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    Clinical Trial Results:
    A Randomized, Controlled, Phase 3 Study to Evaluate Optimized Retreatment and Prolonged Therapy With Bortezomib (VELCADE) in Patients With Multiple Myeloma in First or Second Relapse

    Summary
    EudraCT number
    		 2011-004795-11
    Trial protocol
    		 SE   DE   BE   IT   PT   PL   FI   NL  
    Global end of trial date
    18 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Mar 2017
    First version publication date
    02 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    26866138MMY3033
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01910987
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International N.V.
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.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
    18 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to describe the effect of optimized retreatment with bortezomib in combination with dexamethasone followed by prolonged therapy with bortezomib versus standard retreatment with bortezomib in combination with dexamethasone on progression free survival (PFS).
    Protection of trial subjects
    Safety evaluations included monitoring of adverse events, clinical laboratory tests (hematology and serum chemistry), vital sign measurements, physical examinations, including neurological/peripheral neurological examinations and body weight measurement.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Turkey: 23
    Worldwide total number of subjects
    80
    EEA total number of subjects
    55
    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)
    33
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 80 subjects (53 subjects- Group A and 27 subjects- Group B) were randomized in study and received study agent (intent-to-treat population and safety analysis set). Subjects who had progressive disease, discontinued bortezomib early or started an alternative multiple myeloma therapy were not eligible to enter in prolonged therapy period.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Group A
    Arm description
    		 Subjects randomized to Group A started with 6 cycles of bortezomib 1.3 milligram per meter square (mg/m^2) subcutaneously (SC) and dexamethasone 20 milligram (mg) per oral (two 21-day cycles followed by four 35-day cycles; Optimized Retreatment) followed by a randomization, if criteria are met, into 1 of 2 prolonged therapy groups (A1 and A2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received bortezomib 1.3 mg/m^2 SC on Days 1, 4, 8, 11, every 21 days for Week 1-6 (Cycles 1 and 2) and on Days 1, 8, 15, 22, every 35 days for Week 7-26 (Cycles 3 to 6).

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received dexamethasone 20 mg per oral (PO) on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-6 (Cycle 1 and 2) and on Days 1, 2, 8, 9, 15, 16, 22, 23, every 35 days for Week 7-26 (Cycle 3 to 6).

    Arm title
    		 Group A1 (Prolonged therapy)
    Arm description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A1 and received bortezomib 1.3 mg/m^2 SC injection on Days 1, 8, 15, 22, every 35 days until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received bortezomib 1.3 mg/m^2 SC injection on Days 1, 8, 15, 22, every 35 days.

    Arm title
    		 Group A2 (Prolonged therapy)
    Arm description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A2 and received bortezomib 1.3 mg/m^2 SC once every other week, Days 1, 15, 29, 43, 57, 71, 85, and so on until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received bortezomib 1.3 mg/m^2 SC once every other week, Days 1, 15, 29, 43, 57, 71, 85, and so on until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Arm title
    		 Group B (Standard retreatment)
    Arm description
    		 Subjects randomly assigned to Group B received bortezomib 1.3 mg/m^2 SC injection on Days 1, 4, 8, 11, every 21 days and dexamethasone 20 mg tablet orally on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-24 (maximum of 8 cycles).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received bortezomib 1.3 mg/m^2 SC injection on Days 1, 4, 8, 11, every 21 days for Week 1-24.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received dexamethasone 20 mg tablet orally on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-24.

    Number of subjects in period 1
    		Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Started
    53
    16
    15
    27
    Completed
    0
    0
    0
    0
    Not completed
    53
    16
    15
    27
         Consent withdrawn by subject
    4
    -
    -
    1
         Study end by sponsor
    28
    10
    11
    17
         Death
    13
    5
    1
    8
         Other
    7
    1
    3
    1
         Adverse event
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects randomized to Group A started with 6 cycles of bortezomib 1.3 milligram per meter square (mg/m^2) subcutaneously (SC) and dexamethasone 20 milligram (mg) per oral (two 21-day cycles followed by four 35-day cycles; Optimized Retreatment) followed by a randomization, if criteria are met, into 1 of 2 prolonged therapy groups (A1 and A2).

