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    Clinical Trial Results:
    A randomized phase III trial on the effect of elotuzumab in VRD induction /consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma

    Summary
    EudraCT number
    		 2014-003079-40
    Trial protocol
    		 DE  
    Global end of trial date
    24 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jan 2023
    First version publication date
    16 Jan 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GMMG-HD6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02495922
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Heidelberg
    Sponsor organisation address
    Im Neuenheimer Feld 672, Heidelberg, Germany, 69120
    Public contact
    GMMG Studiensekretariat, GMMG Study Office, 0049 6221568015, studiensekretariat.gmmg@med.uni-heidelberg.de
    Scientific contact
    GMMG Studiensekretariat, GMMG Study Office, 0049 6221568015, studiensekretariat.gmmg@med.uni-heidelberg.de
    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
    02 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the determination of the best of four treatment strategies regarding progression-free survival (PFS). The four treatment strategies are 1. (arm A1): VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, standard intensification, VRD consolidation and lenalidomide maintenance 2. (arm A2): VRD induction, standard intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab 3. (arm B1): VRD + elotuzumab induction, standard intensification, VRD consolidation and lenalidomide maintenance 4. (arm B2): VRD + elotuzumab induction, standard intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Protection of trial subjects
    regular safety assessments: - reporting and assessment of serious adverse events (SAE), all CTC grades, during all treatment phases. - reporting and assessment of adverse events (AE) CTC grade > 3 during induction, consolidation and maintenance. Additionally, the specific AEs polyneuropathy, thromboembolic events, cardiac events and infections already have to be reported if CTCAE grade 2. AEs are assessed according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). List of safety parameter according to protocol to assess “adverse events”: • laboratory findings (hematology, creatinine, blood chemistry incl. ASAT, ALAT, γ-GT, urea, bilirubin, etc., hCG for women of childbearing potential) • physical examination • medical history • ECG and cardiac echo Implementation of "pregnancy prevention programme"
    Background therapy
    		 All patients received during the induction therapy: - VRD (Bortezomib, lenalidomide, dexamethasone) All patients received during intensification: - cyclophosphamide base mobilization therapy (e.g. CAD) and high dose melphalan plus autologous stem cell transplantation All patients received during the maintenance therapy: - lenalidomide
    Evidence for comparator
    		 standard therapy for newly diagnosed multiple myeloma
    Actual start date of recruitment
    29 Jun 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    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
    Germany: 564
    Worldwide total number of subjects
    564
    EEA total number of subjects
    564
    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)
    427
    From 65 to 84 years
    137
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Enrolment periods: 1.) Inclusion of patients no. 0001– 0516 FPI (first patient in): 29.06.2015 LPI (last patient in): 04.05.2017 Aimed patient number was reached prematurely. After an amendment additional patients were enrolled. 2.) Inclusion of patients no. 0517 – 0564: FPI (first patient in): 30.06.2017 LPI (last patient in): 11.09.2017

    Pre-assignment
    Screening details
    		 The investigations required for checking the eligibility criteria and for enrollment usually are consistent with the routine medical care for myeloma patients at diagnosis and prior to treatment. Routine data obtained up to 3 weeks prior to enrollment could be used for screening.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A1
    Arm description
    		 VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm A2
    Arm description
    		 VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Consolidation: Elotuzumab 10mg/kg on d1, d8 and d15 in 2 cycles (21d) Maintenance: Elotuzumab 10mg/kg for first 6 months: d1 and d15 of each cycle (28d cycles) subsequently: d1 of each cycle

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm B1
    Arm description
    		 VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Elotuzumab 10mg/kg - d1, d8 and d15 in cycle 1 and 2 (duration of each cycle: 21d) - d1, d11 in cycle 3 and 4 (duration of each cycle: 21d)

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm B2
    Arm description
    		 VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Elotuzumab 10mg/kg - d1, d8 and d15 in cycle 1 and 2 (duration of each cycle: 21d) - d1, d11 in cycle 3 and 4 (duration of each cycle: 21d) Consolidation: Elotuzumab 10mg/kg on d1, d8 and d15 in 2 cycles (21d) Maintenance: Elotuzumab 10mg/kg for first 6 months: d1 and d15 of each cycle (28d cycles) subsequently: d1 of each cycle

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Number of subjects in period 1
    		Arm A1 Arm A2 Arm B1 Arm B2
    Started
    140
    142
    139
    143
    Completed
    139
    141
    137
    142
    Not completed
    1
    1
    2
    1
         violation of inclusion/exclusion criteria
    1
    1
    2
    1
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A1
    Arm description
    		 VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm A2
    Arm description
    		 VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Consolidation: Elotuzumab 10mg/kg on d1, d8 and d15 in 2 cycles (21d) Maintenance: Elotuzumab 10mg/kg for first 6 months: d1 and d15 of each cycle (28d cycles) subsequently: d1 of each cycle

