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    Clinical Trial Results:
    A PHASE 3, INTERGROUP MULTICENTRE, RANDOMIZED, CONTROLLED 3 ARM PARALLEL GROUP STUDY TO DETERMINE THE EFFICACY AND SAFETY OF LENALIDOMIDE IN COMBINATION WITH DEXAMETHASONE (Rd) VERSUS MELPHALAN, PREDNISONE AND LENALIDOMIDE (MPR) versus CYCLOPHOSPHAMIDE, PREDNISONE AND LENALIDOMIDE (CPR) IN NEWLY DIAGNOSED MULTIPLE MYELOMA SUBJECTS

    Summary
    EudraCT number
    		 2008-008606-52
    Trial protocol
    		 IT   CZ  
    Global end of trial date
    01 Jul 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Feb 2025
    First version publication date
    26 Feb 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EMN01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01093196
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fondazione EMN Italy Onlus
    Sponsor organisation address
    Via Saluzzo I/A, Turin, Italy, 10125
    Public contact
    Clinical Trial Office, Fondazione EMN Italy Onlus, Clinical Trial Office, Fondazione EMN Italy Onlus, 0039 0110243236 , clinicaltrialoffice@emnitaly.org
    Scientific contact
    Clinical Trial Office, Fondazione EMN Italy Onlus, Clinical Trial Office, Fondazione EMN Italy Onlus, 0039 0110243236 , clinicaltrialoffice@emnitaly.org
    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
    27 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of the combination Rd in comparison with MPR and CPR in newly diagnosed, symptomatic MM patients. To assess the efficacy of lenalidomide as maintenance therapy (in conjunction with prednisone) after the consolidation phase
    Protection of trial subjects
    The protocol for this study has been designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the performance of all aspects of the study, including the methods used for obtaining informed consent, must also be in accordance with principles enunciated in the declaration, as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional Review Boards.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czechia: 39
    Country: Number of subjects enrolled
    Italy: 615
    Worldwide total number of subjects
    654
    EEA total number of subjects
    654
    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)
    4
    From 65 to 84 years
    629
    85 years and over
    21

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is an intergroup multicenter, randomized, open label study designed to compare the efficacy and safety of Rd with MPR and CPR in newly diagnosed symptomatic MM patients who are 65 years of age or older. Potential study subjects will sign an informed consent prior to undergoing any study related procedure.

    Pre-assignment
    Screening details
    		 Patients will undergo screening for protocol eligibility within 28 dd (4 weeks) prior to randomization. Subjects who meet all the inclusion criteria will be randomized based on a computer-generated randomization schedule. The randomization will occur for induction and maintenance treatment. They will be stratified according to the ISS and age.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ARM A (Rd)
    Arm description
    		 Patients will start induction treatment with the association of lenalidomide and dexamethasone (Rd) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), • Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15 and 22 every 28 days in patients 65-75 years old and at the dose of 20 mg on days 1,8,15 and 22 every 28 days in patients older than 75 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15 and 22 every 28 days in patients 65-75 years old and at the dose of 20 mg on days 1,8,15 and 22 every 28 days in patients older than 75 years.

    Arm title
    		 ARM B (MPR)
    Arm description
    		 Patients will start induction treatment with the association of melphalan, prednisone and lenalidomide (MPR) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) • Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients 65-75 years old and 0.13 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients older than 75 years • Prednisone will be given orally at the dose of 1.5 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients 65-75 years old and 0.13 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients older than 75 years

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 1.5 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28)

    Arm title
    		 ARM C (CPR)
    Arm description
    		 Patients will start induction treatment with the association of cyclophosphamide, prednisone and lenalidomide (CPR) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) • Cyclophosphamide will be given orally at the dose of 50 mg /day for 21 days followed by a 7 day rest period (days 1 to 28) in patients 65-75 years old and 50 mg every other day (days 1 to 20 followed by a 8 days rest period [day 21 to 28]) in patients older than 75 years • Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28)

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide will be given orally at the dose of 50 mg /day for 21 days followed by a 7 day rest period (days 1 to 28) in patients 65-75 years old and 50 mg every other day (days 1 to 20 followed by a 8 days rest period [day 21 to 28]) in patients older than 75 years.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28)

    Number of subjects in period 1
    		ARM A (Rd) ARM B (MPR) ARM C (CPR)
    Started
    217
    217
    220
    Completed
    133
    126
    143
    Not completed
    84
    91
    77
         Adverse event, serious fatal
    10
    9
    9
         Physician decision
    3
    2
    1
         Consent withdrawn by subject
    2
    7
    3
         not started
    5
    6
    -
         Adverse event, non-fatal
    18
    32
    23
         Lost to follow-up
    6
    4
    1
         Lack of efficacy
    40
    30
    40
         Protocol deviation
    -
    1
    -
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ARM A1, B1 and C1 (R)
    Arm description
    		 Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period.