    Reporting group title
    Group A1 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A1 and received bortezomib 1.3 mg/m^2 SC injection on Days 1, 8, 15, 22, every 35 days until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group A2 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A2 and received bortezomib 1.3 mg/m^2 SC once every other week, Days 1, 15, 29, 43, 57, 71, 85, and so on until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group B (Standard retreatment)
    Reporting group description
    		 Subjects randomly assigned to Group B received bortezomib 1.3 mg/m^2 SC injection on Days 1, 4, 8, 11, every 21 days and dexamethasone 20 mg tablet orally on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-24 (maximum of 8 cycles).

    Reporting group values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment) Total
    Number of subjects
    		 53 16 15 27 80
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 20 8 5 13 33
        From 65 to 84 years
    		 33 8 10 14 47
        85 years and over
    		 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.6 ± 8.88 65.5 ± 8.94 68.6 ± 8.58 64.3 ± 8.77 -
    Title for Gender
    Units: subjects
        Female
    		 25 10 6 9 34
        Male
    		 28 6 9 18 46

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects randomized to Group A started with 6 cycles of bortezomib 1.3 milligram per meter square (mg/m^2) subcutaneously (SC) and dexamethasone 20 milligram (mg) per oral (two 21-day cycles followed by four 35-day cycles; Optimized Retreatment) followed by a randomization, if criteria are met, into 1 of 2 prolonged therapy groups (A1 and A2).

    Reporting group title
    Group A1 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A1 and received bortezomib 1.3 mg/m^2 SC injection on Days 1, 8, 15, 22, every 35 days until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group A2 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A2 and received bortezomib 1.3 mg/m^2 SC once every other week, Days 1, 15, 29, 43, 57, 71, 85, and so on until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group B (Standard retreatment)
    Reporting group description
    		 Subjects randomly assigned to Group B received bortezomib 1.3 mg/m^2 SC injection on Days 1, 4, 8, 11, every 21 days and dexamethasone 20 mg tablet orally on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-24 (maximum of 8 cycles).

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS) [1]
    End point description
    Progression free survival, defined as the time from randomization to time of diagnosis of disease progression or death due to any cause. The intent-to-treat (ITT) analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Primary
    End point timeframe
    From randomization to time of disease progression or death, whichever occurs first (up to 2 years and 10 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not performed for this outcome measure.
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: months
        median (confidence interval 95%)
    7.2 (5.7 to 9)
    8.1 (6.7 to 10.8)
    12 (7.5 to 21.4)
    7.8 (4.9 to 11.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Overall Response Rate (ORR)

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    End point title
    		 Percentage of Subjects With Overall Response Rate (ORR)
    End point description
    ORR defined as the best confirmed response including complete response (CR), very good partial response (VGPR) and partial response (PR). International Myeloma Working Group (IMWG) Criteria for progressive disease (PD): CR- Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and less than (<)5 percent (%) Plasma Cells (PCs) in bone marrow; VGPR- Serum and urine M-component detectable by immunofixation but not on electrophoresis or greater than or equal to (>=)90% reduction in serum M-component plus urine M-component <100 milligram (mg) per 24 hours and PR- >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200mg/24 hours. In addition, if present at baseline, >=50% reduction in the size of soft tissue plasmacytomas is also required. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (30- 35 days after last dose of study drug)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: percentage of subjects
        number (not applicable)
    66
    93.8
    80
    51.9
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression, defined as the time from first randomization to time of diagnosis of disease progression. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received. Here 999 signifies "NE: Not Estimable" because upper limit of 95% CI was not estimable due to the lesser number of subjects who died during the study period.
    End point type
    Secondary
    End point timeframe
    From randomization to disease progression or death, whichever occurs first (up to 2 years and 10 months)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: months
        median (confidence interval 95%)
    7.4 (6.2 to 9)
    8.1 (6.7 to 10.8)
    12 (7.5 to 999)
    7.8 (4.9 to 11.7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response, defined as the time of first confirmed response (CR, VGPR, or PR) to time of diagnosis of disease progression. IMWG Criteria for PD: CR- Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas and <5% PCs in bone marrow; VGPR- Serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-component plus urine M-component <100mg per 24 hours and PR- >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200mg/24 hours. In addition, if present at baseline, >=50% reduction in the size of soft tissue plasmacytomas is also required. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment. Here 999 signifies "NE: Not Estimable" because upper limit of 95% CI was not estimable due to the lesser number of subjects who died during the study period.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented evidence of PD (up to 2 years and 10 months)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    36 [2]
    15 [3]
    12 [4]
    13 [5]
    Units: months
        median (confidence interval 95%)
    6.8 (5.6 to 10.4)
    6.2 (5.6 to 7.9)
    11.7 (6.8 to 999)
    5.6 (2.3 to 8.8)
    Notes
    [2] - Here 'N' signifies number of subjects analysed for this outcome measure.
    [3] - Here 'N' signifies number of subjects analysed for this outcome measure.
    [4] - Here 'N' signifies number of subjects analysed for this outcome measure.
    [5] - Here 'N' signifies number of subjects analysed for this outcome measure.
    No statistical analyses for this end point

