		 Plasma Concentration of Ixazomib [16]
    End point description
    Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) were measured using a validated Liquid Chromatography-tandem Mass Spectrometry (LC/MS/MS) assay. The Pharmacokinetic (PK) Analysis Population was defined as participants with at least one PK sample that was collected and analysed. ‘n’ indicates the number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 1 hour and 4 hour post-dose; Predose on Days 8 and 15 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3 through 10 (each cycle length= 28 days)
    Notes
    [16] - 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: Only the drug-treated Ixazomib Citrate arm was to be analysed for this endpoint.
    End point values
    		 Ixazomib Citrate
    Number of subjects analysed
    393
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 1 Hour Post-dose (n=381)
    27.919 ( 24.7787 )
        Cycle 1 Day 1: 4 Hours Post-dose (n=383)
    10.352 ( 9.8078 )
        Cycle 1 Day 8 (n=387)
    1.584 ( 1.6707 )
        Cycle 1 Day 15 (n=382)
    2.611 ( 1.4305 )
        Cycle 2 Day 1 (n=384)
    1.946 ( 1.0984 )
        Cycle 2 Day 8 (n=374)
    3.232 ( 2.0069 )
        Cycle 3 Day 1 (n=367)
    2.258 ( 1.1508 )
        Cycle 4 Day 1 (n=367)
    2.396 ( 1.7822 )
        Cycle 5 Day 1 (n=360)
    2.400 ( 1.4921 )
        Cycle 6 Day 1 (n=350)
    2.623 ( 1.6994 )
        Cycle 7 Day 1 (n=349)
    2.691 ( 1.9842 )
        Cycle 8 Day 1 (n=338)
    2.637 ( 1.7074 )
        Cycle 9 Day 1 (n=327)
    2.610 ( 1.9380 )
        Cycle 10 Day 1 (n=321)
    2.594 ( 1.9509 )
    No statistical analyses for this end point

    Secondary: Time to Resolution of Peripheral Neuropathy (PN) Events

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    End point title
    		 Time to Resolution of Peripheral Neuropathy (PN) Events
    End point description
    Peripheral neuropathy is defined as the TEAE in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Subjects analysed indicates the number of participants with peripheral neuropathy events.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    39
    73
    Units: days
        median (confidence interval 95%)
    159.0 (45.0 to 736.0)
    225.0 (117.0 to 421.0)
    No statistical analyses for this end point

    Secondary: Time to Improvement of PN Events

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    End point title
    		 Time to Improvement of PN Events
    End point description
    PN is defined as the TEAE in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. A PN event is considered as improved if the event improves from the maximum grade. That is, all the grades recorded after the maximum grade is less than the maximum grade. Time to improvement is defined as the time from the initial onset date (inclusive) of the maximum grade to the first onset date that the toxicity grade is below the maximum grade with no higher grade thereafter, or the resolution date, whichever occurs first. Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo. Subjects analysed indicates number of participants with peripheral neuropathy events.
    End point type
    Secondary
    End point timeframe
    Up to 107 months
    End point values
    		 Placebo Ixazomib Citrate
    Number of subjects analysed
    39
    73
    Units: days
        median (confidence interval 95%)
    130.0 (36.0 to 520.0)
    134.0 (70.0 to 252.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization up to end of follow up period (107 months)
    Adverse event reporting additional description
    All cause-mortality: ITT Population was defined as all participants who were randomized and had post randomization data. Serious and Other Adverse Events: Safety Population was defined as participants who received at least 1 dose of ixazomib citrate or placebo.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Ixazomib Citrate
    Reporting group description
    		 Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who had any dose reductions due to AEs were not dose escalated.

    Reporting group title
    Placebo
    Reporting group description
    		 Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.

