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    Clinical Trial Results:
    A Phase III, Randomized, Open-Label, 3-Arm Study To Determine the Efficacy and Safety of Lenalidomide (Revlimid®) Plus Low-Dose Dexamethasone When Given Until Progressive Disease or for 18 Four-Week Cycles Versus the Combination of Melphalan, Prednisone, and Thalidomide Given for 12 Six-Week Cycles in Patients with Previously Untreated Multiple Myeloma Who Are Either 65 Years of Age or Older or Not Candidates for Stem Cell Transplantation (IFM 07-01)

    Summary
    EudraCT number
    2007-004823-39
    Trial protocol
    FR   GB   IE   IT   AT   ES   SE   BE   PT   DE   GR  
    Global end of trial date
    14 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2017
    First version publication date
    12 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-5013-MM-020
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Annette Ervin-Haynes, Executive Director, Clinical Research and Development, Celgene Corporation, 01 908-673-9732, aervin-haynes@celgene.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
    14 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of lenalidomide plus low-dose dexamethasone given until progressive disease to that of the combination of melphalan, prednisone, and thalidomide given for 12 six week cycles.
    Protection of trial subjects
    Patient Confidentiality, Personal Data Protection and Biomarker Consent
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Aug 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Regulatory reason
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    Switzerland: 26
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    United Kingdom: 71
    Country: Number of subjects enrolled
    United States: 60
    Country: Number of subjects enrolled
    Australia: 72
    Country: Number of subjects enrolled
    Austria: 41
    Country: Number of subjects enrolled
    Belgium: 52
    Country: Number of subjects enrolled
    Canada: 252
    Country: Number of subjects enrolled
    China: 47
    Country: Number of subjects enrolled
    France: 459
    Country: Number of subjects enrolled
    Germany: 97
    Country: Number of subjects enrolled
    Greece: 86
    Country: Number of subjects enrolled
    Italy: 148
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    New Zealand: 12
    Country: Number of subjects enrolled
    Portugal: 27
    Worldwide total number of subjects
    1623
    EEA total number of subjects
    1087
    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)
    92
    From 65 to 84 years
    1475
    85 years and over
    56

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in the Europe, Asia, North America and Pacific regions. Participants were randomized at 246 sites (165 in Europe, 23 in Asia, 39 in North America, and 19 in the Pacific). The study was co-sponsored by Intergroupe Francophone du Myélome (IFM) (for sites in France, Switzerland, and Belgium) and Celgene Corporation.

    Pre-assignment
    Screening details
    Participants were stratified at randomization by 1) age (≤ 75 versus > 75 years), 2) stage (International Staging System Stages I or II versus Stage III), and 3) country.

    Period 1
    Period 1 title
    Active Treatment Phase (Ph) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lenalidomide and Low-Dose Dexamethasone (Rd)
    Arm description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day treatment (rx) cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at (@) the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid CC-5013
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day treatment cycle until disease progression. Subjects with moderate to severe renal insufficiency received 10-15 mg lenalidomide PO on days 1-21 of each 28-day treatment cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Decadron, Dexasone, Diodex, Hexadrol, Maxidex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression. Those with moderate to severe renal insufficiency receive 20 - 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle

    Arm title
    Lenalidomide and Dexamethasone Rd18
    Arm description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on the same schedule as above for up to 18 cycles until PD or intolerable toxicity.
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlimid, CC-5013
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg PO QD on days 1 to 21 of each 28-day treatment cycle for up to 18 cycles or until disease progression. Subjects with moderate to severe renal insufficiency received 10-15 mg lenalidomide PO on days 1-21 of each 28-day treatment cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Decadron, Dexasone, Diodex, Hexadrol, Maxidex
    Pharmaceutical forms
    Tablet, Tablet
    Routes of administration
    Oral use, Oral use
    Dosage and administration details
    Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle. Those with moderate to severe renal insufficiency receive 20 - 40 mg PO on days 1, 8, 15, and 22 of a 28-day cycle up to 18 cycles or until disease progression.

    Arm title
    Melphalan + Prednisone + Thalidomide (MPT)
    Arm description
    Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity.
    Arm type
    Active comparator

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Alkeran, L-PAM, L-Sarcolysin, Phenylalanine Mustard
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Melphalan 0.25 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles or until disease progression.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Deltasone, Orasone, Adasone, Deltacortisone, Prednisonum
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 2 mg/kg PO on days 1 to 4 of each 42-day cycle up to 12 cycles or until disease progression.

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Thalomid, Immunoprin, Talidex, Talizer, Neurosedyn
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle for up to 12 cycles or disease progression.

    Number of subjects in period 1
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Started
    535
    541
    547
    Safety Population
    532
    540
    541
    Untreated
    3
    1
    6
    Completed
    0
    0
    0
    Not completed
    535
    541
    547
         Disease Progression
    273
    362
    339
         Protocol deviation
    2
    2
    4
         Miscellaneous
    52
    34
    47
         Adverse event, serious fatal
    60
    28
    37
         Study Close Out
    64
    26
    21
         Adverse event, non-fatal
    68
    71
    76
         Consent withdrawn by subject
    16
    16
    21
         Lost to follow-up
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide and Low-Dose Dexamethasone (Rd)
    Reporting group description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day treatment (rx) cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at (@) the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.

    Reporting group title
    Lenalidomide and Dexamethasone Rd18
    Reporting group description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on the same schedule as above for up to 18 cycles until PD or intolerable toxicity.

    Reporting group title
    Melphalan + Prednisone + Thalidomide (MPT)
    Reporting group description
    Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity.

    Reporting group values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT) Total
    Number of subjects
    535 541 547 1623
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    73.2 ± 6.57 72.9 ± 6.5 73.1 ± 6.32 -
    Gender, Male/Female
    Units: Subjects
        Female
    241 268 260 769
        Male
    294 273 287 854
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    40 43 44 127
        Black or African American
    9 6 5 20
        Native Hawaiian or other Pacific Islanders
    1 0 1 2
        White or Caucasion
    474 480 491 1445
        Other, Miscellaneous
    6 11 3 20
        Missing
    5 1 3 9
    International Staging System (ISS)
    International Staging System (ISS): ISS is used as a staging system for multiple myeloma and divides myeloma into 3 stages based only on the serum beta-2 microglobulin and serum albumin levels. Higher stages represent more advanced disease.
    Units: Subjects
        Stage I
    106 106 103 315
        Stage II
    227 229 225 681
        Stage III
    202 206 219 627
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status is used to assess the progress of disease in a patient, how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
    Units: Subjects
        0 (fully active)
    155 163 156 474
        1 (restrictive but ambulatory)
    257 263 275 795
        2 (ambulatory but unable to work)
    119 113 111 343
        3-4 (limited self-care, completely disabled)
    2 2 2 6
        Missing
    2 0 3 5
    Creatinine clearance
    Units: Subjects
        >=60 ml/min
    269 280 285 834
        <60 ml/min
    266 261 261 788
        Missing
    0 0 1 1
    Beta2 Microglobulin
    Units: Subjects
        >5.5 mg/L
    224 224 234 682
        <=5.5 mg/L
    309 316 312 937
        Missing
    2 1 1 4
    Albumin
    Units: Subjects
        <=35 g/L
    192 209 223 624
        > 35 g/L
    343 331 324 998
        Missing
    0 1 0 1
    Lactic Dehydrogenase
    Units: Subjects
        <200 U/L
    448 442 434 1324
        >=200 U/L
    86 99 112 297
        Missing
    1 0 1 2
    Multiple Myeloma Subtype
    Units: Subjects
        Immunoglobulin A
    138 142 123 403
        Immunoglobulin A and Immunoglobulin G
    7 6 8 21
        Immunoglobulin A and Immunoglobulin M
    0 0 1 1
        Immunoglobulin D
    4 7 4 15
        Immunoglobulin G
    334 331 350 1015
        Immunoglobulin M
    3 1 1 5
        Not available (includes light-chain disease)
    49 54 60 163
    Cytogenetic Risk
    Cytogenetic risk categories are mutually exclusive. Definitions: Adverse risk category: t(4:14), t(14:16), del (13q) or monosomy 13, del (17p), 1q gain; Non-adverse risk categories include favorable hyperdiploidy: t(11:14), gains of 5/9/15; normal: a normal result, gains other than 5/9/15, IgH deletion, and uncertain risk: probes used for analysis cannot place participant in any risk categories. Not evaluable: no specimen received, test failure or insufficient number of cells available for analysis.
    Units: Subjects
        Adverse Risk
    170 185 189 544
        Favorable Hyperdiploidy
    112 103 102 317
        Normal
    148 131 141 420
        Uncertain Risk
    38 56 40 134
        Not evaluable
    34 35 44 113
        Missing
    33 31 31 95

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide and Low-Dose Dexamethasone (Rd)
    Reporting group description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) administered by mouth (PO) on days 1 to 21 of each 28-day treatment (rx) cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone at (@) the same schedule. Participants with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity. Participants with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle until disease progression or intolerable toxicity.

