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    Clinical Trial Results:
    Randomised phase III trial for previously untreated multiple myeloma to evaluate two regimens of bortezomib based induction therapy and lenalidomide consolidation followed by lenalidomide maintenance treatment

    Summary
    EudraCT number
    		 2010-019173-16
    Trial protocol
    		 DE  
    Global end of trial date
    11 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2022
    First version publication date
    27 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MM5
    Additional study identifiers
    ISRCTN number
    		 ISRCTN05622749
    US NCT number
    		 -
    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 Im Neuenheimer Feld 130.3 69120 Heidelberg, Germany, GMMG Study Office, 0049 6221568198, studiensekretariat.gmmg@med.uni-heidelberg.de
    Scientific contact
    GMMG Studiensekretariat Im Neuenheimer Feld 130.3 69120 Heidelberg, Germany, GMMG Study Office, 0049 6221568198, 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
    16 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.) Demonstration of non-inferiority of VCD induction therapy compared to PAd induction therapy with respect to response rate (very good partial remission or better; response criteria of the International Myeloma Working Group, IMWG). 2.) Determination of the best of four treatment strategies with respect to progression-free survival (PFS). The four treatment strategies are defined by PAd vs. VCD induction treatment, standard intensification therapy, lenalidomide consolidation and maintenance treatment with lenalidomide for 2 years vs. lenalidomide until CR.
    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: - dexamethasone plus doxorubicin (arm A1/B1) or cyclophosphamide (arm A2/B2) as standard therapy Alle patients received during intensification: - cyclophosphamide base mobilization therapy (e.g. CAD) and high dose melphalan plus autologous stem cell transplantation
    Evidence for comparator
    		 standard therapy for newly diagnosed multiple myeloma
    Actual start date of recruitment
    26 Jul 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 9 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 604
    Worldwide total number of subjects
    604
    EEA total number of subjects
    604
    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)
    447
    From 65 to 84 years
    157
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Enrolment periods: 1.) Inclusion of patients no. 0001– 0504 (for primary analyses): FPI (first patient in): 26.07.2010 LPI (last patient in): 11.10.2012 Aimed patient number was reached prematurely. 2.) Inclusion of patients no. 0505 – 0604 (to perform additional descriptive and exploratory analyses): FPI: 12.07.2013 LPI: 14.11.2013

    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
    		 Baseline of Arm A1 (PAd induction, lenalidomide maintenance for 2 years)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of PAd). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    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
    		 Baseline of arm B1 (PAd induction, lenalidomide maintenance if no CR)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of PAd). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In case patients did not achieve a complete response (CR) according to the IMWG criteria 2 after consolidation, maintenance treatment with lenalidomide was given. Maintenance treatment was stopped after achievement of a CR (Lenalidomide is given until confirmation of CR). Dosage: 10 mg/d (continuously) within the first 3 months of maintenance treatment. Subsequently the Lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. In case no CR was achieved, Lenalidomide was given for 2 years or until disease progression.

    Arm title
    		 Arm A2
    Arm description
    		 Baseline of arm A2 (VCD induction, lenalidomide maintenance for 2 years)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of VCD). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    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
    		 Baseline of arm B2 (VCD induction, lenalidomide maintenance if no CR)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of VCD). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In case patients did not achieve a complete response (CR) according to the IMWG criteria 2 after consolidation, maintenance treatment with lenalidomide was given. Maintenance treatment was stopped after achievement of a CR (Lenalidomide is given until confirmation of CR). Dosage: 10 mg/d (continuously) within the first 3 months of maintenance treatment. Subsequently the Lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. In case no CR was achieved, Lenalidomide was given for 2 years or until disease progression.

