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    Clinical Trial Results:
    PHASE II STUDY OF BORTEZOMIB CONSOLIDATION AFTER HIGH DOSE THERAPY AND AUTOLOGOUS STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA

    Summary
    EudraCT number
    		 2008-006751-48
    Trial protocol
    		 GB  
    Global end of trial date
    24 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2021
    First version publication date
    28 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    08/0170
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01517724
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Public contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
    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
    20 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a phase II study of bortezomib consolidation after high dose therapy (HDT) and autologous stem cell transplant (ASCT) for multiple myeloma (MM). The overall aim was to determine the effect of bortezomib consolidation on the outcome of ASCT in patients with MM, and to assess the effect of bortezomib consolidation on bone health, based on serum markers of osteoblast and osteoclast function. The main objectives of the trial were to: • determine the disease response at 6 and 12 months following autologous stem cell transplantation (ASCT) consolidated by bortezomib therapy. This tests the hypothesis that the intervention improves disease response following ASCT • evaluate the safety, toxicity and tolerability of bortezomib as consolidation therapy following high dose melphalan (HDT) with Melphalan (200mg/m2) and ASCT.
    Protection of trial subjects
    The risks to the safety of the trial subjects were those generally associated with chemotherapy. Patients were counselled about these side effects prior to starting treatment. They were monitored closely for toxicity and the protocol continuation criteria for therapy and dose modification prior to each cycle of the study drug. The protocol contained specific instructions for when study treatment should be withheld and when/if it was able to re-start. Those who developed side effects of moderate severity (Grade>2) had their dose of study medication reduced as per the protocol. As appropriate, patients were prescribed supportive medication to minimise any side effects. The protocol also had instructions on prohibited medications and those which could be used with caution. In case side effects did occur out of clinic hours, all trial subjects were given patient cards with contact details of the local haematology team that they could access at any time for advice. Due to the potential effect of the trial treatment on pregnancy and lactation, the trial subjects had consented to use a highly effective method of birth control or a combination of two effective methods of contraception for 4 weeks before, during the trial and for at least 6 months after the last trial treatment administration. All women of childbearing potential had to undergo a pregnancy test prior to starting the study drug and at the start of every cycle. Breast feeding had to be discontinued during treatment with bortezomib
    Background therapy
    		 All patients should receive oral acyclovir according to local hospital policy The following medications and support therapies are examples of supportive care that were permitted: - Laxatives - Loperamide for the treatment of diarrhoea, starting after the first watery stool - Antiemetic agents - rh-EPO - Antibiotics and antifungal treatments - Omeprazole or lansoprazole
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    02 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    31
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The 40 trial subjects were recruited between 02/Dec/2009 and 27/Mar/2014 from two trial sites in the UK (Royal United Hospital and University College London (with whom the Royal Free Hospital merged during the trial).

    Pre-assignment
    Screening details
    		 Patients aged from 18 to 70 years with multiple myeloma who had not progressed 3-4 months after receiving high dose melphalan with ASCT

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Bortezomib consolidaion
    Arm description
    		 Bortezomib was given at 1.3 mg/m² by subcutaneous injection (or intravenously if the patient did not tolerate subcutaneous injection) on days 1, 8, 15 and 22 of each 4-week cycle. After 3 cycles and approximately (within 4 weeks of) 6 months post ASCT, patients underwent re-staging of their disease. Patients with progressive disease came off protocol. All other patients continued treatment for a maximum of 8 cycles, as tolerated, and then stopped treatment. Within 4 weeks of stopping treatment patients underwent re-staging of their disease
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    L01XX32
    Other name
    Velcade
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Bortezomib was given at 1.3mg/m2 by subcutaneous injection on days 1,8,15 and 22 of each 4 week cycle. Patients could receive up to 8 cycles of bortezomib.