    Reporting group title
    Lenalidomide and Dexamethasone Rd18
    Reporting group description
    Participants ≤ 75 years old received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless progressive disease (PD) or intolerable toxicity. Participants > 75 years old received lenalidomide 25 mg PO on the same schedule and frequency plus 20 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with moderate renal insufficiency received 10-15 mg lenalidomide (R) PO on days 1-21 of each 28-day cycle and 20-40 mg dexamethasone (d) PO on days 1, 8, 15, and 22 of a 28-day cycle for up to 18 cycles unless PD or intolerable toxicity. Those with severe renal insufficiency received 15 mg lenalidomide (R) PO every other day (QOD) on days 1-21 of each 28-day treatment cycle and 20-40 mg dexamethasone (d) PO on the same schedule as above for up to 18 cycles until PD or intolerable toxicity.

    Reporting group title
    Melphalan + Prednisone + Thalidomide (MPT)
    Reporting group description
    Participants received melphalan (M) 0.25 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity. Participants with moderate to severe renal insufficiency received melphalan (M) 0.10-0.125 mg/kg PO daily (QD) on days 1 to 4 of each 42-day cycle plus prednisone (P) at 2 mg/kg PO on days 1 to 4 of each 42-day cycle and thalidomide 100-200 mg PO QD on days 1 to 41 of each 42-day cycle. MPT therapy was given for up to 12 cycles unless PD or intolerable toxicity.

    Primary: Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)

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    End point title
    Kaplan-Meier Estimates of Progression-free survival (PFS) Based on the Response Assessment by the Independent Review Adjudication Committee (IRAC)
    End point description
    PFS was calculated as the time from randomization to the lst documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy (AMT) without documented PD were censored on the date of their last response assessment, prior to receiving other AMT. Censoring PFS rules: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any response assessment; Progression documented between scheduled assessments; Death between assessments; no progression; study discontinuations for reasons other than PD or death; new AMT started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's). Intent to Treat population = subjects who were randomized even if no study drug was given.
    End point type
    Primary
    End point timeframe
    From date of randomization until the data cut-off date of 24 May 2013. Median follow-up time for all participants was 17.1 months.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (confidence interval 95%)
    25.5 (20.7 to 29.4)
    20.7 (19.4 to 22)
    21.2 (19.3 to 23.2)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Melphalan + Prednisone + Thalidomide (MPT) v Lenalidomide and Low-Dose Dexamethasone (Rd)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00006 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    0.85
    Notes
    [1] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00001 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    0.82
    Notes
    [2] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.70349 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.2
    Notes
    [3] - The p-value is based on the unstratified log-rank test.

    Primary: Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis

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    End point title
    Kaplan-Meier Estimates of PFS Based on the Response Assessment by the Investigator Assessment at the Time of Final Analysis
    End point description
    PFS was calculated as the time from randomization to the lst documented PD or death due to any cause during the study, which ever occurred first based on the International Myeloma Working Group Uniform Response criteria (IMWG). Those who withdrew for any reason or received another anti-myeloma therapy (AMT) without documented PD were censored on the date of their last response assessment, prior to receiving other AMT. Censoring PFS rules: - No baseline assessments and no progression or death documented within the 2 scheduled assessments; Death within the lst two assessments without any response assessment; Progression documented between scheduled assessments; Death between assessments; no progression; study discontinuations for reasons other than PD or death; new AMT started prior to PD; death or PD after an extended lost to follow-up time period (2 or more missed scheduled assessment's). Intent to Treat population = subjects who were randomized even if no study drug was given.
    End point type
    Primary
    End point timeframe
    From date of randomization to date of data cut-off date of 21 January 2016; median follow-up for all subjects was 17.7 months
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (confidence interval 95%)
    26 (20.7 to 29.7)
    21 (19.7 to 22.4)
    21.9 (19.8 to 23.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    0.79
    Notes
    [4] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    0.81
    Notes
    [5] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.91161 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.14
    Notes
    [6] - The p-value is based on the unstratified log-rank test.

    Secondary: Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis

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    End point title
    Kaplan Meier Estimates of Overall Survival (OS) at the Time of Final Analysis
    End point description
    Overall survival was defined as the time between randomization and death. Subjects who died, regardless of the cause of death, were considered to have had an event. All subjects who were lost to follow-up prior to the end of the trial or who were withdrawn from the trial were censored at the time of last contact. Subjects who were still being treated were censored at the last available date the participant was known to be alive. ITT population (ITT) = all subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of data cut-off of 21 January 2016; median follow-up for all subjects was 48.3 months
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (confidence interval 95%)
    59.1 (53.9 to 65.9)
    62.3 (53.6 to 68.7)
    49.1 (44.3 to 53.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00234 [7]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    0.92
    Notes
    [7] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82903 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.2
    Notes
    [8] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00119 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    0.9
    Notes
    [9] - The p-value is based on the unstratified log-rank test.

    Secondary: Percentage of Participants With an Objective Response based on IRAC Review

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    End point title
    Percentage of Participants With an Objective Response based on IRAC Review
    End point description
    Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to <200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas. The ITT population includes all subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until the end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: percentage of participants
        number (not applicable)
    75.1
    73.4
    62.3
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    2.37
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.53065
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.44
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.29
         upper limit
    2.15

    Secondary: Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis

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    End point title
    Percentage of Participants With an Objective Response based on Investigator Assessment at the Time of Final Analysis
    End point description
    Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the IRAC Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to <200 mg/24 hours. If present at baseline a ≥ 50% reduction in size of soft tissue plasmacytomas. The ITT population includes all subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: percentage of participants
        number (not applicable)
    80.7
    78.6
    67.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.53
         upper limit
    2.68
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.405
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.54
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00004
    Method
    Fisher exact
    Parameter type
    Log odds ratio
    Point estimate
    1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.35
         upper limit
    2.32

    Secondary: Kaplan Meier estimates of duration of myeloma response as determined by the IRAC

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    End point title
    Kaplan Meier estimates of duration of myeloma response as determined by the IRAC
    End point description
    Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first. Includes subjects with at least a partial response.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median follow-up for responders was 20.1 months
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    402
    397
    341
    Units: months
        median (confidence interval 95%)
    35 (27.9 to 43.4)
    22.1 (20.3 to 24)
    22.3 (20.2 to 24.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [10]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.76
    Notes
    [10] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [11]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.72
    Notes
    [11] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7674 [12]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.23
    Notes
    [12] - The p-value is based on the unstratified log-rank test.

    Secondary: Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis

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    End point title
    Kaplan Meier estimates of duration of myeloma response as determined by an investigator assessment at the Time of Final Analysis
    End point description
    Duration of response was defined as the duration from the time when the response criteria were first met for CR or VGPR or PR based on IMWG criteria until the first date the response criteria were met for progressive disease or until the participant died from any cause, whichever occurred first. Includes subjects with at least a partial response.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment; data cut-off date of 21 January 2016; median follow-up for responders was 19.9 months.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    432
    425
    369
    Units: months
        median (confidence interval 95%)
    31.5 (26.2 to 37.3)
    21.5 (19.2 to 23)
    22.1 (20.3 to 24.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    801
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [13]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    0.72
    Notes
    [13] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    857
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [14]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    0.72
    Notes
    [14] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.99537 [15]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.17
    Notes
    [15] - The p-value is based on the unstratified log-rank test.

    Secondary: Time to first response based on the review by the IRAC

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    End point title
    Time to first response based on the review by the IRAC
    End point description
    The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria. Includes subjects with at least a partial response.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    402
    397
    341
    Units: months
        median (full range (min-max))
    1.8 (0.7 to 22.2)
    1.8 (0.8 to 17.1)
    2.8 (1.3 to 49.7)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    799
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46672
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to first response based on the investigator asssessment at the Time of Final Analysis

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    End point title
    Time to first response based on the investigator asssessment at the Time of Final Analysis
    End point description
    The time to first myeloma response was defined as the time from randomization to the time when the response criteria for at least a PR was first met based on the IMWG criteria assessed by the investigator. Includes subjects with at least a partial response.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    430
    425
    368
    Units: months
        median (full range (min-max))
    1.8 (0.5 to 22.2)
    1.8 (0.8 to 34.8)
    2.8 (1.2 to 56.3)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    855
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.46987
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF)

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    End point title
    Kaplan Meier Estimates of Time to Treatment Failure (TTF)
    End point description
    TTF is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by IRAC based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT) and death. Includes the ITT population = subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the data cut-off of 24 May 2013; median follow up for all participants was 16.1 months.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (confidence interval 95%)
    16.9 (14.1 to 18.4)
    17.2 (14.6 to 18.2)
    14.1 (12 to 16.1)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on a stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00012 [16]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.88
    Notes
    [16] - The p-value is based on unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on a stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00187 [17]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    0.93
    Notes
    [17] - The p-value is based on unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Based on a stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45973 [18]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.08
    Notes
    [18] - The p-value is based on unstratified log-rank test.