    Number of subjects in period 1
    		Arm A1 Arm B1 Arm A2 Arm B2
    Started
    150
    150
    151
    153
    Completed
    149
    148
    150
    149
    Not completed
    1
    2
    1
    4
         Consent withdrawn by subject
    -
    -
    1
    1
         violation of inclusion criteria
    1
    -
    -
    2
         Non compliance
    -
    -
    -
    1
         Myocardial infarction previous to therapy
    -
    1
    -
    -
         Death prior to therapy
    -
    1
    -
    -
    Period 2
    Period 2 title
    Induction treatment
    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
    		 PAd (arms A1+B1)
    Arm description
    		 All patients randomized to study arms A1 and B1 received PAd for induction treatment, primary cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of PAd). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Arm title
    		 VCD (arms A2+B2)
    Arm description
    		 All patients randomized to study arms A2 and B2 received VCD for induction treatment, primary cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Bortezomib was given during induction therapy (3 cycles of VCD). Dosage: 1,3 mg/m2 body surface area in induction cycle 1 – 3 on day 1, 4, 8 and 11, respectively. Dose adjustments due to toxicities were performed as described in the study protocol. The route of administration for bortezomib was changed from intravenous (patients 001 – 314) to subcutaneous (patients 315 – 604) after implementation of protocol version 2.0 due to an expected improvement of safety profile.

    Number of subjects in period 2
    		PAd (arms A1+B1) VCD (arms A2+B2)
    Started
    296
    300
    Completed
    265
    280
    Not completed
    31
    20
         Adverse event, serious fatal
    5
    2
         Consent withdrawn by subject
    2
    -
         Physician decision
    1
    2
         Adverse event, non-fatal
    2
    2
         Non compliance
    4
    2
         High risk situation
    5
    9
         Progressive disease
    11
    1
         Lost to follow-up
    -
    1
         Protocol deviation
    1
    -
         patient's condition
    -
    1
    Period 3
    Period 3 title
    Intensification (ASCT) + Consolidation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Intensification + consolidation post PAd (A1+B1)
    Arm description
    		 Standard mobilization + ASCT + Lenalidomide consolidation after PAd induction.
    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
    Standard stem cell mobilisation, standard high dose melphalan (200mg/m²) and autologous stem cell transplantation. Consolidation with Lenalidomide. Dosage: 25 mg/d; day 1-21, start of cycle 2 at day 29.

    Arm title
    		 Standard Intensification + consolidation post VCD (Arm A2+B2
    Arm description
    		 Standard mobilization + ASCT + Lenalidomide consolidation after VCD induction
    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
    Standard stem cell mobilisation, standard high dose melphalan (200mg/m²) and autologous stem cell transplantation. Consolidation with Lenalidomide. Dosage: 25 mg/d; day 1-21, start of cycle 2 at day 29.

    Number of subjects in period 3
    		Standard Intensification + consolidation post PAd (A1+B1) Standard Intensification + consolidation post VCD (Arm A2+B2
    Started
    265
    280
    Completed
    204
    227
    Not completed
    61
    53
         Adverse event, serious fatal
    8
    8
         Mobilization not effective
    2
    -
         Allogeneic transplantation
    1
    1
         observation, completion after 2 years
    8
    4
         patient's condition
    2
    -
         Consent withdrawn by subject
    6
    7
         Adverse event, non-fatal
    3
    7
         Non compliance
    4
    7
         High risk situation
    4
    -
         Progressive disease
    21
    16
         Lost to follow-up
    -
    1
         Lack of efficacy
    2
    1
         Protocol deviation
    -
    1
    Period 4
    Period 4 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Arm A1
    Arm description
    		 Lenalidomide maintenance for 2 years after PAd induction, standard intensification (ASCT) and lenalidomide consolidation
    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
    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
    		 Maintenance Arm B1
    Arm description
    		 Lenalidomide maintenance if no CR; after PAd induction, standard intensification (ASCT) and lenalidomide consolidation
    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
    In case patients did not achieve a complete response (CR) according to the IMWG criteria 2 after consolidation, maintenance treatment with lenalidomide was given. Maintenance treatment was stopped after achievement of a CR (Lenalidomide is given until confirmation of CR). Dosage: 10 mg/d (continuously) within the first 3 months of maintenance treatment. Subsequently the Lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. In case no CR was achieved, Lenalidomide was given for 2 years or until disease progression.