    Number of subjects in period 1
    		Bortezomib consolidaion
    Started
    40
    Completed
    29
    Not completed
    11
         Consent withdrawn by subject
    4
         Disease progression
    1
         Adverse event, non-fatal
    5
         Withdrawn prior to treatment
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 INCLUSION CRITERIA: MM patients who received high dose melphalan with ASCT 3-4 months before registration & have not progressed Age 18 - 70 years Life expectancy >6 months Creatinine <400μmol/L WHO performance status 0-2 Contraceptive precautions EXCLUSION CRITERIA: Received bortezomib previously or bisphosphonates since ASCT On/systemic steroid therapy is planned Disease progression at any stage Past history of polio, cord compression or other neurological condition resulting in persisting neurological deficit ≥ grade 2 Severe hepatic impairment Pregnant/lactating Allergic reaction to compounds containing boron/mannitol Severe cardiovascular disease History of acute infiltrative pulmonary/pericardial disease History of/has hypotension Peripheral neuropathy ≥ grade 2 or neuropathic pain Serious medical/psychiatric condition likely to interfere with participation Received/used an experimental drug/medical device within 4 weeks before the planned start of treatment

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 40 40
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 31 31
        From 65-84 years
    		 9 9
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 61 (43 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 22 22
    Disease isotype
    Units: Subjects
        IgG
    		 22 22
        IgA
    		 9 9
        IgD
    		 1 1
        Light chain only
    		 7 7
        Non-secretory
    		 1 1
    Induction regimen
    Units: Subjects
        Thalidomide-containing
    		 35 35
        Idarubicin/dexamethasone
    		 4 4
        Idarubicin\dexamethasone\cyclophosphaide
    		 1 1
    International staging system
    Units: Subjects
        Stage I
    		 17 17
        Stage II
    		 4 4
        Stage III
    		 2 2
        Not recorded at diagnosis
    		 17 17

    End points

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    End points reporting groups
    Reporting group title
    Bortezomib consolidaion
    Reporting group description
    		 Bortezomib was given at 1.3 mg/m² by subcutaneous injection (or intravenously if the patient did not tolerate subcutaneous injection) on days 1, 8, 15 and 22 of each 4-week cycle. After 3 cycles and approximately (within 4 weeks of) 6 months post ASCT, patients underwent re-staging of their disease. Patients with progressive disease came off protocol. All other patients continued treatment for a maximum of 8 cycles, as tolerated, and then stopped treatment. Within 4 weeks of stopping treatment patients underwent re-staging of their disease

    Primary: Disease response at 6 months post ASCT

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    End point title
    		 Disease response at 6 months post ASCT [1]
    End point description
    End point type
    Primary
    End point timeframe
    6 months post ASCT
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This primary endpoint is the proportion of patients in each of the response categories. No specific statistical analysis is required to establish the percentage of patients. This can be calculated using the number of patients who are in the trial and the number of patients in each response category.
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    34
    Units: Patients
        sCR/CR
    5
        VGPR
    23
        PR
    6
    No statistical analyses for this end point

    Primary: Disease response at 12 months post ASCT

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    End point title
    		 Disease response at 12 months post ASCT [2]
    End point description
    End point type
    Primary
    End point timeframe
    12 months post ASCT
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This primary endpoint is the proportion of patients in each of the response categories. No specific statistical analysis is required to establish the percentage of patients. This can be calculated using the number of patients who are in the trial and the number of patients in each response category.
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    29
    Units: Patients
        sCR/CR
    7
        VGPR
    22
    No statistical analyses for this end point

    Primary: Toxicity

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    End point title
    		 Toxicity [3]
    End point description
    Number of patients suffering grade 3 or 4 toxicity as assessed by the NCI Common Terminology for Adverse Events (v3.0)
    End point type
    Primary
    End point timeframe
    Between informed consent and 30 days post last trial treatment
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This primary endpoint is the number of patients suffering grade 3 or 4 adverse events. No specific statistical analysis is necessary to establish the percentage of patients. This can be calculated using the numbers of patients on the trial and number suffering grade 3 or 4 adverse events.
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    39
    Units: Patients
        Patients reporting grade 3 or 4 AE
    13
        Patients not reporting grade 3 or 4 AE
    26
    No statistical analyses for this end point