    Secondary: Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis

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    End point title
    Kaplan Meier Estimates of Time to Treatment Failure (TTF) at the Time of Final Analysis
    End point description
    Time to treatment failure (TTF) is defined as the time between the randomization and discontinuation of study treatment for any reason, including disease progression (determined by the investigators assessment based on the IMWG response criteria), treatment toxicity, start of another anti-myeloma therapy (AMT), and death. ITT population = subjects who were randomized, independent of whether they received study treatment or not.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of the data cut-off of 21 January 2016; median follow up for all participants was 16.1 months.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (confidence interval 95%)
    16.9 (14.1 to 18.4)
    17.2 (14.6 to 18.2)
    14.1 (12 to 16.1)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00002 [19]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    0.86
    Notes
    [19] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Based on unstratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00126 [20]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    0.92
    Notes
    [20] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.27704 [21]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.06
    Notes
    [21] - The p-value is based on the unstratified log-rank test.

    Secondary: Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)

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    End point title
    Kaplan Meier Estimates for time to second-line anti-myeloma treatment (AMT)
    End point description
    Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Includes ITT population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the data cut-off of 24 May 2013; median follow-up for all participants was 23.0 months
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535 [22]
    541
    547
    Units: months
        median (confidence interval 95%)
    39.1 (32.8 to 99999)
    28.5 (26.9 to 30.4)
    26.7 (24 to 29.9)
    Notes
    [22] - 99999 = Could not be estimated due to the low number of events at the time of analysis.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [23]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    0.78
    Notes
    [23] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.00067 [25]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    0.88
    Notes
    [24] - Based on unstratified Cox proportional hazards model.
    [25] - The p-value is based on the unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.12333 [26]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.03
    Notes
    [26] - The p-value is based on unstratified log-rank test.

    Secondary: Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis

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    End point title
    Kaplan Meier Estimates for time to second-line AMT at the Time of Final Analysis
    End point description
    Time to second-line anti-myeloma therapy was defined as time from randomization to the start of another non-protocol anti-myeloma therapy. Includes ITT population.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the date of the data cut-off of 21 January 2016; median follow-up for all participants was 23.0 months.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    535
    541
    547
    Units: months
        median (full range (min-max))
    36.7 (31.9 to 45.2)
    28.5 (26.9 to 30.4)
    26.7 (24 to 29.1)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1082
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.00001 [27]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.73
    Notes
    [27] - The p-value is based on unstratified log-rank test.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    1076
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00001 [28]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    0.83
    Notes
    [28] - The p-value is based on unstratified log-rank test.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Hazard Ratio is based on stratified Cox proportional hazards model.
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    1088
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05821 [29]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1
    Notes
    [29] - The p-value is based on unstratified log-rank test.

    Secondary: Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review

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    End point title
    Percentage of Participants with a myeloma response by adverse risk cytogenetic risk category based on IRAC review
    End point description
    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place those in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT with cytogenetic adverse risk.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    170
    185
    189
    Units: percentage of participants
        number (not applicable)
    70
    69.7
    58.2
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    359
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02134
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.59
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.59
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02374
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.53

    Secondary: Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review

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    End point title
    Percentage of participants with a myeloma response by favorable hyperdiploidy risk cytogenetic risk category based on IRAC Review
    End point description
    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT with favorable hyperdiploidy risk
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    112
    103
    102
    Units: percentage of participants
        number (not applicable)
    80.4
    81.6
    70.6
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11152
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    3.21
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86336
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.83
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07321
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    3.55

    Secondary: Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review

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    End point title
    Percentage of participants with a myeloma response by normal risk cytogenetic risk category based on IRAC Review
    End point description
    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT population with normal risk.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    148
    131
    141
    Units: percentage of participants
        number (not applicable)
    80.4
    74.8
    61
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.00043
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.55
         upper limit
    4.45
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    279
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.31274
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    2.43
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01936
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.13
         upper limit
    3.19

    Secondary: Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review

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    End point title
    Percentage of participants with a myeloma response by uncertain risk cytogenetic risk category based on IRAC Review
    End point description
    Participants were placed in adverse and non-adverse cytogenetic risk categories at baseline and response rates evaluated. Adverse Risk: t(4;14), t(14;16), del(13q) or monosomy 13, del(17p), 1q gain Favorable Hyperdiploidy: : t(11;14), gains of 5/9/15; Normal: a normal result, gains other than 5/9/15, IgH deletion Uncertain risk: probes used for analysis cannot place participant in any of the other risk categories. Objective response = best overall response including CR, VGPR or PR; A CR is negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is ≥50% reduction of serum M-Protein and urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. ITT population with uncertain risk.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    38
    56
    40
    Units: percentage of participants
        number (not applicable)
    60.5
    76.8
    57.5
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.82128
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    2.8
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11041
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    1.14
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07302
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    5.91