    Arm title
    		 Maintenance Arm A2
    Arm description
    		 Lenalidomide maintenance for 2 years after VCD induction, standard intensification (ASCT) and lenalidomide consolidation
    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
    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
    		 Maintenance Arm B2
    Arm description
    		 Lenalidomide maintenance if no CR after VCD induction, standard intensification (ASCT) and lenalidomide consolidation
    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
    In case patients did not achieve a complete response (CR) according to the IMWG criteria 2 after consolidation, maintenance treatment with lenalidomide was given. Maintenance treatment was stopped after achievement of a CR (Lenalidomide is given until confirmation of CR). Dosage: 10 mg/d (continuously) within the first 3 months of maintenance treatment. Subsequently the Lenalidomide dose was increased to 15mg/d if the treatment was well tolerated. In case no CR was achieved, Lenalidomide was given for 2 years or until disease progression.

    Number of subjects in period 4
    		Maintenance Arm A1 Maintenance Arm B1 Maintenance Arm A2 Maintenance Arm B2
    Started
    109
    95
    116
    111
    Completed
    78
    69
    76
    68
    Not completed
    31
    26
    40
    43
         Adverse event, serious fatal
    -
    -
    3
    1
         Physician decision
    1
    1
    -
    -
         Consent withdrawn by subject
    -
    -
    3
    -
         Adverse event, non-fatal
    3
    -
    1
    2
         Non compliance
    -
    2
    1
    -
         Patient's decision
    -
    -
    1
    -
         Progressive disease
    27
    23
    29
    39
         High risk situation
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    		 Baseline of Arm A1 (PAd induction, lenalidomide maintenance for 2 years)

    Reporting group title
    Arm B1
    Reporting group description
    		 Baseline of arm B1 (PAd induction, lenalidomide maintenance if no CR)

    Reporting group title
    Arm A2
    Reporting group description
    		 Baseline of arm A2 (VCD induction, lenalidomide maintenance for 2 years)

    Reporting group title
    Arm B2
    Reporting group description
    		 Baseline of arm B2 (VCD induction, lenalidomide maintenance if no CR)

    Reporting group values
    		 Arm A1 Arm B1 Arm A2 Arm B2 Total
    Number of subjects
    		 150 150 151 153 604
    Age categorical
    Units: Subjects
        Adults - 18-70 years
    		 150 150 151 153 604
    Gender categorical
    Units: Subjects
        Female
    		 81 88 87 97 353
        Male
    		 69 62 64 56 251
    Subject analysis sets

    Subject analysis set title
    ITT - expanded cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analysed according to treatment randomized. The expanded cohort consists of n=604 enrolled patients (increased patient number for additional exploratory analyses)

    Subject analysis set title
    Safety - expanded cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consists of all patients randomized which received at least one dose of trial medication, out of the expanded cohort of n=604 enrolled patients. Patients are analysed as treated.

    Subject analysis set title
    ITT - primary cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analysed according to treatment randomized. The primary cohort consists of n=504 enrolled patients (inital cohort, for primary analyses)

    Subject analysis set title
    Safety - primary cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (primary cohort) consists of all patients randomized which received at least one dose of trial medication - out of the primarily enrolled n=504 patients (initial cohort, for primary analyses). Patients are analysed as treated.