    Secondary: MRD status at 6 months post ASCT

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    End point title
    		 MRD status at 6 months post ASCT
    End point description
    End point type
    Secondary
    End point timeframe
    6 months post ASCT
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    19
    Units: Patients
        MRD negative
    9
        MRD positive
    10
    No statistical analyses for this end point

    Secondary: MRD status at 12 months post ASCT

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    End point title
    		 MRD status at 12 months post ASCT
    End point description
    End point type
    Secondary
    End point timeframe
    12 months post ASCT
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    19
    Units: Patients
        MRD negative
    13
        MRD positive
    6
    No statistical analyses for this end point

    Secondary: Median progression free survival from ASCT

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    End point title
    		 Median progression free survival from ASCT
    End point description
    End point type
    Secondary
    End point timeframe
    Endpoint was analysed once all the trial data had been entered
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    40
    Units: Number of months
    median (confidence interval 95%)
        Number of months
    41.6 (37.3 to 41.6)
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    		 Quality of life
    End point description
    Change in quality of life score between baseline and 12 months post ASCT
    End point type
    Secondary
    End point timeframe
    Between baseline and 12 months post ASCT
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    6
    Units: Quality of life score
    median (confidence interval 95%)
        Change in quality of life score
    0.0 (-16.7 to 33.3)
    No statistical analyses for this end point

    Secondary: Outcome of relapse - salvage regimen

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    End point title
    		 Outcome of relapse - salvage regimen
    End point description
    Salvage regimens used for patients who relapsed
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    28
    Units: Patients
        Bortezomib based regimen
    13
        Carfilzomib based regimen
    5
        Not started second line therapy
    10
    No statistical analyses for this end point

    Secondary: Progression free survival from the start of second line therapy

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    End point title
    		 Progression free survival from the start of second line therapy
    End point description
    Progression free survival from the start of second line therapy
    End point type
    Secondary
    End point timeframe
    Duration of trial
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    18
    Units: Months
    median (confidence interval 95%)
        Number of months
    17.7 (13.7 to 21.7)
    No statistical analyses for this end point

    Secondary: Best response to salvage regimen

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    End point title
    		 Best response to salvage regimen
    End point description
    Response with bortezomib salvage regimen
    End point type
    Secondary
    End point timeframe
    Salvage regimen assessment
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    13
    Units: Patients
        VGPR
    6
        PR
    4
        SD
    3
    No statistical analyses for this end point

    Secondary: Second progression free survival

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    End point title
    		 Second progression free survival
    End point description
    Second progression free survival from start of second line therapy
    End point type
    Secondary
    End point timeframe
    Whole trial
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    18
    Units: Months
    median (confidence interval 95%)
        Months
    17.7 (13.7 to 21.7)
    No statistical analyses for this end point

    Secondary: Second progression free survival

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    End point title
    		 Second progression free survival
    End point description
    Second progression free survival from registration
    End point type
    Secondary
    End point timeframe
    Whole trial
    End point values
    		 Bortezomib consolidaion
    Number of subjects analysed
    18
    Units: Months
    median (confidence interval 95%)
        Months
    71.4 (54.1 to 88.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between informed consent and 30 days post last trial treatment administration
    Adverse event reporting additional description
    Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events were recorded in the patient notes and the trial CRFs. Those meeting the definition of a Serious Adverse Event were also reported using the trial specific SAE Reporting template.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI-CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Bortezomib
    Reporting group description
    		 -