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in QOL or functioning and positive values indicate improvement.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    508 [30]
    507 [31]
    508 [32]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    0.4 ± 23.98
    -1.3 ± 23.93
    1 ± 23.68
        Month 3
    4.8 ± 24.15
    4.7 ± 25.15
    4.3 ± 26.04
        Month 6
    5.9 ± 25.93
    5.4 ± 23.88
    6.1 ± 25.98
        Month 12
    4.8 ± 26.42
    3.2 ± 25.38
    6.5 ± 25.9
        Month 18
    6.4 ± 28.02
    5.7 ± 24.86
    4.8 ± 27.05
        Study discontinuation
    -0.1 ± 27.07
    5 ± 27.33
    0.3 ± 28.07
    Notes
    [30] - Month 1 = 438 Month 3 = 421 Month 6 = 369 Month 12 = 302 Month 18 = 246 Discontinuation = 203
    [31] - Month 1 = 441 Month 3 = 413 Month 6 = 376 Month 12 = 299 Month 18 = 238 Discontinuation = 261
    [32] - Month 1 = 415 Month 3 = 396 Month 6 = 351 Month 12 = 252 Month 18 = 178 Discontinuation = 257
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    511 [33]
    514 [34]
    509 [35]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -1.7 ± 21.11
    -1.4 ± 19.56
    -0.9 ± 21.28
        Month 3
    3.4 ± 23.33
    4.7 ± 22.94
    2.2 ± 23.68
        Month 6
    4.7 ± 25.09
    7.6 ± 22.85
    5.3 ± 24.52
        Month 12
    5 ± 25.65
    7.4 ± 23.4
    6.9 ± 27.22
        Month 18
    6.9 ± 26.71
    6.8 ± 23.58
    8.3 ± 27.1
        Discontinuation Visit
    -0.1 ± 29.7
    3 ± 27.32
    -0.1 ± 27.58
    Notes
    [33] - Month 1 = 445 Month 3 = 426 Month 6 = 376 Month 12 = 307 Month 18 = 247 Discontinuation = 207
    [34] - Month 1 = 449 Month 3 = 421 Month 6 = 382 Month 12 = 302 Month 18 = 243 Discontinuation = 267
    [35] - Month 1 = 419 Month 3 = 396 Month 6 = 352 Month 12 = 253 Month 18 = 183 Discontinuation = 256
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Role Functioning Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Role Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [36]
    508 [37]
    508 [38]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -2.7 ± 29.94
    -4.6 ± 28.2
    -2.4 ± 30.48
        Month 3
    2.4 ± 33.32
    6.3 ± 32.43
    4.1 ± 34.23
        Month 6
    6.3 ± 35.44
    8.6 ± 32.42
    8.2 ± 36.09
        Month 12
    7.8 ± 36.6
    9.4 ± 34.15
    11.8 ± 38.94
        Month 18
    8 ± 35.34
    9.1 ± 34.35
    14.5 ± 39.03
        Discontinuation Visit
    -0.3 ± 39.58
    3.8 ± 36.34
    -1 ± 38.41
    Notes
    [36] - Month 1 = 442 Month 3 = 422 Month 6 = 373 Month 12 = 305 Month 18 = 245 Discontinuation = 206
    [37] - Month 1 = 445 Month 3 = 419 Month 6 = 378 Month 12 = 300 Month 18 = 240 Discontinuation = 264
    [38] - Month 1 = 415 Month 3 = 395 Month 6 = 352 Month 12 = 252 Month 18 = 182 Discontinuation = 256
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [39]
    510 [40]
    510 [41]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    0.6 ± 22.13
    0.1 ± 20.73
    1 ± 21.52
        Month 3
    3.8 ± 22.29
    3.9 ± 22.11
    2.1 ± 22.27
        Month 6
    4.6 ± 24.36
    5.8 ± 22.39
    5.5 ± 22.55
        Month 12
    4.6 ± 24.08
    4.9 ± 22.23
    5.1 ± 22.37
        Month 18
    5.8 ± 25.61
    3.1 ± 23.31
    5.1 ± 22.99
        Discontinuation Visit
    2.6 ± 24.3
    3.7 ± 23.77
    0 ± 24.72
    Notes
    [39] - Month 1 = 443 Month 3 = 423 Month 6 = 375 Month 12 = 305 Month 18 = 246 Discontinuation = 205
    [40] - Month 1 = 446 Month 3 = 415 Month 6 = 379 Month 12 = 301 Month 18 = 242 Discontinuation = 263
    [41] - Month 1 = 419 Month 3 = 397 Month 6 = 351 Month 12 = 254 Month 18 = 179 Discontinuation = 256
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Cognitive Functioning Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Cognitive Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [42]
    510 [43]
    510 [44]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -1.2 ± 21.73
    -1.7 ± 19.08
    -1.8 ± 24.07
        Month 3
    -0.7 ± 22.89
    1.8 ± 20.94
    -1.5 ± 24.02
        Month 6
    -0.9 ± 22.57
    0.9 ± 19.77
    -0.3 ± 23.55
        Month 12
    -1.6 ± 25.05
    -1.2 ± 20.19
    -0.6 ± 22.97
        Month 18
    -2.2 ± 25.61
    -2.8 ± 20.97
    -0.7 ± 23.99
        Discontinuation Visit
    -4.9 ± 27.57
    -2.6 ± 22.34
    -7.1 ± 25.15
    Notes
    [42] - Month 1 = 443 Month 3 = 424 Month 6 = 375 Month 12 = 306 Month 18 = 246 Discontinuation = 206
    [43] - Month 1 = 447 Month 3 = 415 Month 6 = 379 Month 12 = 301 Month 18 = 242 Discontinuation = 263
    [44] - Month 1 = 419 Month 3 = 397 Month 6 = 353 Month 12 = 254 Month 18 = 179 Discontinuation = 256
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Social Functioning Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Social Functioning Scale is scored between 0 and 100, with a high score indicating better functioning/support. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    505 [45]
    503 [46]
    503 [47]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -4.3 ± 29.1
    -2.2 ± 27.44
    -1.4 ± 30.52
        Month 3
    0.7 ± 29.36
    2 ± 30.93
    2.4 ± 30.7
        Month 6
    4 ± 32.48
    5.2 ± 28.5
    3.4 ± 35.24
        Month 12
    2.9 ± 34.96
    3.8 ± 32.29
    5.8 ± 33.68
        Month 18
    4.2 ± 34.99
    3.2 ± 31.67
    6 ± 35.2
        Discontinuation Visit
    -1.2 ± 33.5
    2.7 ± 33.37
    -3.5 ± 33.2
    Notes
    [45] - Month 1 = 439 Month 3 = 419 Month 6 = 374 Month 12 = 305 Month 18 = 247 Discontinuation = 204
    [46] - Month 1 = 441 Month 3 = 410 Month 6 = 374 Month 12 = 298 Month 18 = 239 Discontinuation = 257
    [47] - Month 1 = 414 Month 3 = 389 Month 6 = 348 Month 12 = 252 Month 18 = 177 Discontinuation = 254
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Fatigue Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Fatigue Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    511 [48]
    514 [49]
    512 [50]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    2.6 ± 25.32
    4.4 ± 24.03
    2.8 ± 25.44
        Month 3
    -2.5 ± 28.15
    -3.4 ± 25.16
    -1.8 ± 28.53
        Month 6
    -3.7 ± 28.54
    -5.9 ± 26.37
    -4.5 ± 29.09
        Month 12
    -4.3 ± 29.47
    -2.3 ± 26.63
    -3.9 ± 29.56
        Month 18
    -3.1 ± 29.82
    0.1 ± 29.12
    -4.3 ± 30.05
        Discontinuation Visit
    0.3 ± 29.75
    -1.6 ± 29.11
    2.7 ± 30.15
    Notes
    [48] - Month 1 = 445 Month 3 = 425 Month 6 = 376 Month 12 = 306 Month 18 = 244 Discontinuation = 207
    [49] - Month 1 = 448 Month 3 = 423 Month 6 = 383 Month 12 = 303 Month 18 = 242 Discontinuation = 267
    [50] - Month 1 = 421 Month 3 = 400 Month 6 = 355 Month 12 = 255 Month 18 = 184 Discontinuation = 258
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Pain Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Pain Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Pain Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    511 [51]
    514 [52]
    512 [53]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -5.4 ± 31.89
    -4.4 ± 30.7
    -7.8 ± 30.93
        Month 3
    -13.4 ± 34.28
    -13.1 ± 32.32
    -12.1 ± 31.98
        Month 6
    -14.4 ± 35.64
    -16.1 ± 33.44
    -13.4 ± 34.45
        Month 12
    -14 ± 36.05
    -14.7 ± 32.34
    -14.3 ± 32.85
        Month 18
    -14.4 ± 35.03
    -12.4 ± 35.28
    -14.7 ± 32.81
        Discontinuation Visit
    -8 ± 39.37
    -7.9 ± 37.65
    -6 ± 37.09
    Notes
    [51] - Month 1 = 446 Month 3 = 426 Month 6 = 379 Month 12 = 306 Month 18 = 248 Discontinuation = 207
    [52] - Month 1 = 453 Month 3 = 423 Month 6 = 384 Month 12 = 304 Month 18 = 242 Discontinuation = 266
    [53] - Month 1 = 423 Month 3 = 399 Month 6 = 355 Month 12 = 255 Month 18 = 183 Discontinuation = 259
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Nausea/Vomiting Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Nausea/Vomiting Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    511 [54]
    513 [55]
    512 [56]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    1.8 ± 20.05
    -0.5 ± 23.19
    4 ± 22.91
        Month 3
    -1.1 ± 19.42
    -2.5 ± 21.92
    -1.2 ± 19.89
        Month 6
    -1.3 ± 18.53
    -4 ± 21.52
    -3.9 ± 19.57
        Month 12
    -2.2 ± 17.16
    -3.6 ± 18.86
    -3.9 ± 19.09
        Month 18
    -2.3 ± 19.2
    -2.7 ± 18.92
    -3.9 ± 19.44
        Discontinuation Visit
    0.4 ± 21.43
    -4.2 ± 24.37
    1 ± 21.46
    Notes
    [54] - Month 1 = 446 Month 3 = 426 Month 6 = 377 Month 12 = 306 Month 18 = 246 Discontinuation = 206
    [55] - Month 1 = 449 Month 3 = 422 Month 6 = 381 Month 12 = 302 Month 18 = 242 Discontinuation = 267
    [56] - Month 1 = 424 Month 3 = 399 Month 6 = 355 Month 12 = 255 Month 18 = 184 Discontinuation = 258
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnoea Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1(Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [57]
    508 [58]
    506 [59]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    0.9 ± 30.87
    3.6 ± 29.85
    4.2 ± 32.04
        Month 3
    -0.8 ± 31.87
    -1.9 ± 29.45
    2 ± 32.49
        Month 6
    -2.3 ± 33.12
    -2.9 ± 29.66
    0.1 ± 30.29
        Month 12
    -3.5 ± 30.97
    -1.6 ± 29.23
    -1.6 ± 32.76
        Month 18
    -1.8 ± 32.73
    2.9 ± 28.33
    0.4 ± 32.68
        Discontinuation Visit
    -1 ± 37.42
    0.8 ± 31.01
    7.8 ± 33.72
    Notes
    [57] - Month 1 = 439 Month 3 = 423 Month 6 = 372 Month 12 = 303 Month 18 = 244 Discontinuation = 204
    [58] - Month 1 = 440 Month 3 = 417 Month 6 = 375 Month 12 = 294 Month 18 = 238 Discontinuation = 262
    [59] - Month 1 = 417 Month 3 = 390 Month 6 = 351 Month 12 = 253 Month 18 = 182 Discontinuation = 255
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Insomnia Domain