    Arm title
    		 ARM A2, B2 and C2 (RP)
    Arm description
    		 • Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. • Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28) Each cycle will be repeated every 28 days, until any sign of disease progression (PD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28)

    Number of subjects in period 2
    		ARM A1, B1 and C1 (R) ARM A2, B2 and C2 (RP)
    Started
    204
    198
    Completed
    0
    0
    Not completed
    204
    198
         Adverse event, serious fatal
    8
    11
         Physician decision
    5
    15
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    39
    37
         Other
    28
    16
         Lost to follow-up
    4
    4
         Treatment will be continued outside the scope of t
    2
    2
         Lack of efficacy
    116
    108
         Protocol deviation
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction
    Reporting group description
    		 -

    Reporting group values
    		 Induction Total
    Number of subjects
    		 654 654
    Age categorical
    Units: Subjects
        <= 75
    		 429 429
        > 75
    		 225 225
    Age continuous
    Units: years
        median (full range (min-max))
    		 73 (50 to 91) -
    Gender categorical
    Units: Subjects
        Female
    		 335 335
        Male
    		 319 319
    ISS Stage
    Units: Subjects
        ISS I
    		 181 181
        ISS II
    		 296 296
        ISS III
    		 177 177
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population

    Subject analysis sets values
    		 ITT
    Number of subjects
    654
    Age categorical
    Units: Subjects
        <= 75
    429
        > 75
    225
    Age continuous
    Units: years
        median (full range (min-max))
    73 (50 to 91)
    Gender categorical
    Units: Subjects
        Female
    335
        Male
    319
    ISS Stage
    Units: Subjects
        ISS I
    181
        ISS II
    296
        ISS III
    177

    End points

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    End points reporting groups
    Reporting group title
    ARM A (Rd)
    Reporting group description
    		 Patients will start induction treatment with the association of lenalidomide and dexamethasone (Rd) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28), • Dexamethasone will be given orally at the dose of 40 mg on days 1, 8, 15 and 22 every 28 days in patients 65-75 years old and at the dose of 20 mg on days 1,8,15 and 22 every 28 days in patients older than 75 years.

    Reporting group title
    ARM B (MPR)
    Reporting group description
    		 Patients will start induction treatment with the association of melphalan, prednisone and lenalidomide (MPR) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 10 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) • Melphalan will be given orally at the dose of 0.18 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients 65-75 years old and 0.13 mg/Kg for 4 days, followed by a 24 days rest period (day 5 to 28) in patients older than 75 years • Prednisone will be given orally at the dose of 1.5 mg/Kg for 4 days followed by a 24 day rest period (days 5 to 28)

    Reporting group title
    ARM C (CPR)
    Reporting group description
    		 Patients will start induction treatment with the association of cyclophosphamide, prednisone and lenalidomide (CPR) for 9 cycles every 28 days: • Lenalidomide will be given orally at the dose of 25 mg/day for 21 days followed by a 7 days rest period (day 22 to 28) • Cyclophosphamide will be given orally at the dose of 50 mg /day for 21 days followed by a 7 day rest period (days 1 to 28) in patients 65-75 years old and 50 mg every other day (days 1 to 20 followed by a 8 days rest period [day 21 to 28]) in patients older than 75 years • Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28)
    Reporting group title
    ARM A1, B1 and C1 (R)
    Reporting group description
    		 Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period.

    Reporting group title
    ARM A2, B2 and C2 (RP)
    Reporting group description
    		 • Lenalidomide will be given at the dose of 10 mg/day on day 1-21 followed by a 7 days rest period. • Prednisone will be given orally at the dose of 25 mg every other day (days 1 to 28) Each cycle will be repeated every 28 days, until any sign of disease progression (PD).

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression free survival (PFS), defined as time from start of treatment to the first documentation of progressive disease based on the International Uniform Response Criteria, Appendix V or death due to any cause during the treatment phase
    End point type
    Primary
    End point timeframe
    5 years
    End point values
    		 ARM A (Rd) ARM B (MPR) ARM C (CPR) ARM A1, B1 and C1 (R) ARM A2, B2 and C2 (RP)
    Number of subjects analysed
    217
    217
    220
    204
    198
    Units: month
        median (confidence interval 95%)
    17.9 (15.7 to 22.4)
    22.6 (18.6 to 28.3)
    18.6 (15.4 to 22.2)
    18.6 (14.6 to 22)
    21.6 (15.9 to 29.6)
    Statistical analysis title
    		 R1 Analysis
    Comparison groups
    ARM A (Rd) v ARM B (MPR)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1072
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.104405
    Statistical analysis title
    		 R1 Analysis (2)
    Comparison groups
    ARM A (Rd) v ARM C (CPR)
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4935
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.101377
    Statistical analysis title
    		 R2 Analysis
    Comparison groups
    ARM A1, B1 and C1 (R) v ARM A2, B2 and C2 (RP)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42957
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.107536