    Subject analysis sets values
    		 ITT - expanded cohort Safety - expanded cohort ITT - primary cohort Safety - primary cohort
    Number of subjects
    601
    598
    502
    498
    Age categorical
    Units: Subjects
        Adults - 18-70 years
    601
    598
    502
    498
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    		 Baseline of Arm A1 (PAd induction, lenalidomide maintenance for 2 years)

    Reporting group title
    Arm B1
    Reporting group description
    		 Baseline of arm B1 (PAd induction, lenalidomide maintenance if no CR)

    Reporting group title
    Arm A2
    Reporting group description
    		 Baseline of arm A2 (VCD induction, lenalidomide maintenance for 2 years)

    Reporting group title
    Arm B2
    Reporting group description
    		 Baseline of arm B2 (VCD induction, lenalidomide maintenance if no CR)
    Reporting group title
    PAd (arms A1+B1)
    Reporting group description
    		 All patients randomized to study arms A1 and B1 received PAd for induction treatment, primary cohort.

    Reporting group title
    VCD (arms A2+B2)
    Reporting group description
    		 All patients randomized to study arms A2 and B2 received VCD for induction treatment, primary cohort.
    Reporting group title
    Standard Intensification + consolidation post PAd (A1+B1)
    Reporting group description
    		 Standard mobilization + ASCT + Lenalidomide consolidation after PAd induction.

    Reporting group title
    Standard Intensification + consolidation post VCD (Arm A2+B2
    Reporting group description
    		 Standard mobilization + ASCT + Lenalidomide consolidation after VCD induction
    Reporting group title
    Maintenance Arm A1
    Reporting group description
    		 Lenalidomide maintenance for 2 years after PAd induction, standard intensification (ASCT) and lenalidomide consolidation

    Reporting group title
    Maintenance Arm B1
    Reporting group description
    		 Lenalidomide maintenance if no CR; after PAd induction, standard intensification (ASCT) and lenalidomide consolidation

    Reporting group title
    Maintenance Arm A2
    Reporting group description
    		 Lenalidomide maintenance for 2 years after VCD induction, standard intensification (ASCT) and lenalidomide consolidation

    Reporting group title
    Maintenance Arm B2
    Reporting group description
    		 Lenalidomide maintenance if no CR after VCD induction, standard intensification (ASCT) and lenalidomide consolidation

    Subject analysis set title
    ITT - expanded cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analysed according to treatment randomized. The expanded cohort consists of n=604 enrolled patients (increased patient number for additional exploratory analyses)

    Subject analysis set title
    Safety - expanded cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consists of all patients randomized which received at least one dose of trial medication, out of the expanded cohort of n=604 enrolled patients. Patients are analysed as treated.

    Subject analysis set title
    ITT - primary cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population is defined as all patients randomized with written informed consent, excluding patients with violation of major eligibility criteria. Patients in the ITT population are analysed according to treatment randomized. The primary cohort consists of n=504 enrolled patients (inital cohort, for primary analyses)

    Subject analysis set title
    Safety - primary cohort
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population (primary cohort) consists of all patients randomized which received at least one dose of trial medication - out of the primarily enrolled n=504 patients (initial cohort, for primary analyses). Patients are analysed as treated.

    Primary: Progression free survival (primary cohort)

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    End point title
    		 Progression free survival (primary cohort)
    End point description
    time from randomisation to progression or death from any cause whichever occurs first
    End point type
    Primary
    End point timeframe
    response assessment visits (after induction, after mobilization, after ASCT, after consolidation, every 3 months during maintenance)
    End point values
    		 Arm A1 Arm B1 Arm A2 Arm B2
    Number of subjects analysed
    125
    126
    126
    125
    Units: months
        median (confidence interval 95%)
    43.2 (37.3 to 51.8)
    35.9 (26.4 to 47.7)
    40.9 (32.8 to 56.2)
    35.7 (30.5 to 41.6)
    Statistical analysis title
    		 PFS in all four treatment arms
    Statistical analysis description
    The second primary endpoint of the trial is progression-free survival in all four treatment arms. The second primary analysis will be based on the ITT population as this is a superiority objective. Treatment arms are compared in a closed testing procedure as introduced by Marcus, Peritz and Gabriel (Biometrika, 1976).
    Comparison groups
    Arm A1 v Arm B1 v Arm A2 v Arm B2
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.6
    Method
    		 Logrank
    Confidence interval
    Notes
    [1] - closed testing procedure