    Close Top of page
    End point title
    Change From Baseline in the EORTC QLQ-C30 Insomnia Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Insomnia Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate improvement in symptoms and positive values indicate worsening symptoms. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    510 [60]
    513 [61]
    511 [62]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    2.1 ± 33.34
    3.2 ± 34.32
    -10.5 ± 30.47
        Month 3
    0.2 ± 35.11
    -1.3 ± 33.54
    -8.9 ± 35.28
        Month 6
    -1.2 ± 34.84
    -1.9 ± 31.43
    -11.6 ± 32.96
        Month 12
    -1 ± 34.78
    1.1 ± 32.47
    -9.6 ± 31
        Month 18
    -0.5 ± 37.11
    1.4 ± 35.72
    -6 ± 34.42
        Discontinuation Visit
    -5.2 ± 36.47
    -1.6 ± 31.27
    -4.5 ± 36.98
    Notes
    [60] - Month 1 = 443 Month 3 = 422 Month 6 = 374 Month 12 = 303 Month 18 = 243 Discontinuation = 204
    [61] - Month 1 = 447 Month 3 = 420 Month 6 = 382 Month 12 = 300 Month 18 = 241 Discontinuation = 265
    [62] - Month 1 = 421 Month 3 = 399 Month 6 = 353 Month 12 = 253 Month 18 = 182 Discontinuation = 254
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Appetite Loss Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Appetite Loss Scale is scored between 0 and 100, with a high score indicating a higher level of appetite loss. Negative change from Baseline values indicate improvement in appetite and positive values indicate worsening of appetite.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [63]
    512 [64]
    510 [65]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    1.3 ± 33.46
    2.9 ± 31.87
    1 ± 32.35
        Month 3
    -5.9 ± 38.34
    -3.3 ± 35.25
    -6.2 ± 35.03
        Month 6
    -9.8 ± 40.02
    -8.6 ± 33.98
    -13.5 ± 35.98
        Month 12
    -7.3 ± 37.07
    -6.4 ± 35.3
    -10.5 ± 34.16
        Month 18
    -8.1 ± 35.97
    -5.1 ± 33.29
    -12.2 ± 31.88
        Discontinuation Visit
    -1 ± 36.77
    -7.5 ± 37.49
    -2.6 ± 37.18
    Notes
    [63] - Month 1 = 442 Month 3 = 424 Month 6 = 374 Month 12 = 307 Month 18 = 246 Discontinuation = 203
    [64] - Month 1 = 447 Month 3 = 421 Month 6 = 381 Month 12 = 299 Month 18 = 241 Discontinuation = 267
    [65] - Month 1 = 422 Month 3 = 396 Month 6 = 354 Month 12 = 253 Month 18 = 183 Discontinuation = 257
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Constipation Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Constipation Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Constipation Scale is scored between 0 and 100, with a high score indicating a higher level of constipation. Negative change from Baseline values indicate improvement in constipation and positive values indicate worsening of constipation.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    508 [66]
    511 [67]
    510 [68]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    8.3 ± 36.74
    6.3 ± 36.18
    18.4 ± 41.23
        Month 3
    1.8 ± 37.53
    0 ± 37.02
    13.9 ± 39.3
        Month 6
    -2.4 ± 37.51
    -5.1 ± 37.39
    6.8 ± 40.41
        Month 12
    -2.4 ± 38.79
    -5.2 ± 38.09
    3.7 ± 38.28
        Month 18
    -4.5 ± 35.42
    -5.9 ± 36.65
    0 ± 37.06
        Discontinuation Visit
    -7.9 ± 39.98
    -7.5 ± 39.2
    -2.2 ± 38.86
    Notes
    [66] - Month 1 = 441 Month 3 = 422 Month 6 = 373 Month 12 = 304 Month 18 = 246 Discontinuation = 203
    [67] - Month 1 = 446 Month 3 = 416 Month 6 = 377 Month 12 = 301 Month 18 = 242 Discontinuation = 261
    [68] - Month 1 = 419 Month 3 = 397 Month 6 = 353 Month 12 = 255 Month 18 = 179 Discontinuation = 257
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Diarrhea Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Diarrhea Scale is scored between 0 and 100, with a high score indicating a higher level of diarrhea. Negative change from Baseline values indicate improvement in diarrhea and positive values indicate worsening of diarrhea. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    508 [69]
    509 [70]
    510 [71]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    3.8 ± 25.53
    2.3 ± 24.94
    -0.6 ± 18.79
        Month 3
    3.7 ± 24.99
    3.4 ± 27.27
    -2.4 ± 18.61
        Month 6
    8.2 ± 28.36
    6 ± 27.95
    -2.2 ± 21.19
        Month 12
    11.8 ± 31.35
    9.1 ± 28.74
    -2.5 ± 17.26
        Month 18
    14.8 ± 31.2
    10.9 ± 30.96
    -1.7 ± 17.46
        Discontinuation Visit
    10.8 ± 29.56
    6.4 ± 31.38
    -0.5 ± 19.39
    Notes
    [69] - Month 1 = 438 Month 3 = 419 Month 6 = 373 Month 12 = 303 Month 18 = 246 Discontinuation = 206
    [70] - Month 1 = 444 Month 3 = 413 Month 6 = 376 Month 12 = 299 Month 18 = 241 Discontinuation = 261
    [71] - Month 1 = 416 Month 3 = 395 Month 6 = 351 Month 12 = 253 Month 18 = 178 Discontinuation = 255
    No statistical analyses for this end point

    Secondary: Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain

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    End point title
    Change From Baseline in the EORTC QLQ-C30 Financial Difficulties Domain
    End point description
    The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used in clinical research to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Financial Difficulties Scale is scored between 0 and 100, with a high score indicating a higher level of financial difficulties. Negative change from Baseline values indicate improvement in financial difficulties and positive values indicate worsening of financial difficulties. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    501 [72]
    504 [73]
    502 [74]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    2.1 ± 21.43
    -0.3 ± 20.59
    0.5 ± 22.98
        Month 3
    1.9 ± 23.09
    -0.4 ± 21.88
    1.9 ± 21.48
        Month 6
    1.4 ± 22.92
    -0.3 ± 21.24
    0.7 ± 24.57
        Month 12
    0.4 ± 23.99
    1.6 ± 23.28
    1.1 ± 23.16
        Month 18
    2 ± 22.23
    1.8 ± 23.3
    0.4 ± 21.2
        Discontinuation Visit
    1.9 ± 27.19
    0.5 ± 23.84
    5 ± 24.82
    Notes
    [72] - Month 1 = 435 Month 3 = 413 Month 6 = 370 Month 12 = 302 Month 18 = 244 Discontinuation = 197
    [73] - Month 1 = 441 Month 3 = 407 Month 6 = 373 Month 12 = 299 Month 18 = 239 Discontinuation = 255
    [74] - Month 1 = 409 Month 3 = 388 Month 6 = 345 Month 12 = 249 Month 18 = 174 Discontinuation = 254
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms Scale
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score indicates more severe disease symptom(s). Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    510 [75]
    512 [76]
    511 [77]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -4 ± 18.75
    -4.1 ± 19.37
    -4.4 ± 19.04
        Month 3
    -9.1 ± 21.66
    -10 ± 19.97
    -7 ± 20.43
        Month 6
    -8.8 ± 20.89
    -9.9 ± 20.94
    -7.9 ± 21.94
        Month 12
    -7.8 ± 21.74
    -8.7 ± 20.29
    -6.5 ± 21.58
        Month 18
    -8.7 ± 23.5
    -6.2 ± 23.3
    -7.9 ± 21.26
        Discontinuation Visit
    -3.5 ± 24.82
    -4.5 ± 24.9
    -3.7 ± 23.54
    Notes
    [75] - Month 1 = 442 Month 3 = 422 Month 6 = 375 Month 12 = 306 Month 18 = 249 Discontinuation = 205
    [76] - Month 1 = 448 Month 3 = 418 Month 6 = 381 Month 12 = 303 Month 18 = 243 Discontinuation = 266
    [77] - Month 1 = 421 Month 3 = 396 Month 6 = 353 Month 12 = 254 Month 18 = 183 Discontinuation = 259
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Side Effects Treatment Scale
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; a higher score represents a more severe overall side effect of treatment. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    509 [78]
    511 [79]
    510 [80]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    2.5 ± 13.72
    4 ± 14.89
    5.6 ± 15
        Month 3
    1 ± 15.23
    1.2 ± 14.67
    3.5 ± 15.4
        Month 6
    1.7 ± 15.58
    -0.4 ± 14.39
    2.9 ± 17.28
        Month 12
    1.9 ± 14.49
    1.2 ± 16.2
    4.7 ± 17.17
        Month 18
    2.2 ± 15.63
    2.3 ± 17.36
    4.3 ± 16.37
        Discontinuation Visit
    0.6 ± 15.85
    -1 ± 15.81
    3.8 ± 16.52
    Notes
    [78] - Month 1 = 438 Month 3 = 421 Month 6 = 374 Month 12 = 305 Month 18 = 247 Discontinuation = 205
    [79] - Month 1 = 446 Month 3 = 417 Month 6 = 378 Month 12 = 301 Month 18 = 243 Discontinuation = 262
    [80] - Month 1 = 418 Month 3 = 393 Month 6 = 351 Month 12 = 254 Month 18 = 182 Discontinuation = 258
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Future Perspective Scale
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the future perspective scale, a higher score indicates a better perspective of the future. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    504 [81]
    508 [82]
    509 [83]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    4.7 ± 22.17
    3.9 ± 20.94
    3.3 ± 23.2
        Month 3
    8.5 ± 23.28
    9.2 ± 22.95
    6.3 ± 25.06
        Month 6
    9.8 ± 23.67
    12.3 ± 24.84
    8 ± 25.26
        Month 12
    10.8 ± 21.9
    12.1 ± 24.41
    10 ± 26.3
        Month 18
    12.7 ± 23.96
    11.7 ± 24.76
    9.5 ± 21.75
        Discontinuation Visit
    5.8 ± 25.91
    8.8 ± 26.71
    3.2 ± 27.13
    Notes
    [81] - Month 1 = 433 Month 3 = 416 Month 6 = 367 Month 12 = 303 Month 18 = 245 Discontinuation = 203
    [82] - Month 1 = 443 Month 3 = 414 Month 6 = 377 Month 12 = 299 Month 18 = 239 Discontinuation = 264
    [83] - Month 1 = 415 Month 3 = 394 Month 6 = 350 Month 12 = 249 Month 18 = 179 Discontinuation = 254
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale

