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    Clinical Trial Results:
    A multicenter phase II study of subcutaneous Velcade plus oral Melphalna and Prednisone or plus Oral cyclophosphamide and Prednisone or plus Prednisone in newly diagnosed elderly multiple myeloma patients.

    Summary
    EudraCT number
    		 2010-018873-39
    Trial protocol
    		 IT  
    Global end of trial date
    18 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2024
    First version publication date
    12 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    26866138MMY2069
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01913730
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    STICHTING EUROPEAN MYELOMA NETWORK
    Sponsor organisation address
    Dr. Molewaterplein 40, ROTTERDAM, Netherlands, 3015 GD
    Public contact
    Clinical Trial Office, Fondazione EMN Italy Onlus, 0039 0110243236, clinicaltrialoffice@emnitaly.org
    Scientific contact
    Clinical Trial Office, Fondazione EMN Italy Onlus, 0039 0110243236, clinicaltrialoffice@emnitaly.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. Determine wheter VMP and VCP and VP induce a significant Very Good partial response`` rate in patients wwith newly diagnosed MM 2. determine the Complete Response (CR) rate 3. Determine the Partial response rate
    Protection of trial subjects
    The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety and well-being of the patients. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written information given to the patients (including diary cards), safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 152
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    2
    From 65 to 84 years
    139
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 This protocol is a single-arm, three-cohort, phase II multicenter study designed to assess the safety and the efficacy of VMP and VCP and VP as up-front treatment in elderly MM patients. Patients will be evaluated at scheduled visits in up to 3 study periods: pre-treatment, treatment and long-term follow-up (LTFU).

    Pre-assignment
    Screening details
    		 The pre-treatment period includes screening visits, performed at study entry. After providing written informed consent to participate in the study, patients will be evaluated for study eligibility. The screening period includes the availability of inclusion criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VMP cohort
    Arm description
    		 •Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Melphalan will be given orally at the dose of 2 mg every other day for 28 days for a total dose 28 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28days. Each cycle will be repeated every 28 days, for a total of 9 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    26866138
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Melphalan will be given orally at the dose of 2 mg every other day for 28 days for a total dose 28 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Arm title
    		 VCP cohort
    Arm description
    		 • Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. • Cyclophosphamide will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles. • Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    26866138
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cyclophosphamide will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Arm title
    		 VP cohort
    Arm description
    		 •Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Prednisone will be given orally at the dose of 50 mg every other day for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    26866138
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Number of subjects in period 1
    		VMP cohort VCP cohort VP cohort
    Started
    50
    51
    51
    Completed
    29
    25
    25
    Not completed
    21
    26
    26
         Adverse event, serious fatal
    2
    5
    6
         Consent withdrawn by subject
    1
    -
    2
         Physician decision
    -
    2
    -
         Adverse event, non-fatal
    9
    7
    5
         Lost to follow-up
    1
    1
    3
         Lack of efficacy
    8
    11
    10
    Period 2
    Period 2 title
    Maintenance therapy
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Velcade
    Arm description
    		 Velcade will be given at the dose of 1.3 mg/m2 as SC injection every 2 weeks. Each cycle will be repeated every 28 days, until PD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Velcade
    Investigational medicinal product code
    26866138
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Velcade will be given at the dose of 1.3 mg/m2 as SC injection every 2 weeks. Each cycle will be repeated every 28 days, until PD.

    Number of subjects in period 2
    		Velcade
    Started
    79
    Completed
    0
    Not completed
    79
         Adverse event, serious fatal
    3
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    20
         Lost to follow-up
    5
         Lack of efficacy
    46
         Protocol deviation
    1

    Baseline characteristics

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

    Reporting group values
    		 Induction therapy Total
    Number of subjects
    		 152 152
    Age categorical
    Units: Subjects
        <= 75
    		 39 39
        > 75
    		 113 113
    Age continuous
    Units: years
        median (full range (min-max))
    		 78 (59 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 74 74
        Male
    		 78 78
    ISS Stage
    Units: Subjects
        ISS Stage I
    		 41 41
        ISS Stage II
    		 44 44
        ISS Stage III
    		 67 67
    Subject analysis sets

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

    Subject analysis sets values
    		 ITT
    Number of subjects
    152
    Age categorical
    Units: Subjects
        <= 75
    39
        > 75
    113
    Age continuous
    Units: years
        median (full range (min-max))
    78 (59 to 88)
    Gender categorical
    Units: Subjects
        Female
    74
        Male
    78
    ISS Stage
    Units: Subjects
        ISS Stage I
    41
        ISS Stage II
    44
        ISS Stage III
    67

    End points

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    End points reporting groups
    Reporting group title
    VMP cohort
    Reporting group description
    		 •Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Melphalan will be given orally at the dose of 2 mg every other day for 28 days for a total dose 28 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Reporting group title
    VCP cohort
    Reporting group description
    		 • Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. • Cyclophosphamide will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles. • Prednisone will be given orally at the dose of 50 mg every other day for 28 days for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.