    Primary: VGPR+ rate after induction therapy (primary cohort)

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    End point title
    		 VGPR+ rate after induction therapy (primary cohort)
    End point description
    The first primary endpoint aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (≥VGPR).
    End point type
    Primary
    End point timeframe
    Response assessment after end of 3 cycles induction treatment
    End point values
    		 PAd (arms A1+B1) VCD (arms A2+B2)
    Number of subjects analysed
    251
    251
    Units: Number of responders
        Responders (VGPR+)
    86
    93
        Non-responder
    165
    158
    Statistical analysis title
    		 Response (VGPR+) to treatment
    Statistical analysis description
    The proportions of responders after induction treatment are compared between induction regimens at the non-inferiority margin of 10% difference. Patients without response assessment after induction therapy are defi ned as non-responders for the ITT analysis. The two-sided con fidence interval using Newcombe's Hybrid score interval is calculated. This is the primary analysis as described in the protocol.
    Comparison groups
    PAd (arms A1+B1) v VCD (arms A2+B2)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.0013
    Method
    		 Newcombe's Hybrid score interval
    Confidence interval
    Notes
    [2] - If the lower limit of the con fidence interval is above the non-inferiority margin, non-inferiority is established. In order to demonstrate non-inferiority of VCD, for both ITT and PP population NI needs to be confi rmed. In addition, the one-sided null hypothesis of non-inferiority is tested with the method of Farrington and Manning matching sample size calculation methodology. The two-sided signi ficance level for this final analysis is set to 2.4%, the one-sided level accordingly to 1.2%.

    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 30days. During intensification: only SAE reporting. Re-start of reporting: during consolidation/maintenance, up to 30d after last study visit or start of subsequent therapy.
    Adverse event reporting additional description
    All AEs CTCAE grade 3, 4 and 5 had to be reported during induction, consolidation and maintenance. For specific AEs (polyneuropathy, thromboembolic events, infections, cardiac disorders) also CTC grade 2 events had to be reported. All SAEs have to be reporting independent from CTCAE grade.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Safety population - expanded cohort
    Reporting group description
    		 The safety population consists of all patients randomized which received at least one dose of trial medication. Patients are analysed as treated. This is the safety population for the expanded cohort (after n=604 patients randomized)

    Reporting group title
    Safety population - primary cohort
    Reporting group description
    		 The safety population consists of all patients randomized which received at least one dose of trial medication. Patients are analysed as treated. This is the safety population for the primary cohort (after n=504 patients randomized)