    Secondary: Time to Next Therapy (TTNT)

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    End point title
    		 Time to Next Therapy (TTNT)
    End point description
    Time to next therapy, defined as the time from first randomization to therapy to the start date of alternative multiple myeloma therapy. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From first randomization to the start date of alternative multiple myeloma therapy (up to 2 years and 10 months)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: months
        median (confidence interval 95%)
    8.6 (7.1 to 12.2)
    12.4 (10.3 to 17.2)
    13 (8.2 to 22.8)
    9 (4.4 to 11.4)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival, defined as the time from first randomization to therapy to time of death due to any cause. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received. Here 999 represents "NE: Not Estimable" because median and upper limit of 95% CI was not estimable due to the lesser number of subjects who died during the study period.
    End point type
    Secondary
    End point timeframe
    From first randomization to time of death due to any cause (up to 2 years and 10 months)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: months
        median (confidence interval 95%)
    30.3 (25.2 to 30.3)
    25.2 (22.5 to 999)
    999 (21.4 to 999)
    999 (19.1 to 999)
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    The ECOG Performance Status was used to assess how a subjects's disease was progressing, assess how the disease affects the daily living abilities of the subject, and determine appropriate treatment and prognosis. The score ranges from 0 "fully active, able to carry on all pre-disease performance without restriction" to 5 "dead". The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (30- 35 days after last dose of study drug) and at endpoint (subjects last visit for efficacy evaluation)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        At End of Treatment (n= 46, 14, 14, 26)
    0.1 ± 0.74
    0 ± 0.78
    -0.1 ± 0.66
    0.3 ± 0.83
        At Endpoint (n= 52, 16, 15, 27)
    0.1 ± 0.73
    -0.1 ± 0.77
    -0.1 ± 0.64
    0.3 ± 0.81
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L) Index Score

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    End point title
    		 Change From Baseline in European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L) Index Score
    End point description
    The EQ-5D-5L is a 5-item questionnaire instrument for use as a measure of health outcome. It has 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. Each dimension has 5 response levels (e.g., no problems with performing activity, slight problems, moderate problems, severe problems, unable to perform [extreme problems]). The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (30- 35 days after last dose of study drug) and at endpoint (subjects last visit for efficacy evaluation)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        At End of Treatment (n= 23, 6, 6, 13)
    -0.0485 ± 0.18659
    0.01 ± 0.1627
    0.0017 ± 0.19637
    -0.0625 ± 0.1433
        At Endpoint (n= 42, 12, 12, 26)
    -0.0381 ± 0.18139
    -0.01 ± 0.16685
    -0.0363 ± 0.15088
    -0.0419 ± 0.18564
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality Visual Analogue Scale (EQ VAS)