    Serious adverse events
    		 Bortezomib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 39 (10.26%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection with normal ANC
    Additional description: Infection with normal ANC was a grade 2 AE. Reported as SAE due to previous drug overdose for this patient.
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bortezomib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Nervous system disorders
    Neuropathy (sensory)
         subjects affected / exposed
    24 / 39 (61.54%)
         occurrences all number
    108
    Dizziness
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    9
    Neuropathy (autonomic)
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Peripheral neuropathy (motor)
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Cranial - various motor
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    31 / 39 (79.49%)
         occurrences all number
    121
    Flu like symptoms
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Injection site reaction
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Hot flushes
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Platelets
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    6
    Neutrophils
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Hearing
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Eye disorders
    Vision - blurred vision
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Dry eye syndrome
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Watery eye
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    6
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 39 (46.15%)
         occurrences all number
    58
    Diarrhoea
         subjects affected / exposed
    15 / 39 (38.46%)
         occurrences all number
    27
    Nausea
         subjects affected / exposed
    14 / 39 (35.90%)
         occurrences all number
    26
    Pain - abdominal
         subjects affected / exposed
    11 / 39 (28.21%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    8
    Dyspnoea
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dermatology/Skin - other
         subjects affected / exposed
    11 / 39 (28.21%)
         occurrences all number
    26
    Rash: Erythema multiforme
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Pain - Joint
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    13
    Pain - back
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    9
    Infections and infestations
    Infection - Pulmonary/Upper Respiratory
         subjects affected / exposed
    10 / 39 (25.64%)
         occurrences all number
    12
    Infection - lung
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Infections - other
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Infection - mucosa
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Infection - conjunctiva
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Oct 2009
    To show changes from protocol version 1.0 to protocol v2.1 a) Clarified that Derralyn Hughes is the Principal Investigator at the Royal Free Hospital site (Section 1). b) Updated the protocol exclusion criteria to accurately reflect the SmPc (section 11.2). c) Clarified that the hospital pharmacy would re-constitute the IMP, rather than the pharmacist, as a pharmacy technician might be responsible for reconstitution as per standard hospital practice (section 13.1.1). d) Clarified in the protocol the total number of visits required for patients (section 15). e) The protocol was amended so as to clarify the purpose of the the inclusion of the control group and its impact on data analysis (section 26.3). f) Provided in the protocol a statement which clearly defines Janssen Cilag's involvement in the proposed research (Section 33). g) Changed the formula used to calculate the body surface area to the Dubois formula (Appendix 4)
    17 Dec 2009
    Updated IRAS form with details of radiation dose (section 3, Part B)
    14 Jun 2010
    Notification of urgent safety measure - changed the days of dosing in each cycle from Days 1, 4, 8 and 11 to Days 1, 8, 15 and 22, as we consider that treatment regime will be better tolerated. Also notified the MHRA of minor changes made to the protocol (ie to create version 2.2, dated 27 Nov 2009) since the last version they reviewed (ie. version 2.1, dated 7 Aug 2009).
    17 Sep 2010
    To submit IMP labels for carton and blister vial for bortezomib
    14 Jan 2011
    Temporary halt to recruitment
    03 Mar 2011
    Changes made throughout protocol (many for clarification).
    09 Mar 2011
    Request to re-start trial
    21 Nov 2011
    Change for bortezomib administration from IV to subcut; Amended IMP labels for subcut bortezomib Addition of MRD tests by multiparameter flow cytometry Transfer of administration from UCL JRO to UCL CTC
    08 Dec 2011
    Urgent Safety Measure: Trial bortezomib (Velcade) IV stock temporarily used for subcutaneous administration in place of subcutaneous stock that could not be shipped to sites.
    18 Jun 2012
    Protocol and CTA were amended to reflect the following changes: • Skeletal survey (CT, MRI, PET) are now optional • Changes to exclusion criteria (bisphosphonate treatment; CYP219 and CYP3A4 inhibitors and inducers) • Intravenous administration of bortezomib brought back for patients who cannot tolerate the subcut administration • Ambiguity in Interim analysis section corrected
    25 Sep 2015
    Protocol updated to version 7.0, - Addition of secondary endpoints - Extension of trial follow up period and avoidance of trial closure - Adoption of bortezomib SPC as RSI for both IV and SC, replacing IB and protocol 6.0 Appendix 6.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    31 Dec 2010
    A key member of the trial team, with responsibilities for co-ordination, had recently left. A temporary halt was put in place on 31/12/2010 to allow sufficient time for an appropriate replacement to be put in place. The trial was re-started on 28/02/2011
    28 Feb 2011

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Serious and non serious AEs are listed under non-serious adverse events

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30460696
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