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival (OS), defined as time from start of treatment to death due to any cause
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 ARM A (Rd) ARM B (MPR) ARM C (CPR) ARM A1, B1 and C1 (R) ARM A2, B2 and C2 (RP)
    Number of subjects analysed
    217
    217
    220
    204
    198
    Units: month
        median (confidence interval 95%)
    61.5 (48.2 to 80.5)
    65.2 (53.4 to 79)
    63.5 (57 to 76.1)
    71.4 (57.6 to 91.7)
    69.9 (55.5 to 87.8)
    Statistical analysis title
    		 R1 Analysis
    Comparison groups
    ARM A (Rd) v ARM B (MPR)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.90404
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.120631
    Statistical analysis title
    		 Copy of R1 Analysis
    Comparison groups
    ARM A (Rd) v ARM C (CPR)
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65351
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.121143
    Statistical analysis title
    		 Copy of R1 Analysis
    Comparison groups
    ARM A2, B2 and C2 (RP) v ARM A1, B1 and C1 (R)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65397
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13121

    Secondary: Time to progression (TTP)

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    End point title
    		 Time to progression (TTP)
    End point description
    Time to progression (TTP), defined as time from start of treatment to the first documentation of progressive disease or death due to progressive disease during the treatment phase
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 ARM A (Rd) ARM B (MPR) ARM C (CPR) ARM A1, B1 and C1 (R) ARM A2, B2 and C2 (RP)
    Number of subjects analysed
    217
    217
    220
    204
    198
    Units: month
        median (confidence interval 95%)
    18.8 (16.2 to 24.5)
    26.3 (21.7 to 34.4)
    19.1 (16.2 to 24.4)
    19.1 (15.2 to 24.3)
    24.4 (18.7 to 30.9)
    Statistical analysis title
    		 R1 Analysis
    Comparison groups
    ARM A (Rd) v ARM B (MPR)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1072
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.104405
    Statistical analysis title
    		 R1 Analysis (2)
    Comparison groups
    ARM A (Rd) v ARM C (CPR)
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4935
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.101377
    Statistical analysis title
    		 R2 Analysis
    Comparison groups
    ARM A1, B1 and C1 (R) v ARM A2, B2 and C2 (RP)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36947
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1134

    Secondary: VGPR rate

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    End point title
    		 VGPR rate
    End point description
    Objective overall response rate, including complete response (CR) and partial response (PR) using the International Uniform Response Criteria, Appendix IV
    End point type
    Secondary
    End point timeframe
    Overall
    End point values
    		 ARM A (Rd) ARM B (MPR) ARM C (CPR)
    Number of subjects analysed
    217
    217
    220
    Units: patients
        < VGPR
    130
    131
    145
        >= VGPR
    87
    86
    75
    Statistical analysis title
    		 Fisher test
    Comparison groups
    ARM A (Rd) v ARM B (MPR) v ARM C (CPR)
    Number of subjects included in analysis
    654
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.361
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to the next anti-myeloma therapy

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    End point title
    		 Time to the next anti-myeloma therapy
    End point description
    Time to the next anti-myeloma therapy
    End point type
    Secondary
    End point timeframe
    7 Years
    End point values
    		 ARM A (Rd) ARM B (MPR) ARM C (CPR) ARM A1, B1 and C1 (R) ARM A2, B2 and C2 (RP)
    Number of subjects analysed
    217
    217
    220
    204
    198
    Units: month
        median (confidence interval 95%)
    23.8 (20.8 to 30.7)
    26.4 (21.6 to 37)
    23.8 (20.2 to 28.1)
    29.4 (25.3 to 34.6)
    32.2 (27.1 to 40.3)
    Statistical analysis title
    		 R1 Analysis
    Comparison groups
    ARM A (Rd) v ARM B (MPR)
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.20548
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.106426
    Statistical analysis title
    		 R1 Analysis (2)
    Comparison groups
    ARM A (Rd) v ARM C (CPR)
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52519
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.103407
    Statistical analysis title
    		 R2 Analysis
    Comparison groups
    ARM A1, B1 and C1 (R) v ARM A2, B2 and C2 (RP)
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95712
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.111566

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27
    Reporting groups
    Reporting group title
    Per protocol
    Reporting group description
    		 -