    Serious adverse events
    		 Ixazomib Citrate Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    108 / 394 (27.41%)
    51 / 259 (19.69%)
         number of deaths (all causes)
    144
    93
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell leukaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (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
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    2 / 394 (0.51%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (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
    Pyrexia
         subjects affected / exposed
    5 / 394 (1.27%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (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
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         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 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Light chain analysis increased
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone contusion
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         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 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radicular pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 394 (1.02%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         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 / 394 (0.25%)
    0 / 259 (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
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kyphosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         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 / 394 (0.76%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankylosing spondylitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    4 / 394 (1.02%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    3 / 394 (0.76%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (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 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 394 (0.76%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (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 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 394 (0.76%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    4 / 394 (1.02%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    4 / 394 (1.02%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 394 (0.51%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Picornavirus infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    3 / 394 (0.76%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    25 / 394 (6.35%)
    10 / 259 (3.86%)
         occurrences causally related to treatment / all
    7 / 30
    2 / 16
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ixazomib Citrate Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    371 / 394 (94.16%)
    229 / 259 (88.42%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 394 (5.33%)
    19 / 259 (7.34%)
         occurrences all number
    23
    22
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    41 / 394 (10.41%)
    23 / 259 (8.88%)
         occurrences all number
    57
    26
    Paraesthesia
         subjects affected / exposed
    27 / 394 (6.85%)
    8 / 259 (3.09%)
         occurrences all number
    31
    8
    Neuropathy peripheral
         subjects affected / exposed
    40 / 394 (10.15%)
    19 / 259 (7.34%)
         occurrences all number
    49
    23
    Headache
         subjects affected / exposed
    43 / 394 (10.91%)
    23 / 259 (8.88%)
         occurrences all number
    86
    38
    Dizziness
         subjects affected / exposed
    33 / 394 (8.38%)
    18 / 259 (6.95%)
         occurrences all number
    49
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 394 (7.11%)
    8 / 259 (3.09%)
         occurrences all number
    35
    11
    Neutropenia
         subjects affected / exposed
    24 / 394 (6.09%)
    15 / 259 (5.79%)
         occurrences all number
    33
    16
    Thrombocytopenia
         subjects affected / exposed
    40 / 394 (10.15%)
    6 / 259 (2.32%)
         occurrences all number
    68
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    79 / 394 (20.05%)
    43 / 259 (16.60%)
         occurrences all number
    108
    52
    Influenza like illness
         subjects affected / exposed
    37 / 394 (9.39%)
    18 / 259 (6.95%)
         occurrences all number
    57
    30
    Oedema peripheral
         subjects affected / exposed
    34 / 394 (8.63%)
    11 / 259 (4.25%)
         occurrences all number
    44
    13
    Pyrexia
         subjects affected / exposed
    78 / 394 (19.80%)
    37 / 259 (14.29%)
         occurrences all number
    190
    56
    Asthenia
         subjects affected / exposed
    30 / 394 (7.61%)
    17 / 259 (6.56%)
         occurrences all number
    43
    21
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    135 / 394 (34.26%)
    61 / 259 (23.55%)
         occurrences all number
    265
    160
    Dyspepsia
         subjects affected / exposed
    13 / 394 (3.30%)