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    End point title
    		 Change From Baseline in European Quality Visual Analogue Scale (EQ VAS)
    End point description
    EQ VAS is a “thermometer” visual analogue scale (VAS; referred to as EQ VAS) ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The EQ VAS is used as a quantitative measure of health outcome as judged by the individual subject. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, end of treatment (30- 35 days after last dose of study drug) and at endpoint (subjects last visit for efficacy evaluation)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        At End of Treatment (n= 23, 6, 6, 13)
    2 ± 22.84
    4.5 ± 18.69
    22 ± 26.14
    -17.5 ± 25.55
        At Endpoint (n= 42, 12, 12, 26)
    -2.5 ± 23.59
    7.2 ± 18.92
    4.3 ± 28.14
    -7.7 ± 24.79
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30)

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    End point title
    		 Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30)
    End point description
    The EORTC QLQ-C30 incorporates 5 functional scales (physical, role, emotional, cognitive and social functioning), 1 global health and quality of life scale, 3 symptom scales (fatigue, nausea/vomiting and pain), and 6 single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall period is 1 week (the past week). It is a 30-item questionnaire with responses ranging for the functional scales from not at all to very much and the global health/QOL ranging from very poor to excellent. Scores are transformed to 0-100 scale. The ITT analysis set was defined as all subjects randomly assigned to a treatment group, regardless of whether they received any treatment and the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, at end of treatment (30-35 days after last dose of study drug) and at endpoint ((subjects last visit for efficacy evaluation)
    End point values
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Number of subjects analysed
    53
    16
    15
    27
    Units: units on a scale
    arithmetic mean (standard deviation)
        At End of Treatment (n= 23, 6, 6, 13)
    2.5 ± 21.82
    -1.4 ± 15.29
    12.5 ± 25.69
    -13.5 ± 32.37
        At Endpoint (n= 42, 12, 12, 26)
    1 ± 21.56
    4.2 ± 14.86
    6.9 ± 22.14
    -4.2 ± 31.56
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to end of study (maximum of 18 months after the last subject is enrolled in the study)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects randomized to Group A started with 6 cycles of bortezomib 1.3 mg/m^2 SC and dexamethasone 20 mg per oral (two 21-day cycles followed by four 35-day cycles; Optimized Retreatment) followed by a randomization, if criteria are met, into 1 of 2 prolonged therapy groups (A1 and A2).

    Reporting group title
    Group A1 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A1 and received bortezomib 1.3 mg/m^2 SC injection on Days 1, 8, 15, 22, every 35 days until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group A2 (Prolonged therapy)
    Reporting group description
    		 Subjects randomly assigned to Group A who completed the Optimized Retreatment period (6 cycles) and met the criteria for entry into Prolonged Therapy Period were randomised to Group A2 and received bortezomib 1.3 mg/m^2 SC once every other week, Days 1, 15, 29, 43, 57, 71, 85, and so on until disease progression, start of alternative MM therapy, or the end of the study (maximum of 18 months after the last subject was enrolled in the study).

    Reporting group title
    Group B (Standard retreatment)
    Reporting group description
    		 Subjects randomly assigned to Group B received bortezomib 1.3 mg/m^2 SC injection on Days 1, 4, 8, 11, every 21 days and dexamethasone 20 mg tablet orally on Days 1, 2, 4, 5, 8, 9, 11, 12, every 21 days for Week 1-24 (maximum of 8 cycles).