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm B1
    Arm description
    		 VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Elotuzumab 10mg/kg - d1, d8 and d15 in cycle 1 and 2 (duration of each cycle: 21d) - d1, d11 in cycle 3 and 4 (duration of each cycle: 21d)

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Arm title
    		 Arm B2
    Arm description
    		 VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Induction Elotuzumab 10mg/kg - d1, d8 and d15 in cycle 1 and 2 (duration of each cycle: 21d) - d1, d11 in cycle 3 and 4 (duration of each cycle: 21d) Consolidation: Elotuzumab 10mg/kg on d1, d8 and d15 in 2 cycles (21d) Maintenance: Elotuzumab 10mg/kg for first 6 months: d1 and d15 of each cycle (28d cycles) subsequently: d1 of each cycle

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was given in induction, consolidation and maintenance. Induction: 25mg/d for d1-d14 in 4 cycles of 21 days. Consolidation: 25mg/d for d1-d14 in 2 cycles of 21 days. Maintenance: Continuous treatment with Lenalidomide. Dosage: 10 mg/d within the first 3 months of maintenance treatment. Subsequently the lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. Lenalidomide maintenance was continued for 2 years or until disease progression.

    Number of subjects in period 2
    		Arm A1 Arm A2 Arm B1 Arm B2
    Started
    139
    141
    137
    142
    Completed
    68
    80
    68
    76
    Not completed
    71
    61
    69
    66
         Adverse event, serious fatal
    4
    4
    6
    5
         Consent withdrawn by subject
    5
    8
    2
    7
         Physician decision
    5
    4
    6
    3
         Adverse event, non-fatal
    20
    16
    24
    16
         Subject non-compliance
    3
    1
    1
    2
         other
    7
    3
    6
    5
         Progressive disease
    26
    23
    22
    26
         Lost to follow-up
    1
    -
    1
    2
         High risk situation and change of therapy
    -
    2
    -
    -
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    		 VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm A2
    Reporting group description
    		 VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab

    Reporting group title
    Arm B1
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm B2
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab

    Reporting group values
    		 Arm A1 Arm A2 Arm B1 Arm B2 Total
    Number of subjects
    		 140 142 139 143 564
    Age categorical
    Units: Subjects
        Adults 18-64 years
    		 107 111 105 104 427
        Adults 65-70 years
    		 33 31 34 39 137
    Gender categorical
    Units: Subjects
        Female
    		 59 66 54 65 244
        Male
    		 81 76 85 78 320
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized. Not included in the ITT population are patients who withdraw informed consent before start of treatment or about whom it becomes known, that major in/exclusion criteria were violated which would have excluded them from study treatment when known at start of treatment.

    Subject analysis sets values
    		 ITT population
    Number of subjects
    559
    Age categorical
    Units: Subjects
        Adults 18-64 years
    136
        Adults 65-70 years
    423
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    243
        Male
    316

    End points

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    End points reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    		 VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm A2
    Reporting group description
    		 VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab

    Reporting group title
    Arm B1
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm B2
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab
    Reporting group title
    Arm A1
    Reporting group description
    		 VRD (Bortezomib (Velcade) / Lenalidomide (Revlimid) / Dexamethasone) induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm A2
    Reporting group description
    		 VRD induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab

    Reporting group title
    Arm B1
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD consolidation and lenalidomide maintenance

    Reporting group title
    Arm B2
    Reporting group description
    		 VRD + elotuzumab induction, intensification, VRD + elotuzumab consolidation and lenalidomide maintenance + elotuzumab

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomized. Not included in the ITT population are patients who withdraw informed consent before start of treatment or about whom it becomes known, that major in/exclusion criteria were violated which would have excluded them from study treatment when known at start of treatment.