    Reporting group title
    VP cohort
    Reporting group description
    		 •Velcade will be given at the dose of 1.3 mg/m2 as subcutaneous (SC) injection on days 1, 8, 15, 22. Each cycle will be repeated every 28 days, for a total of 9 cycles. •Prednisone will be given orally at the dose of 50 mg every other day for a total dose 700 mg/28 days. Each cycle will be repeated every 28 days, for a total of 9 cycles.
    Reporting group title
    Velcade
    Reporting group description
    		 Velcade will be given at the dose of 1.3 mg/m2 as SC injection every 2 weeks. Each cycle will be repeated every 28 days, until PD.

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

    Primary: The primary endpoints of the study is the VGPR, CR, PR rates.

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    End point title
    		 The primary endpoints of the study is the VGPR, CR, PR rates.
    End point description
    Objective overall Response rate (including CR and PR using the International Response Criteria reported by Durie et al.). Categories of response will include stringent Complete Response (sCR), CR, VGPR, PR and PD. If, during the course of the study, other relevant categories are identified in the literature, then these categories may be added. Responders are defined as subjects with at least a PR.
    End point type
    Primary
    End point timeframe
    24 monhts
    End point values
    		 VMP cohort VCP cohort VP cohort ITT
    Number of subjects analysed
    50
    51
    51
    152
    Units: Patients
        at least PR
    43
    36
    32
    111
        < PR
    7
    15
    19
    41
    Statistical analysis title
    		 No statistical analysis
    Comparison groups
    VP cohort v VCP cohort v VMP cohort
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0 [2]
    Method
    		 No statistical analysis
    Parameter type
    		 No statistical analysis
    Point estimate
    111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 111
         upper limit
    		 111
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [1] - No statistical analysis
    [2] - No statistical analysis

    Secondary: PFS

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    End point title
    		 PFS
    End point description
    PFS will be measured in months from the date of enrolment to the date of first observation of disease progression, or relapse from CR or death to any cause as an event. Subjects who withdraw from the study will be considered censored at the time of the last complete disease assessment. Subject who complete the study, have no progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to follow-up prior to the end of the study will also be censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    monhts
    End point values
    		 VMP cohort VCP cohort VP cohort
    Number of subjects analysed
    50
    51
    51
    Units: month
        median (confidence interval 95%)
    18.7 (14.4 to 40.6)
    15.8 (12.8 to 19.6)
    14.4 (10.5 to 20.9)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    VMP cohort v VCP cohort v VP cohort
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.36
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Confidence interval
         level
    		 95%
    Notes
    [3] - Log rank test

    Secondary: TTP

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    End point title
    		 TTP
    End point description
    TTP will be measured in months from the date of enrolment to the date of first observation of disease progression, or relapse from CR or deaths related to disease progression. Subjects who withdraw from the study or die of causes other than disease progression will be considered censored at the time of the last complete disease assessment. Subject who complete the study, have no progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to follow-up prior to the end of the study will also be censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    months
    End point values
    		 VMP cohort VCP cohort VP cohort
    Number of subjects analysed
    50
    51
    51
    Units: month
        median (confidence interval 95%)
    25 (16.1 to 95.5)
    18.1 (14.2 to 34.6)
    15.7 (12.6 to 30.6)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    VMP cohort v VCP cohort v VP cohort
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.23 [5]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.23
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [4] - Log rank test
    [5] - Log rank test

    Secondary: OS

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    End point title
    		 OS
    End point description
    OS is defined as the time between enrolment and death. Subject who die, regardless the cause of the death, will be censored as an event. Subjects who withdraw consent for study will be censored at the time of withdrawal. Subject who complete the study and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to follow-up prior to the end of the study will also be censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 VMP cohort VCP cohort VP cohort
    Number of subjects analysed
    50
    51
    51
    Units: percent
        number (confidence interval 95%)
    0.52 (0.39 to 0.7)
    0.48 (0.35 to 0.65)
    0.58 (0.46 to 0.75)
    Statistical analysis title
    		 Log rank test
    Comparison groups
    VMP cohort v VCP cohort v VP cohort
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.97 [7]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 0.97
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [6] - Log rank test
    [7] - Log rank test