    Serious adverse events
    		 Safety population - expanded cohort Safety population - primary cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    305 / 598 (51.00%)
    253 / 498 (50.80%)
         number of deaths (all causes)
    177
    160
         number of deaths resulting from adverse events
    22
    19
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    28 / 598 (4.68%)
    23 / 498 (4.62%)
         occurrences causally related to treatment / all
    24 / 33
    21 / 28
         deaths causally related to treatment / all
    4 / 7
    4 / 7
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    17 / 598 (2.84%)
    16 / 498 (3.21%)
         occurrences causally related to treatment / all
    15 / 22
    15 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
         subjects affected / exposed
    12 / 598 (2.01%)
    11 / 498 (2.21%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    52 / 598 (8.70%)
    40 / 498 (8.03%)
         occurrences causally related to treatment / all
    24 / 72
    23 / 52
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    1 / 598 (0.17%)
    0 / 498 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Social circumstances
         subjects affected / exposed
    1 / 598 (0.17%)
    1 / 498 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 598 (0.17%)
    1 / 498 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    27 / 598 (4.52%)
    18 / 498 (3.61%)
         occurrences causally related to treatment / all
    16 / 44
    12 / 31
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    4 / 598 (0.67%)
    3 / 498 (0.60%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Product issues
         subjects affected / exposed
    1 / 598 (0.17%)
    1 / 498 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    27 / 598 (4.52%)
    24 / 498 (4.82%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 36
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    14 / 598 (2.34%)
    9 / 498 (1.81%)
         occurrences causally related to treatment / all
    2 / 19
    1 / 14
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    32 / 598 (5.35%)
    28 / 498 (5.62%)
         occurrences causally related to treatment / all
    22 / 47
    21 / 41
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    28 / 598 (4.68%)
    26 / 498 (5.22%)
         occurrences causally related to treatment / all
    23 / 48
    22 / 45
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    3 / 598 (0.50%)
    3 / 498 (0.60%)
         occurrences causally related to treatment / all
    4 / 7
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    4 / 598 (0.67%)
    3 / 498 (0.60%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    50 / 598 (8.36%)
    44 / 498 (8.84%)
         occurrences causally related to treatment / all
    53 / 109
    49 / 99
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    3 / 598 (0.50%)
    3 / 498 (0.60%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    7 / 598 (1.17%)
    4 / 498 (0.80%)
         occurrences causally related to treatment / all
    4 / 9
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    20 / 598 (3.34%)
    17 / 498 (3.41%)
         occurrences causally related to treatment / all
    9 / 28
    9 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    31 / 598 (5.18%)
    26 / 498 (5.22%)
         occurrences causally related to treatment / all
    8 / 37
    7 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    150 / 598 (25.08%)
    119 / 498 (23.90%)
         occurrences causally related to treatment / all
    139 / 267
    121 / 205
         deaths causally related to treatment / all
    1 / 7
    1 / 4
    Investigations
         subjects affected / exposed
    10 / 598 (1.67%)
    9 / 498 (1.81%)
         occurrences causally related to treatment / all
    5 / 15
    5 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    11 / 598 (1.84%)
    9 / 498 (1.81%)
         occurrences causally related to treatment / all
    5 / 20
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population - expanded cohort Safety population - primary cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    446 / 598 (74.58%)
    370 / 498 (74.30%)
    Investigations
    Investigations
         subjects affected / exposed
    113 / 598 (18.90%)
    93 / 498 (18.67%)
         occurrences all number
    275
    231
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    30 / 598 (5.02%)
    26 / 498 (5.22%)
         occurrences all number
    37
    32
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    103 / 598 (17.22%)
    91 / 498 (18.27%)
         occurrences all number
    128
    112
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    253 / 598 (42.31%)
    214 / 498 (42.97%)
         occurrences all number
    798
    684
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    49 / 598 (8.19%)
    40 / 498 (8.03%)
         occurrences all number
    60
    49
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    32 / 598 (5.35%)
    30 / 498 (6.02%)
         occurrences all number
    39
    37
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    25 / 598 (4.18%)
    22 / 498 (4.42%)
         occurrences all number
    29
    25
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    25 / 598 (4.18%)
    24 / 498 (4.82%)
         occurrences all number
    32
    31
    Infections and infestations
    Infections and infestations
    alternative assessment type: Systematic
         subjects affected / exposed
    214 / 598 (35.79%)
    170 / 498 (34.14%)
         occurrences all number
    461
    369
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    59 / 598 (9.87%)
    57 / 498 (11.45%)
         occurrences all number
    89
    87

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2011
    The route of administration for bortezomib was changed from intravenous to subcutaneous for all patients newly randomized due to an expected improvement of safety profile.
    06 Jun 2013
    (a) Enrollment of additional 100 patients for additional descriptive and explorative analyses (i.e. to test the expected improvement in the safety profile of subcutaneous administration compared to intravenous administration of bortezomib in a comparable number of patients). (b) Change of bortezomib from study drug to commercial drug.

    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/32034285
    http://www.ncbi.nlm.nih.gov/pubmed/25787915
    http://www.ncbi.nlm.nih.gov/pubmed/27540135
    For support, Contact us.
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