    Primary: Progression free survival

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    End point title
    		 Progression free survival
    End point description
    Progression-free survival (PFS) is defined as time from randomization to progression or death from any cause, whichever occurs first. PFS is censored at the date of the last response assessment. Patients without any response assessment after randomization are censored at the date of randomization. High-risk patients leaving the study and receiving an allogeneic transplantation are censored at the date of transplantation. If the interval between two response assessments exceeds 5.5 months during protocol treatment (until end of study) or 8 months during follow-up right before the diagnosis of PD, PFS is censored at the last date of response before this interval.
    End point type
    Primary
    End point timeframe
    Response assessment visits (after induction, after mobilization, after ASCT, every 3month during maintenance)
    End point values
    		 Arm A1 Arm A2 Arm B1 Arm B2
    Number of subjects analysed
    139
    141
    137
    142
    Units: survival probability
    number (confidence interval 95%)
        3 year PFS rate
    68.8 (60.9 to 76.8)
    68.5 (60.7 to 76.4)
    66.2 (58.2 to 74.3)
    67.2 (59.2 to 75.2)
    Statistical analysis title
    		 progression free survival
    Statistical analysis description
    The primary analysis of PFS is based on the ITT population. The four treatment arms were compared in a closed testing procedure as introduced by Marcus, Peritz and Gabriel (1976). Kaplan-Meier estimates are provided giving the 3 year survival probability including 95% confidence interval.
    Comparison groups
    Arm A1 v Arm A2 v Arm B1 v Arm B2
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting: from start of study treatment, during induction and subsequent 40days. During intensification: only SAE reporting. Re-start of reporting: during consolidation/maintenance, up to 40d after last study visit or start of subsequent therapy.
    Adverse event reporting additional description
    All AEs CTCAE grade 3, 4 and 5 have to be reported during induction, consolidation and maintenance. For specific AEs (polyneuropathy, thromboembolic events, infections, cardiac disorders) also CTC grade 2 events have to be reported. All SAEs have to be reporting independent from CTCAE grade.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    351 / 555 (63.24%)
         number of deaths (all causes)
    78
         number of deaths resulting from adverse events
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms
         subjects affected / exposed
    32 / 555 (5.77%)
         occurrences causally related to treatment / all
    24 / 36
         deaths causally related to treatment / all
    2 / 5
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    16 / 555 (2.88%)
         occurrences causally related to treatment / all
    8 / 18
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    3 / 555 (0.54%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    59 / 555 (10.63%)
         occurrences causally related to treatment / all
    24 / 73
         deaths causally related to treatment / all
    0 / 4
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    5 / 555 (0.90%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    33 / 555 (5.95%)
         occurrences causally related to treatment / all
    16 / 37
         deaths causally related to treatment / all
    1 / 4
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    6 / 555 (1.08%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Product issues
         subjects affected / exposed
    2 / 555 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Investigations
         subjects affected / exposed
    13 / 555 (2.34%)
         occurrences causally related to treatment / all
    3 / 15
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    27 / 555 (4.86%)
         occurrences causally related to treatment / all
    1 / 30
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    26 / 555 (4.68%)
         occurrences causally related to treatment / all
    16 / 30
         deaths causally related to treatment / all
    1 / 2
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    47 / 555 (8.47%)
         occurrences causally related to treatment / all
    21 / 57
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 555 (3.06%)
         occurrences causally related to treatment / all
    7 / 19
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    1 / 555 (0.18%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    5 / 555 (0.90%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    49 / 555 (8.83%)
         occurrences causally related to treatment / all
    12 / 63
         deaths causally related to treatment / all
    1 / 1
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    9 / 555 (1.62%)
         occurrences causally related to treatment / all
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    7 / 555 (1.26%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    27 / 555 (4.86%)
         occurrences causally related to treatment / all
    15 / 32
         deaths causally related to treatment / all
    2 / 2
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    1 / 555 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    27 / 555 (4.86%)
         occurrences causally related to treatment / all
    3 / 29
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    188 / 555 (33.87%)
         occurrences causally related to treatment / all
    129 / 300
         deaths causally related to treatment / all
    6 / 14
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    27 / 555 (4.86%)
         occurrences causally related to treatment / all
    11 / 32
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    468 / 555 (84.32%)
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    130 / 555 (23.42%)
         occurrences all number
    151
    Peripheral sensory neuropathy
         subjects affected / exposed
    61 / 555 (10.99%)
         occurrences all number
    76
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    77 / 555 (13.87%)
         occurrences all number
    184
    Thrombocytopenia
         subjects affected / exposed
    54 / 555 (9.73%)
         occurrences all number
    82
    Neutrophil count decrease
         subjects affected / exposed
    52 / 555 (9.37%)
         occurrences all number
    128
    Lymphocyte count decreased
         subjects affected / exposed
    42 / 555 (7.57%)
         occurrences all number
    94
    Platelet count decrease
         subjects affected / exposed
    41 / 555 (7.39%)
         occurrences all number
    58
    Leukopenia
         subjects affected / exposed
    35 / 555 (6.31%)
         occurrences all number
    45
    Lymphopenia
         subjects affected / exposed
    33 / 555 (5.95%)
         occurrences all number
    66
    Anaemia
         subjects affected / exposed
    28 / 555 (5.05%)
         occurrences all number
    51
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    30 / 555 (5.41%)
         occurrences all number
    38
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    30 / 555 (5.41%)
         occurrences all number
    39
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    92 / 555 (16.58%)
         occurrences all number
    153
    Bronchitis
         subjects affected / exposed
    64 / 555 (11.53%)
         occurrences all number
    83
    Nasopharyngitis
         subjects affected / exposed
    43 / 555 (7.75%)
         occurrences all number
    83
    Respiratory tract infection
         subjects affected / exposed
    35 / 555 (6.31%)
         occurrences all number
    47

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2016
    (a) Changes in the scientific program (inclusion of additional objectives and requirement of additional blood and bone marrow samples) (b) Implementation of the updated Pregnancy Prevention Program (c) Clarification of definitions for “end of study”
    03 May 2017
    (a) Change in sample size and trial duration: sample size was increased to n=564 patients. (b) Marketing Authorization of Lenalidomide for maintenance therapy (c) Correction of detailed definition of primary endpoint (d) Clarifications regarding laboratory investigations and Follow up documentation

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    not applicable

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31138244
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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