    Secondary: TTNT

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    End point title
    		 TTNT
    End point description
    TTNT will be measured in months from the date of enrolment to the date of next anti-myeloma therapy. Death due to disease progression before starting therapy will be considered an event. Subjects who withdraw from the study or die of causes other than disease progression will be considered censored at the time of the last complete disease assessment. Subject who complete the study, have no progressed, and are still alive at the cut-off date of final analysis will be censored at the cut-off date. All subjects who were lost to follow-up prior to the end of the study will also be censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    onths
    End point values
    		 VMP cohort VCP cohort VP cohort
    Number of subjects analysed
    50
    51
    51
    Units: month
        median (confidence interval 95%)
    24.8 (14.9 to 42.9)
    16.5 (13 to 20.3)
    14.4 (11.8 to 21.2)
    Statistical analysis title
    		 Log rank test
    Statistical analysis description
    Log rank test
    Comparison groups
    VMP cohort v VCP cohort v VP cohort
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [8]
    P-value
    		 = 0.27 [9]
    Method
    		 Logrank
    Parameter type
    		 Log rank test
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.27
    Variability estimate
    Standard deviation
    Dispersion value
    0
    Notes
    [8] - Log rank test
    [9] - Log rank test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Per protocol
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Per Protocol
    Reporting group description
    		 -

    Serious adverse events
    		 Per Protocol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 148 (50.00%)
         number of deaths (all causes)
    16
         number of deaths resulting from adverse events
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic neuroendocrine tumour
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 148 (5.41%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 2
    Surgical and medical procedures
    Haemorrhoid operation
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Fatigue
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Mucosal inflammation
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    9 / 148 (6.08%)
         occurrences causally related to treatment / all
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 148 (3.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    Pleural effusion
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Bradyphrenia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Insomnia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Epiphyseal fracture
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    6 / 148 (4.05%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Carotid sinus syndrome
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 148 (8.11%)
         occurrences causally related to treatment / all
    5 / 16
         deaths causally related to treatment / all
    0 / 4
    Neutropenia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Incontinence
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Renal failure
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 148 (2.03%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 148 (6.76%)
         occurrences causally related to treatment / all
    5 / 10
         deaths causally related to treatment / all
    1 / 2
    Postoperative wound infection
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hyperglycaemia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 148 (0.68%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 148 (1.35%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Per Protocol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 148 (93.92%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    8 / 148 (5.41%)
         occurrences all number
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 148 (6.08%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    85 / 148 (57.43%)
         occurrences all number
    85
    Neutropenia
         subjects affected / exposed
    21 / 148 (14.19%)
         occurrences all number
    21
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    35 / 148 (23.65%)
         occurrences all number
    35
    Fatigue
         subjects affected / exposed
    22 / 148 (14.86%)
         occurrences all number
    22
    Gastrointestinal disorders
    Pyrexia
         subjects affected / exposed
    24 / 148 (16.22%)
         occurrences all number
    24
    Diarrhoea
         subjects affected / exposed
    17 / 148 (11.49%)
         occurrences all number
    17
    Constipation
         subjects affected / exposed
    10 / 148 (6.76%)
         occurrences all number
    10
    Nausea
         subjects affected / exposed
    8 / 148 (5.41%)
         occurrences all number
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    15 / 148 (10.14%)
         occurrences all number
    15
    Cough
         subjects affected / exposed
    9 / 148 (6.08%)
         occurrences all number
    9
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 148 (9.46%)
         occurrences all number
    14
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    11 / 148 (7.43%)
         occurrences all number
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2017
    Amendment 1: The substantive amendment request concerns updating the criteria for disease response assessment. With this Amendment, side effects of the drug Velcade, risks to fetus and fertility (male and female) and the appendix on confidentiality protection were also updated on the Information Sheet and Informed Consent Form. Instructions on temperature monitoring of the drug bortezomib, provided by the drug supplier B&C, are also forwarded, following instructions from Janssen International. Participating centers will be required to report any temperature excursions, verified during transport until delivery to each individual center. The expiration of the insurance certificate has been extended.
    08 Jun 2021
    Amendment 2: The substantive amendment request concerns the change of the study Promoter with change from HOVON Foundation to STICHTING EUROPEAN MYELOMA NETWORK (EMN), the change of name of the requesting entity and Italian co-promoter from FONESA Onlus to Fondazione EMN Italy Onlus, and the update of the side effects of the drug bortezomib, reported on the information sheet and informed consent form. As a result of this Promoter change, all study documents, including the bortezomib drug labels, were modified. In addition, the bortezomib drug release sites have been updated: - FISHER Clinical Services GmbH (FCS) Germany - FISHER Clinical Services GmbH (FCS) Switzerland FCS Germany will assume all responsibilities that Fisher Horsham has had until now. FCS Switzerland may be involved for the relabeling activities of the drug bortezomib, so both sites are identified as importers and manufacturers for the final release of the drug.
    10 Nov 2023
    Amendment 3: The substantive amendment request concerns the study duration per patient, which was reduced to 10 years from enrollment.

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

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