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    End point title
    Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Body Image Scale
    End point description
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in patients with multiple myeloma. EORTC QLQ-MY20 includes four scales: disease symptoms, treatment side-effects, future perspective, and body image. Questions used a 4-point scale (from 1 'Not at All' to 4 'Very Much'). Scores were averaged, and transformed to a 0-100 scale; for the body image scale, a higher score indicates a better body image. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    492 [84]
    498 [85]
    504 [86]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    -4.5 ± 29.44
    -1.5 ± 27.19
    -1.6 ± 29.97
        Month 3
    -1.7 ± 27.54
    0.8 ± 26.23
    -3 ± 29.38
        Month 6
    -1.4 ± 27.84
    1.5 ± 29.72
    -2.8 ± 33.07
        Month 12
    -1.4 ± 29.6
    -0.4 ± 31.64
    -2.6 ± 31.96
        Month 18
    -2.3 ± 28.09
    -0.3 ± 31.04
    -1.1 ± 33.6
        Discontinuation Visit
    -5.6 ± 34.29
    1.8 ± 30.66
    -5.6 ± 33.73
    Notes
    [84] - Month 1 = 417 Month 3 = 404 Month 6 = 357 Month 12 = 292 Month 18 = 236 Discontinuation = 197
    [85] - Month 1 = 422 Month 3 = 398 Month 6 = 366 Month 12 = 284 Month 18 = 227 Discontinuation = 253
    [86] - Month 1 = 408 Month 3 = 387 Month 6 = 347 Month 12 = 242 Month 18 = 174 Discontinuation = 250
    No statistical analyses for this end point

    Secondary: Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score

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    End point title
    Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Health Utility Index Score
    End point description
    EQ-5D is a self-administered questionnaire that assesses health-related quality of life. The EQ-5D descriptive health profile comprises five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 levels of response: No problem (1), some problems (2), and extreme problems (3). A unique EQ-5D health state is defined by combining one level from each of the five dimensions into a single utility index score. EQ-5D index values range from -0.59 to 1.00 where higher EQ-5D scores represent better health status. A positive change from baseline score indicates improvement in health status and better health state. Includes the ITT population with available data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (Baseline), then Months 1, 3, 6, 12, 18 and Discontinuation visit
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    490 [87]
    492 [88]
    490 [89]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 1
    0 ± 0.29
    0 ± 0.31
    0 ± 0.28
        Month 3
    0.1 ± 0.33
    0.1 ± 0.32
    0.1 ± 0.32
        Month 6
    0.1 ± 0.32
    0.1 ± 0.31
    0.1 ± 0.34
        Month 12
    0.1 ± 0.33
    0.1 ± 0.31
    0.1 ± 0.35
        Month 18
    0.1 ± 0.36
    0.1 ± 0.32
    0.1 ± 0.35
        Discontinuation Visit
    0 ± 0.4
    0 ± 0.35
    0 ± 0.39
    Notes
    [87] - Month 1 = 400 Month 3 = 389 Month 6 = 341 Month 12 = 283 Month 18 = 219 Discontinuation = 186
    [88] - Month 1 = 420 Month 3 = 383 Month 6 = 351 Month 12 = 278 Month 18 = 230 Discontinuation = 231
    [89] - Month 1 = 381 Month 3 = 366 Month 6 = 323 Month 12 = 231 Month 18 = 170 Discontinuation = 240
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

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    End point title
    Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year
    End point description
    HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of inpatient hospitalizations per patient year was calculated as the total number of hospitalizations divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient. HRU data not analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (randomization) up to last visit completed 25 July 2016
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    0 [90]
    0 [91]
    0 [92]
    Units: hospitalizations per patient year
        number (not applicable)
    Notes
    [90] - 0 = HRU data not analyzed.
    [91] - 0 = HRU data not analyzed.
    [92] - 0 = HRU data not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs) During the Active Treatment Phase

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    End point title
    Number of Participants With Adverse Events (AEs) During the Active Treatment Phase
    End point description
    A treatment emergent adverse event (TEAE) is any AE occurring or worsening on or after the first treatment of any study drug, and within 30 days after the last dose of the last study drug. Severity grades according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE) on a 1-5 scale: Grade 1= Mild AE, Grade 2= Moderate AE, Grade 3= Severe AE, Grade 4= Life-threatening or disabling AE, Grade 5=Death related to AE. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. Safety population included all subjects who received at least one dose of treatment in any arm.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through 28 days following the discontinuation visit from active treatment phase; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    532
    540
    541
    Units: Participants
        ≥ 1 adverse event (AE)
    529
    536
    539
        ≥ 1 grade (Gr) 3 or 4 AE
    453
    433
    480
        ≥ 1 grade (Gr) 5 AE
    50
    36
    38
        ≥ 1 serious adverse event (SAE)
    359
    308
    270
        ≥ 1 AE related to Len/Dex/MPT
    506
    501
    527
        ≥ 1 AE related to Lenalidomide
    482
    481
    0
        ≥ 1 AE related to dexamethasone
    429
    410
    0
        ≥ 1 AE related to melphalan
    0
    0
    441
        ≥ 1 AE related to prednisone
    0
    0
    326
        ≥ 1 AE related to thalidomide
    0
    0
    493
        ≥1 AE related to Len/Dex or MPT
    269
    269
    145
        ≥ 1 Gr 3 or 4 AE related to Len/Dex/MPT
    373
    326
    423
        ≥ 1 grade 3 or 4 AE related to Lenalidomide
    342
    290
    0
        ≥ 1 grade 3 or 4 AE related to dexamethasone
    229
    177
    0
        ≥ 1 grade 3 or 4 AE related to melphalan
    0
    0
    307
        ≥ 1 grade 3 or 4 AE related to prednisone
    0
    0
    118
        ≥ 1 grade 3 or 4 AE related to Thalidomide
    0
    0
    316
        ≥1 Gr 3 or 4 AE related to Len/Dex or MPT
    131
    104
    49
        ≥ 1 Grade 5 AE related to Len/Dex/MPT
    17
    11
    10
        ≥ 1 Grade 5 AE related to Lenalidomide
    12
    9
    0
        ≥ 1 Grade 5 AE related to Dexamethasone
    16
    7
    0
        ≥ 1 Grade 5 AE related to melphalan
    0
    0
    6
        ≥ 1 Grade 5 AE related to prednisone
    0
    0
    5
        ≥ 1 Grade 5 AE related to Thalidomide
    0
    0
    5
        ≥ 1 Grade 5 AE related to Len/Dex or MPT
    11
    5
    2
        ≥1 SAE related to Len/Dex/MPT
    195
    158
    142
        ≥1 SAE related to Lenalidomide
    165
    130
    0
        ≥1 SAE related to dexamethasone
    130
    97
    0
        ≥1 SAE related to melphalan
    0
    0
    75
        ≥1 SAE related to prednisone
    0
    0
    62
        ≥1 SAE related to thalidomide
    0
    0
    94
        ≥1 SAE related to Len/Dex or MPT
    95
    64
    27
        ≥1 AE leading to Len/Dex/MPT Withdrawal
    157
    109
    153
        ≥1 AE leading to Lenalidomide withdrawal
    109
    93
    0
        ≥1 AE leading to dexamethasone withdrawal
    152
    104
    0
        ≥1 AE leading to melphalan withdrawal
    0
    0
    83
        ≥1 AE leading to prednisone withdrawal
    0
    0
    78
        ≥1 AE leading to Thalidomide withdrawal
    0
    0
    146
        ≥1AE leading to Len/Dex OR MPT Withdrawal
    96
    84
    71
        ≥1 AE leading to Len/Dex/MPT reduction
    279
    214
    348
        ≥1 AE leading to Lenalidomide reduction
    203
    155
    0
        ≥1 AE leading to dexamethasone reduction
    170
    118
    0
        ≥1 AE leading to melphalan reduction
    0
    0
    199
        ≥1 AE leading to prednisone reduction
    0
    0
    47
        ≥1 AE leading to thalidomide reduction
    0
    0
    254
        ≥1AE leading to Len/Dex OR MPT reduction
    30
    20
    2
        ≥1 AE leading to Len/Dex/ MPT interruption
    368
    321
    419
        ≥1 AE leading to Lenalidomide interruption
    353
    301
    0
        ≥1 AE leading to dexamethasone interruption
    319
    280
    0
        ≥1 AE leading to melphalan interruption
    0
    0
    328
        ≥1 AE leading to prednisone interruption
    0
    0
    324
        ≥1 AE leading to Thalidomide interruption
    0
    0
    388
        ≥1 AE leading to Len/Dex or MPT interruption
    290
    241
    249
    No statistical analyses for this end point

    Secondary: Shift from baseline to most extreme postbaseline value in creatinine clearance (CrCl) during the active treatment phase