    Serious adverse events
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 53 (33.96%)
    5 / 16 (31.25%)
    3 / 15 (20.00%)
    12 / 27 (44.44%)
         number of deaths (all causes)
    5
    1
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma Cell Leukaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism Venous
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive Disorder
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A Group A1 (Prolonged therapy) Group A2 (Prolonged therapy) Group B (Standard retreatment)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 53 (96.23%)
    16 / 16 (100.00%)
    15 / 15 (100.00%)
    26 / 27 (96.30%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Hypotension
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    4 / 27 (14.81%)
         occurrences all number
    5
    0
    3
    8
    Pallor
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Peripheral Artery Aneurysm
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 53 (13.21%)
    3 / 16 (18.75%)
    3 / 15 (20.00%)
    4 / 27 (14.81%)
         occurrences all number
    11
    5
    4
    11
    Chest Pain
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    2 / 27 (7.41%)
         occurrences all number
    2
    0
    2
    2
    Chills
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    4
    Face Oedema
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Fatigue
         subjects affected / exposed
    9 / 53 (16.98%)
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    7 / 27 (25.93%)
         occurrences all number
    9
    3
    1
    10
    Influenza Like Illness
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Injection Site Erythema
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    3 / 27 (11.11%)
         occurrences all number
    2
    1
    1
    3
    Injection Site Pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Injection Site Rash
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    15
    15
    0
    0
    Injection Site Reaction
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Injection Site Vasculitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    8 / 53 (15.09%)
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    5 / 27 (18.52%)
         occurrences all number
    9
    2
    3
    5
    Pyrexia
         subjects affected / exposed
    12 / 53 (22.64%)
    3 / 16 (18.75%)
    3 / 15 (20.00%)
    4 / 27 (14.81%)
         occurrences all number
    19
    9
    3
    5
    Reproductive system and breast disorders
    Erectile Dysfunction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pelvic Pain
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 53 (18.87%)
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    7 / 27 (25.93%)
         occurrences all number
    13
    3
    2
    8
    Dyspnoea
         subjects affected / exposed
    9 / 53 (16.98%)
    3 / 16 (18.75%)
    3 / 15 (20.00%)
    1 / 27 (3.70%)
         occurrences all number
    10
    3
    4
    1
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Productive Cough
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Depression
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Hallucination, Visual
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Insomnia
         subjects affected / exposed
    9 / 53 (16.98%)
    2 / 16 (12.50%)
    5 / 15 (33.33%)
    1 / 27 (3.70%)
         occurrences all number
    16
    2
    6
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood Testosterone Decreased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Light Chain Analysis Increased
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Forearm Fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Atrial Fibrillation
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    5
    4
    0
    2
    Cardiac Failure
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cardiomyopathy
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Mitral Valve Incompetence
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Amnesia
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Carpal Tunnel Syndrome
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    0
    4
    Dizziness Postural
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    3
    Dysaesthesia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    1
    2
    Headache
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    2 / 27 (7.41%)
         occurrences all number
    6
    2
    3
    2
    Hypersomnia
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hypertonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    5 / 27 (18.52%)
         occurrences all number
    3
    2
    1
    5
    Neuropathy Peripheral
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 16 (18.75%)
    0 / 15 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    9
    8
    0
    14
    Paraesthesia
         subjects affected / exposed
    7 / 53 (13.21%)
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    7
    3
    1
    3
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    8 / 53 (15.09%)
    3 / 16 (18.75%)
    4 / 15 (26.67%)
    4 / 27 (14.81%)
         occurrences all number
    17
    3
    13
    4
    Sciatica
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Syncope
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    0
    1
    Tremor
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 53 (20.75%)
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    7 / 27 (25.93%)
         occurrences all number
    16
    4
    2
    9
    Leukocytosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    11
    2
    0
    4
    Neutrophilia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    7 / 53 (13.21%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    6 / 27 (22.22%)
         occurrences all number
    24
    4
    8
    10
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dry Eye
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 27 (3.70%)
         occurrences all number
    3
    0
    3
    1
    Eye Disorder
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Glaucoma
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    0
    1
    Panophthalmitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pterygium
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Visual Acuity Reduced
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 16 (12.50%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    2
    2
    0
    1