    15 / 259 (5.79%)
         occurrences all number
    17
    15
    Nausea
         subjects affected / exposed
    154 / 394 (39.09%)
    40 / 259 (15.44%)
         occurrences all number
    292
    111
    Vomiting
         subjects affected / exposed
    105 / 394 (26.65%)
    28 / 259 (10.81%)
         occurrences all number
    219
    44
    Constipation
         subjects affected / exposed
    41 / 394 (10.41%)
    21 / 259 (8.11%)
         occurrences all number
    47
    29
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    26 / 394 (6.60%)
    9 / 259 (3.47%)
         occurrences all number
    34
    16
    Oropharyngeal pain
         subjects affected / exposed
    29 / 394 (7.36%)
    18 / 259 (6.95%)
         occurrences all number
    35
    26
    Cough
         subjects affected / exposed
    87 / 394 (22.08%)
    55 / 259 (21.24%)
         occurrences all number
    123
    87
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    35 / 394 (8.88%)
    19 / 259 (7.34%)
         occurrences all number
    39
    26
    Rash maculo-papular
         subjects affected / exposed
    24 / 394 (6.09%)
    9 / 259 (3.47%)
         occurrences all number
    33
    9
    Rash macular
         subjects affected / exposed
    24 / 394 (6.09%)
    8 / 259 (3.09%)
         occurrences all number
    33
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 394 (7.87%)
    12 / 259 (4.63%)
         occurrences all number
    34
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    105 / 394 (26.65%)
    43 / 259 (16.60%)
         occurrences all number
    174
    63
    Back pain
         subjects affected / exposed
    77 / 394 (19.54%)
    47 / 259 (18.15%)
         occurrences all number
    103
    57
    Bone pain
         subjects affected / exposed
    37 / 394 (9.39%)
    19 / 259 (7.34%)
         occurrences all number
    47
    21
    Muscle spasms
         subjects affected / exposed
    35 / 394 (8.88%)
    21 / 259 (8.11%)
         occurrences all number
    47
    25
    Musculoskeletal chest pain
         subjects affected / exposed
    20 / 394 (5.08%)
    15 / 259 (5.79%)
         occurrences all number
    23
    18
    Myalgia
         subjects affected / exposed
    22 / 394 (5.58%)
    14 / 259 (5.41%)
         occurrences all number
    29
    15
    Pain in extremity
         subjects affected / exposed
    32 / 394 (8.12%)
    26 / 259 (10.04%)
         occurrences all number
    41
    31
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    91 / 394 (23.10%)
    69 / 259 (26.64%)
         occurrences all number
    161
    125
    Bronchitis
         subjects affected / exposed
    40 / 394 (10.15%)
    19 / 259 (7.34%)
         occurrences all number
    55
    23
    Conjunctivitis
         subjects affected / exposed
    28 / 394 (7.11%)
    10 / 259 (3.86%)
         occurrences all number
    34
    12
    Herpes zoster
         subjects affected / exposed
    37 / 394 (9.39%)
    14 / 259 (5.41%)
         occurrences all number
    38
    16
    Influenza
         subjects affected / exposed
    38 / 394 (9.64%)
    29 / 259 (11.20%)
         occurrences all number
    42
    32
    Sinusitis
         subjects affected / exposed
    20 / 394 (5.08%)
    6 / 259 (2.32%)
         occurrences all number
    29
    8
    Pneumonia
         subjects affected / exposed
    24 / 394 (6.09%)
    15 / 259 (5.79%)
         occurrences all number
    31
    16
    Pharyngitis
         subjects affected / exposed
    20 / 394 (5.08%)
    9 / 259 (3.47%)
         occurrences all number
    21
    13
    Upper respiratory tract infection
         subjects affected / exposed
    100 / 394 (25.38%)
    54 / 259 (20.85%)
         occurrences all number
    187
    89
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 394 (5.33%)
    17 / 259 (6.56%)
         occurrences all number
    26
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2019
    The following changes were made as per Amendment 3: 1. Added 3 interim analysis (IAs) for OS—at approximately 140 OS events, 170 OS events, and 230 OS events. 2. Updated details of the already completed PFS analysis (first IA) to align with the statistical analysis plan (SAP).
    21 Nov 2021
    The following changes were made as per Amendment 4: 1. Created Streamlined Schedule of Events to show only the assessments needed now that all participants are in follow-up, essentially replacing the original Schedule of Events. 2. Removed investigator assessment of disease response/status. 3. Added information about alternative monitoring approaches in the event a monitor cannot visit the site in a timely manner due to the coronavirus disease 2019 (COVID-19) pandemic. 3. Added death as a reason for a participant’s withdrawal from the study.

    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.
    Not specified
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    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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