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    End point title
    Shift from baseline to most extreme postbaseline value in creatinine clearance (CrCl) during the active treatment phase
    End point description
    Renal function was assessed for participants from baseline to the most extreme value in creatinine clearance calculated using the Cockcroft-Gault estimation. Safety Population with baseline and postbaseline CrCl data.
    End point type
    Secondary
    End point timeframe
    Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    494
    506
    484
    Units: participants
        CrCl< 30 mL/min to CrCl< 30 mL/min
    15
    17
    19
        CrCl < 30 mL/min to CrCl ≥ 30 but < 50 mL/min
    18
    14
    19
        CrCl < 30 mL/min to CrCl ≥ 50 but < 80 mL/min
    7
    8
    5
        CrCl< 30 mL/min to ≥ 80 mL/min
    2
    2
    0
        CrCl≥ 30 but < 50 mL/min to < 30 mL/min
    1
    2
    0
        CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 30 but < 50 mL
    37
    41
    41
        CrCl ≥ 30 but < 50 mL/min to CrCl ≥ 50 but < 80 mL
    67
    55
    65
        CrCl ≥ 30 but < 50 mL/min to ≥ 80 mL/min
    9
    12
    2
        CrCl ≥ 50 but < 80 mL to CrCl< 30 mL/min
    0
    0
    0
        CrCl ≥ 50 but < 80 mL to CrCl ≥ 30 but < 50 mL/min
    4
    1
    4
        CrCl ≥ 50 but < 80 mL to CrCl ≥ 50 but < 80 mL/min
    112
    130
    102
        CrCl ≥ 50 but < 80 mL to ≥ 80 mL/min
    107
    99
    97
        CrCl ≥ 80 mL/min to CrCl< 30 mL/min
    0
    1
    0
        CrCl ≥ 80 mL/min to CrCl ≥ 30 but < 50 mL/min
    0
    0
    0
        CrCl ≥ 80 mL/min to CrCl ≥ 50 but < 80 mL/min
    6
    10
    9
        CrCl ≥ 80 mL/min to CrCl ≥ 80 mL/min
    109
    114
    121
    No statistical analyses for this end point

    Secondary: Shift from baseline to most extreme postbaseline value in absolute neutrophil count during the active treatment phase

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    End point title
    Shift from baseline to most extreme postbaseline value in absolute neutrophil count during the active treatment phase
    End point description
    Neutrophil counts was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety Population; includes participants with baseline and postbaseline absolute neutrophil laboratory test grade information.
    End point type
    Secondary
    End point timeframe
    Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    525
    534
    526
    Units: participants
        Normal Baseline Grade to Normal Postbaseline Grade
    103
    133
    37
        Normal Baseline Grade to Grade 1 postbaseline
    96
    85
    79
        Normal Baseline Grade to Grade 2 postbaseline
    121
    109
    128
        Normal Baseline Grade to Grade 3 postbaseline
    70
    71
    141
        Normal Baseline Grade to Grade 4 postbaseline
    21
    30
    45
        Grade 1 Baseline to Normal postbaseline Grade
    7
    6
    2
        Grade 1 Baseline to Grade 1 postbaseline
    8
    11
    2
        Grade 1 Baseline to Grade 2 postbaseline
    17
    15
    11
        Grade1 Baseline Grade to Grade3 postbaseline Grade
    25
    30
    20
        Grade 1 Baseline to Grade 4 postbaseline
    9
    4
    21
        Grade 2 Baseline to normal postbaseline Grade
    1
    0
    0
        Grade 2 Baseline to Grade 1 postbaseline
    1
    1
    1
        Grade 2 Baseline to Grade 2 postbaseline
    14
    11
    7
        Grade 2 Baseline to Grade 3 postbaseline
    18
    18
    21
        Grade 2 Baseline to Grade 4 postbaseline
    9
    5
    10
        Grade 3 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 3 Baseline to Grade 1 postbaseline
    0
    0
    0
        Grade 3 Baseline to Grade 2 postbaseline
    2
    1
    0
        Grade 3 Baseline to Grade 3 postbaseline
    2
    2
    0
        Grade 3 Baseline to Grade 4 postbaseline
    0
    2
    1
        Grade 4 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 4 Baseline to Grade1 postbaseline Grade 1
    1
    0
    0
        Grade 4 Baseline to Grade 2 postbaseline
    0
    0
    0
        Grade 4 Baseline to Grade 3 postbaseline
    0
    0
    0
        Grade 4 Baseline Grade to Grade 4 postbaseline
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Shift from baseline to most extreme in hemoglobin during the active treatment phase

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    End point title
    Shift from baseline to most extreme in hemoglobin during the active treatment phase
    End point description
    Hemoglobin was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety Population; Includes participants with baseline and postbaseline hemoglobin laboratory test grade information.
    End point type
    Secondary
    End point timeframe
    Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    527
    535
    526
    Units: participants
        Normal Baseline Grade to Normal Postbaseline Grade
    6
    10
    9
        Normal Baseline Grade to Grade 1 postbaseline
    39
    30
    25
        Normal Baseline Grade to Grade 2 postbaseline
    8
    8
    4
        Normal Baseline Grade to Grade 3 postbaseline
    0
    1
    1
        Normal Baseline Grade to Grade 4 postbaseline
    0
    0
    0
        Grade 1 Baseline to Normal postbaseline
    0
    0
    0
        Grade 1 Baseline to Grade 1 postbaseline
    106
    126
    110
        Grade 1 Baseline to Grade 2 postbaseline
    128
    123
    123
        Grade 1 Baseline to Grade 3 postbaseline
    25
    17
    20
        Grade 1 Baseline to Grade 4 postbaseline
    2
    5
    4
        Grade 2 Baseline to normal postbaseline Grade
    0
    0
    0
        Grade 2 Baseline to Grade 1 postbaseline
    8
    12
    14
        Grade 2 Baseline to Grade 2 postbaseline
    125
    135
    133
        Grade 2 Baseline to Grade 3 postbaseline
    48
    41
    47
        Grade 2 Baseline to Grade 4 postbaseline
    4
    9
    11
        Grade 3 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 3 Baseline to Grade 1 postbaseline
    0
    1
    0
        Grade 3 Baseline to Grade 2 postbaseline
    12
    4
    10
        Grade 3 Baseline to Grade 3 postbaseline
    10
    8
    10
        Grade 3 Baseline to Grade 4 postbaseline
    5
    3
    2
        Grade 4 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 4 Baseline to Grade 1 postbaseline
    0
    0
    0
        Grade 4 Baseline to Grade 2 postbaseline
    0
    0
    1
        Grade 4 Baseline to Grade 3 postbaseline
    0
    1
    0
        Grade 4 Baseline to Grade 4 postbaseline
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Shift from baseline to most extreme postbaseline extreme value in platelet count during the active treatment phase

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    End point title
    Shift from baseline to most extreme postbaseline extreme value in platelet count during the active treatment phase
    End point description
    Improvement in platelets was assessed for participants from baseline grade to most extreme severity grade using the NCI CTCAE v 3.0 grading scale. Safety population; includes participants with baseline and postbaseline platelet laboratory test grade information.
    End point type
    Secondary
    End point timeframe
    Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    527
    535
    526
    Units: participants
        Normal Baseline Grade to Normal Postbaseline Grade
    197
    197
    165
        Normal Baseline Grade to Grade 1 postbaseline
    216
    211
    208
        Normal Baseline Grade to Grade 2 postbaseline
    24
    30
    27
        Normal Baseline Grade to Grade 3 postbaseline
    15
    12
    31
        Normal Baseline Grade to Grade 4 postbaseline
    4
    5
    11
        Grade 1 Baseline to Normal postbaseline Grade
    1
    3
    6
        Grade 1 Baseline to Grade 1 postbaseline
    34
    38
    51
        Grade 1 Baseline to Grade 2 postbaseline
    15
    19
    7
        Grade 1 Baseline to Grade 3 postbaseline
    10
    12
    10
        Grade 1 Baseline to Grade 4 postbaseline
    2
    1
    1
        Grade 2 Baseline to normal postbaseline Grade
    0
    0
    0
        Grade 2 Baseline to Grade 1 postbaseline
    0
    1
    2
        Grade 2 Baseline to Grade 2 postbaseline
    3
    3
    1
        Grade 2 Baseline to Grade 3 postbaseline
    3
    2
    2
        Grade 2 Baseline to Grade 4 postbaseline
    1
    0
    2
        Grade 3 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 3 Baseline to Grade 1 postbaseline
    0
    0
    0
        Grade 3 Baseline to Grade 2 postbaseline
    0
    0
    1
        Grade 3 Baseline to Grade 3 postbaseline
    0
    0
    1
        Grade 3 Baseline to Grade 4 postbaseline
    2
    1
    0
        Grade 4 Baseline to Normal postbaseline Grade
    0
    0
    0
        Grade 4 Baseline to Grade 1 postbaseline
    0
    0
    0
        Grade 4 Baseline to Grade 2 postbaseline
    0
    0
    0
        Grade 4 Baseline to Grade 3 postbaseline
    0
    0
    0
        Grade 4 Baseline to Grade 4 postbaseline
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Improvement of infection rate by observing the historical data compared to the clinical data base

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    End point title
    Improvement of infection rate by observing the historical data compared to the clinical data base
    End point description
    Improvement of infection rate by observing historical data compared to the data within the clinical database was not analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to end of treatment or the data cut off of 24 May 2013; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    0 [93]
    0 [94]
    0 [95]
    Units: participants
        number (not applicable)
    Notes
    [93] - Data for infection rate was not analyzed.
    [94] - Data for infection rate was not analyzed.
    [95] - Data for infection rate was not analyzed.
    No statistical analyses for this end point

    Secondary: Percentage of participants with an objective response after second-line anti-myeloma treatment at the Time of Final Analysis