    Serious adverse events
    		 Per protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    272 / 643 (42.30%)
         number of deaths (all causes)
    406
         number of deaths resulting from adverse events
    39
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Basal cell carcinoma
         subjects affected / exposed
    6 / 643 (0.93%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal oncocytoma
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plasma cell leukaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Meningioma
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    8 / 643 (1.24%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hypotension
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    General physical health deterioration
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    11 / 643 (1.71%)
         occurrences causally related to treatment / all
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    15 / 643 (2.33%)
         occurrences causally related to treatment / all
    7 / 17
         deaths causally related to treatment / all
    1 / 1
    Sudden cardiac death
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sudden death
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 643 (0.78%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 643 (0.93%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    1 / 1
    Respiratory failure
         subjects affected / exposed
    5 / 643 (0.78%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    Pleurisy
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Bronchial disorder
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    11 / 643 (1.71%)
         occurrences causally related to treatment / all
    5 / 11
         deaths causally related to treatment / all
    2 / 6
    Cardiac failure acute
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Ventricular tachycardia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial hypoxia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atrioventricular block
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Hemiparesis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Essential tremor
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Memory impairment
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Cytopenia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 643 (1.09%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Ascites
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    7 / 643 (1.09%)
         occurrences causally related to treatment / all
    4 / 7
         deaths causally related to treatment / all
    1 / 1
    Enteritis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia strangulated
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    Pancreatitis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    1 / 1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 643 (1.40%)
         occurrences causally related to treatment / all
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash vesicular
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urticaria
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    10 / 643 (1.56%)
         occurrences causally related to treatment / all
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    Crush syndrome
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    5 / 643 (0.78%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Osteoarthritis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    bronchitis
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Citrobacter infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Ear infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    7 / 643 (1.09%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    1 / 1
    Pneumonia
         subjects affected / exposed
    31 / 643 (4.82%)
         occurrences causally related to treatment / all
    18 / 35
         deaths causally related to treatment / all
    2 / 6
    Sepsis
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Septic shock
         subjects affected / exposed
    3 / 643 (0.47%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 2
    Systemic infection
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 643 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    4 / 643 (0.62%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 643 (0.16%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Per protocol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    577 / 643 (89.74%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    39 / 643 (6.07%)
         occurrences all number
    39
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    37 / 643 (5.75%)
         occurrences all number
    37
    Peripheral sensory neuropathy
         subjects affected / exposed
    37 / 643 (5.75%)
         occurrences all number
    37
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    410 / 643 (63.76%)
         occurrences all number
    410
    Anaemia
         subjects affected / exposed
    398 / 643 (61.90%)
         occurrences all number
    398
    Thrombocytopenia
         subjects affected / exposed
    260 / 643 (40.44%)
         occurrences all number
    260
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    150 / 643 (23.33%)
         occurrences all number
    150
    Pyrexia
         subjects affected / exposed
    111 / 643 (17.26%)
         occurrences all number
    111
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    115 / 643 (17.88%)
         occurrences all number
    115
    Constipation
         subjects affected / exposed
    79 / 643 (12.29%)
         occurrences all number
    79
    Nausea
         subjects affected / exposed
    37 / 643 (5.75%)
         occurrences all number
    37
    Skin and subcutaneous tissue disorders
    Exfoliative rash
         subjects affected / exposed
    78 / 643 (12.13%)
         occurrences all number
    78
    Pruritus
         subjects affected / exposed
    37 / 643 (5.75%)
         occurrences all number
    37
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    51 / 643 (7.93%)
         occurrences all number
    51

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Mar 2009
    Amendment 1: Addition of an observational substudy for asymptomatic patients.
    07 Jul 2010
    Amendment Sponsor: Change of sponsor's legal represenative.
    04 Aug 2010
    Amendment 2: Statistical updates and new MPR arm treatment scheme.
    03 May 2011
    Amendment 3: Regarding the modification to the information sheet/informed consent, for an update on the risks related to the use of Lenalidomide, following the AIFA communication of 6 April 2011 on the emergency “Safety Lenalidomide”.
    01 Sep 2016
    Amendment PI's ECC: Change PI's ECC
    04 May 2017
    Amendment 4: Update protocol, ICF side effects, SAE_SUSAR form, SmPC, PPG, Sponsor contacts.
    28 Jan 2019
    Amendment 5: Added new site for import and release of drug Lenalidomide.
    04 Nov 2019
    Amendment 6: New version of the Lenalidomide IB and the updated Informed Consent with the new side effects relating to the drug Lenalidomide.
    20 Mar 2020
    Urgent Amendment 1: COVID updates.
    20 Oct 2020
    Amendment 7: New version of the Lenalidomide IB and the updated Informed Consent with the new side effects relating to the drug Lenalidomide. The drug labels and the SAE form have been updated.
    31 Aug 2023
    Amendment CEC-CET: Change from CEC to CET.
    27 Feb 2024
    Amendment 8: Central laboratory change, study duration updates and drug information

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

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