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    2 / 27 (7.41%)
         occurrences all number
    4
    0
    3
    2
    Constipation
         subjects affected / exposed
    13 / 53 (24.53%)
    3 / 16 (18.75%)
    5 / 15 (33.33%)
    5 / 27 (18.52%)
         occurrences all number
    16
    4
    6
    8
    Diarrhoea
         subjects affected / exposed
    10 / 53 (18.87%)
    3 / 16 (18.75%)
    4 / 15 (26.67%)
    10 / 27 (37.04%)
         occurrences all number
    15
    3
    9
    17
    Dyspepsia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    1 / 27 (3.70%)
         occurrences all number
    2
    0
    2
    1
    Nausea
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    5 / 27 (18.52%)
         occurrences all number
    3
    1
    1
    8
    Tongue Ulceration
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    4 / 27 (14.81%)
         occurrences all number
    4
    1
    1
    8
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 27 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Hyperhidrosis
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 27 (3.70%)
         occurrences all number
    3
    1
    1
    1
    Nail Dystrophy
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pruritus
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    2 / 27 (7.41%)
         occurrences all number
    3
    0
    2
    2
    Rash
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    5 / 27 (18.52%)
         occurrences all number
    5
    0
    3
    6
    Rash Erythematous
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin Lesion
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin Mass
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin Ulcer
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Swelling Face
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    0
    1
    Endocrine disorders
    Thyroiditis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Back Pain
         subjects affected / exposed
    6 / 53 (11.32%)
    0 / 16 (0.00%)
    6 / 15 (40.00%)
    4 / 27 (14.81%)
         occurrences all number
    6
    0
    6
    5
    Bone Pain
         subjects affected / exposed
    6 / 53 (11.32%)
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    3 / 27 (11.11%)
         occurrences all number
    9
    5
    1
    3
    Muscle Spasms
         subjects affected / exposed
    6 / 53 (11.32%)
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    1 / 27 (3.70%)
         occurrences all number
    6
    2
    2
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 27 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Osteolysis
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    0
    2
    Pain in Extremity
         subjects affected / exposed
    6 / 53 (11.32%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    3 / 27 (11.11%)
         occurrences all number
    9
    0
    6
    3
    Pain in Jaw
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 53 (9.43%)
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    1 / 27 (3.70%)
         occurrences all number
    6
    4
    1
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    0
    2
    Herpes Virus Infection
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Hordeolum
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Influenza
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    2 / 27 (7.41%)
         occurrences all number
    4
    0
    3
    2
    Localised Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 27 (3.70%)
         occurrences all number
    5
    1
    1
    1
    Oral Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    5 / 53 (9.43%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    6
    1
    0
    2
    Respiratory Tract Infection
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 16 (18.75%)
    1 / 15 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    7
    6
    1
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 53 (11.32%)
    1 / 16 (6.25%)
    3 / 15 (20.00%)
    1 / 27 (3.70%)
         occurrences all number
    7
    1
    4
    1
    Urinary Tract Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    2 / 27 (7.41%)
         occurrences all number
    6
    0
    2
    3
    Diabetes Mellitus
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    2 / 27 (7.41%)
         occurrences all number
    5
    1
    2
    3
    Hyperkalaemia
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Type 2 Diabetes Mellitus
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2012
    The first amendment included the following changes: 1) Bortezomib dose and schedule in the control group (Group B) was updated to reflect the bortezomib schedule given in the Summary of Product Characteristics (SmPC), 2) change in study design and description of study phases and periods based on addition of 2 randomizations, with the first one performed at inclusion (pretreatment on Day 1 of Cycle 1) to randomly assign subjects to an “optimized” retreatment group (Group A), which could potentially reduce the drop-out rate and increase protocol adherence, or to a control group (Group B) that received standard retreatment. A second randomization performed at the end of the optimized retreatment period (Group A only) that was included to describe 2 schedules of prolonged therapy following the initial optimized retreatment period, 3) eligibility criteria for entry into optimized prolonged therapy (Group A) revised, 4) primary, secondary, and exploratory objectives, hypothesis, endpoints, sample size, and statistical methods were updated to reflect the new study design, 5) end of the study was changed to event-driven (disease progression or death) and 6) adverse event reporting and use of information and publication standard text updated.
    01 Aug 2014
    The second amendment incorporated the rationale and details for the premature closure of enrollment, clarification of collection period for survival data, removal of formal statistical testing, inclusion of descriptive statistical analyses for efficacy endpoints, and some minor editorial changes.

    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.
    Due to a reduced commitment towards enrollment of subjects, the sponsor decided to stop the study early. Consequently, low number of subjects and inadequate statistical power were study limitations.
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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
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