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    End point title
    Percentage of participants with an objective response after second-line anti-myeloma treatment at the Time of Final Analysis
    End point description
    Objective response according to IMWG Uniform Response Criteria was defined as a best overall response including a complete response (CR), very good partial response (VGPR) or partial response (PR) based on the Investigators Review. A CR is defined as: negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; A VGPR is serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein level <100 mg/24 hours; A PR is: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. Includes ITT population that received second-line AMT.
    End point type
    Secondary
    End point timeframe
    Disease response was assessed every 28 days until end of treatment or the data cut-off date of 21 January 2016; median duration of treatment was 80.2 weeks in the Rd arm; 72 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    End point values
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone Rd18 Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects analysed
    299
    377
    381
    Units: percentage of participants
        number (not applicable)
    46.2
    53.1
    45.7
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    680
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.93824
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.38
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Lenalidomide and Low-Dose Dexamethasone (Rd) v Lenalidomide and Dexamethasone Rd18
    Number of subjects included in analysis
    676
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08836
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.03
    Statistical analysis title
    Statistical Analysis 3
    Comparison groups
    Lenalidomide and Dexamethasone Rd18 v Melphalan + Prednisone + Thalidomide (MPT)
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04974
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    1.79

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug treatment to at least 28 days after discontinuation of active treatment for those not continuing in the PFS phase; Up to the last study visit of 14 July 2016.
    Adverse event reporting additional description
    Median duration of treatment was 80.2 weeks in the Rd arm, 72.0 weeks in the Rd18 arm and 67.1 weeks in the MPT arm.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Lenalidomide and Low-Dose Dexamethasone (Rd)
    Reporting group description
    Subjects received 25 mg lenalidomide (R) PO QD on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO QD on days 1, 8, 15, and 22 of a 28-day cycle until disease progression; (subjects > 75 years of age received 20 mg dexamethasone).

    Reporting group title
    Lenalidomide and Dexamethasone (Rd18)
    Reporting group description
    Subjects received 25 mg lenalidomide (R) PO on days 1 to 21 of each 28-day treatment cycle plus 40 mg dexamethasone (d) PO daily on days 1, 8, 15, and 22 of a 28-day cycle for 18 four-week cycle or until disease progression; (participants > 75 years of age received 20 mg dexamethasone).

    Reporting group title
    Melphalan + Prednisone + Thalidomide (MPT)
    Reporting group description
    Subjects received melphalan (M) 0.25 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles plus prednisone (P) at 2 mg/kg PO QD on days 1 to 4 of each 42-day cycle up to 12 cycles and thalidomide (T) 200 mg PO QD on days 1 to 41 of each 42-day cycle for up to 12 cycles until progressive PD.

    Serious adverse events
    Lenalidomide and Low-Dose Dexamethasone (Rd) Lenalidomide and Dexamethasone (Rd18) Melphalan + Prednisone + Thalidomide (MPT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    378 / 532 (71.05%)
    308 / 540 (57.04%)
    270 / 541 (49.91%)
         number of deaths (all causes)
    55
    36
    38
         number of deaths resulting from adverse events
    17
    11
    10
    Vascular disorders
    AORTIC ANEURYSM
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC ANEURYSM RUPTURE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    AORTIC DISSECTION
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ARTERIAL HAEMORRHAGE
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    19 / 532 (3.57%)
    11 / 540 (2.04%)
    8 / 541 (1.48%)
         occurrences causally related to treatment / all
    18 / 19
    10 / 11
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    8 / 532 (1.50%)
    7 / 540 (1.30%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOVOLAEMIC SHOCK
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    3 / 532 (0.56%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERY ANEURYSM
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERY THROMBOSIS
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PHLEBITIS
         subjects affected / exposed
    2 / 532 (0.38%)
    0 / 540 (0.00%)
    5 / 541 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SHOCK
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOPHLEBITIS
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOPHLEBITIS SUPERFICIAL
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENOUS THROMBOSIS
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE LYMPHOCYTIC LEUKAEMIA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACUTE MYELOID LEUKAEMIA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    11 / 532 (2.07%)
    4 / 540 (0.74%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    8 / 24
    2 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER CANCER
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER TRANSITIONAL CELL CARCINOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BOWEN'S DISEASE
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    1 / 532 (0.19%)
    2 / 540 (0.37%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER IN SITU
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CANCER PAIN
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARCINOID TUMOUR OF THE APPENDIX
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CARDIAC MYXOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLON ADENOMA
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER METASTATIC
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COLON CANCER STAGE IV
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL CANCER METASTATIC
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENDOMETRIAL CANCER STAGE III
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRIC CANCER
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL NEOPLASM
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HEPATIC NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LENTIGO MALIGNA
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEUKAEMIA PLASMACYTIC
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA METASTATIC
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG ADENOCARCINOMA STAGE IV
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG CANCER METASTATIC
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG NEOPLASM
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG SQUAMOUS CELL CARCINOMA STAGE I
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUNG SQUAMOUS CELL CARCINOMA STAGE UNSPECIFIED
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENINGIOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    METASTATIC MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MULTIPLE MYELOMA
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    MYELODYSPLASTIC SYNDROME
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEOPLASM SWELLING
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL ADENOCARCINOMA
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ORAL NEOPLASM BENIGN
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLASMACYTOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    3 / 541 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    PROSTATE CANCER
         subjects affected / exposed
    2 / 532 (0.38%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER RECURRENT
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATIC ADENOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RECTAL CANCER
         subjects affected / exposed
    2 / 532 (0.38%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SALIVARY GLAND CANCER
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SMALL INTESTINE CARCINOMA METASTATIC
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    16 / 532 (3.01%)
    5 / 540 (0.93%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    20 / 37
    2 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TRANSITIONAL CELL CANCER OF THE RENAL PELVIS AND URETER
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    TUMOUR FLARE
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    AMYLOIDOSIS
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANAPHYLACTIC SHOCK
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    12 / 532 (2.26%)
    2 / 540 (0.37%)
    5 / 541 (0.92%)
         occurrences causally related to treatment / all
    2 / 16
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHEST DISCOMFORT
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CHILLS
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    3 / 532 (0.56%)
    3 / 540 (0.56%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 3
    1 / 3
    1 / 1
    FATIGUE
         subjects affected / exposed
    3 / 532 (0.56%)
    3 / 540 (0.56%)
    3 / 541 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 4
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    16 / 532 (3.01%)
    13 / 540 (2.41%)
    12 / 541 (2.22%)
         occurrences causally related to treatment / all
    7 / 17
    4 / 17
    5 / 16
         deaths causally related to treatment / all
    1 / 2
    0 / 4
    1 / 6
    GENERALISED OEDEMA
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERPYREXIA
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTHERMIA
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTHERMIA
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLAMMATION
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INJECTION SITE HAEMORRHAGE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MULTI-ORGAN FAILURE
         subjects affected / exposed
    0 / 532 (0.00%)
    3 / 540 (0.56%)
    3 / 541 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    1 / 3
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    4 / 532 (0.75%)
    4 / 540 (0.74%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    5 / 532 (0.94%)
    2 / 540 (0.37%)
    3 / 541 (0.55%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    5 / 532 (0.94%)
    0 / 540 (0.00%)
    4 / 541 (0.74%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERFORMANCE STATUS DECREASED
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    22 / 532 (4.14%)
    11 / 540 (2.04%)
    8 / 541 (1.48%)
         occurrences causally related to treatment / all
    3 / 29
    5 / 15
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL PAIN
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    5 / 532 (0.94%)
    2 / 540 (0.37%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 5
    0 / 2
    0 / 2
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ULCER HAEMORRHAGE
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    AGITATED DEPRESSION
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANXIETY
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COMPLETED SUICIDE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    7 / 532 (1.32%)
    6 / 540 (1.11%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    4 / 8
    3 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    DELIRIUM
         subjects affected / exposed
    4 / 532 (0.75%)
    2 / 540 (0.37%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    4 / 532 (0.75%)
    2 / 540 (0.37%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DISORIENTATION
         subjects affected / exposed
    0 / 532 (0.00%)
    2 / 540 (0.37%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EUPHORIC MOOD
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HALLUCINATION
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IMPAIRED SELF-CARE
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MAJOR DEPRESSION
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    2 / 532 (0.38%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EPIDIDYMITIS
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENITAL PROLAPSE
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATITIS
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ACCIDENTAL OVERDOSE
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ACETABULUM FRACTURE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ALCOHOL POISONING
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    2 / 532 (0.38%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BLADDER INJURY
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CERVICAL VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    2 / 541 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLAVICLE FRACTURE
         subjects affected / exposed
    1 / 532 (0.19%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONTUSION
         subjects affected / exposed
    1 / 532 (0.19%)
    0 / 540 (0.00%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CRANIOCEREBRAL INJURY
         subjects affected / exposed
    0 / 532 (0.00%)
    0 / 540 (0.00%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FACE INJURY
         subjects affected / exposed
    0 / 532 (0.00%)
    1 / 540 (0.19%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    5 / 532 (0.94%)
    3 / 540 (0.56%)
    4 / 541 (0.74%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    3 / 532 (0.56%)
    2 / 540 (0.37%)
    1 / 541 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    6 / 532 (1.13%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FOOT FRACTURE
         subjects affected / exposed
    2 / 532 (0.38%)
    1 / 540 (0.19%)
    0 / 541 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all