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    Clinical Trial Results:
    A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma who Have Received at least 2 Prior Lines of Therapy including Lenalidomide and a Proteasome Inhibitor.

    Summary
    EudraCT number
    		 2017-003951-44
    Trial protocol
    		 GR  
    Global end of trial date
    26 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2022
    First version publication date
    09 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ΕΑΕ-2017/ΜΜ01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03475628
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hellenic Society of Hematology
    Sponsor organisation address
    27 Kifisias Ave, Athens, Greece, 11523
    Public contact
    info@heads-research.com, Health Data Specialists Ireland Limited, 0035 3906480600,
    Scientific contact
    info@heads-research.com, Health Data Specialists Ireland Limited, 0035 3906480600,
    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
    17 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate changes in bone resorption markers after 4 months of daratumumab monotherapy. Namely, C-telopeptide of collagen type 1 (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b) will be evaluated.
    Protection of trial subjects
    This study was conducted in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and and regulations of the country in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 30 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 57
    Worldwide total number of subjects
    57
    EEA total number of subjects
    57
    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)
    12
    From 65 to 84 years
    44
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 57 patients were enrolled and initiated study treatment across 6 sites in Greece. Among them, 33 had available results for bone resorption markers at baseline and at 4 months post-treatment onset. All 24 patients with no bone resorption markers at 4 months post-treatment onset discontinued treatment prior 4 months.

    Pre-assignment
    Screening details
    		 Patients who did not meet all the inclusion criteria or met any of the exclusion criteria were considered screening failures. Two patients signed an informed consent form and were screened but not enrolled (1 patient due to being lost-to follow-up during screening and 1 patient due to not fulfilling inclusion criteria).

    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
    		 Daratumuamb
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose: 16 mg/kg milligrams(s) / kilogram Treatment with study design continues until disease progression, unacceptable toxicity (adverse event related to study drug), or the subject meets other criteria for discontinuation of study drug, for a maximum duration of 24 months.

    Number of subjects in period 1
    		Daratumuamb
    Started
    57
    Completed
    18
    Not completed
    39
         Consent withdrawn by subject
    1
         Death
    38

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial (overall period) Total
    Number of subjects
    		 57 57
    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)
    		 12 12
        From 65-84 years
    		 44 44
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 73.0 (65.0 to 79.0) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 26 26
    Ethnic Group
    Units: Subjects
        Greek
    		 55 55
        Albanian
    		 1 1
        Bulgarian
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Daratumuamb
    Reporting group description
    		 -

    Subject analysis set title
    Intra-group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Baseline control group

    Primary: % Median Changes in Bone Resorption Marker, Namely C-telopeptide of Collagen Type 1 (CTX) From Baseline to 4 Months.

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    End point title
    		 % Median Changes in Bone Resorption Marker, Namely C-telopeptide of Collagen Type 1 (CTX) From Baseline to 4 Months.
    End point description
    Percent changes in bone resorption marker, namely C-telopeptide of collagen type 1 (CTX) from baseline to 4 months.
    End point type
    Primary
    End point timeframe
    Assessed on baseline and after 4 months from initiation of daratumumab monotherapy.
    End point values
    		 Daratumuamb Intra-group
    Number of subjects analysed
    33
    33 [1]
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        % change in CTX from baseline to 4 months
    3.9 (-38.6 to 30.1)
    0 (0 to 0)
    Notes
    [1] - Intra-group used for baseline statistical analysis.
    Statistical analysis title
    		 Non-Parametric Statistical Hypothesis Test
    Comparison groups
    Daratumuamb v Intra-group
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.747
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - The primary efficacy variable, the median percent change in CTX from baseline to endpoint after 4 months of daratumumab monotherapy, was analyzed by means of an analysis of covariance (Wilcoxon) model with site as fixed effect and baseline value as covariate.

    Primary: % Median Changes in Bone Resorption Marker, Namely Tartrate-resistant Acid Phosphatase-5b (TRACP-5b) From Baseline to 4 Months.

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    End point title
    		 % Median Changes in Bone Resorption Marker, Namely Tartrate-resistant Acid Phosphatase-5b (TRACP-5b) From Baseline to 4 Months.
    End point description
    Percent median changes in Bone Resorption Marker, namely tartrate-resistant acid phosphatase-5b (TRACP-5b) from Baseline to 4 months.
    End point type
    Primary
    End point timeframe
    Assessed on baseline and after 4 months from initiation of daratumumab monotherapy.
    End point values
    		 Daratumuamb Intra-group
    Number of subjects analysed
    33
    33
    Units: percent volume/volume
    median (inter-quartile range (Q1-Q3))
        % change in TRACP-5b from baseline to 4 months
    -2.6 (-23.6 to 31.7)
    0 (0 to 0)
    Statistical analysis title
    		 Non-Parametric Statistical Hypothesis Test
    Comparison groups
    Daratumuamb v Intra-group
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.694
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [3] - The primary efficacy variables, the percent median changes in TRACP-5B from baseline to endpoint after 4 months of daratumumab monotherapy, was analyzed by means of an analysis of covariance (Wilcoxon) model with site as fixed effect and baseline value as covariate.

    Secondary: % Median Changes in Bone Formation Marker, bALP

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    End point title
    		 % Median Changes in Bone Formation Marker, bALP
    End point description
    Percent median change from baseline in bone formation marker bALP (measured in U/L) after 4, 8 and 12 months of daratumumab monotherapy (or at the end of therapy). 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change in bALP from baseline to 4 months
    18.4 (-8.3 to 45.5)
        Percent change in bALP from baseline to 8 months
    27.3 (-16.8 to 71.5)
        Percent change in bALP from baseline to 12 months
    22.5 (-2.9 to 78.6)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Formation Marker, OC

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    End point title
    		 % Median Changes in Bone Formation Marker, OC
    End point description
    Change from baseline in bone formation marker OC (measured in ng/ml) after 4, 8 and 12 months of daratumumab monotherapy (or at the end of therapy). 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    Median change from baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    92.6 (-18.1 to 352.1)
        Percent change from baseline to 8 months
    267.2 (98.1 to 571.8)
        Percent change from baseline to 12 months
    297.1 (29.2 to 447.2)
    No statistical analyses for this end point

    Secondary: % Median changes in Bone Formation Marker, PINP

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    End point title
    		 % Median changes in Bone Formation Marker, PINP
    End point description
    Median change from baseline in bone formation marker PINP (measured in ng/ml) after 4, 8 and 12 months of daratumumab monotherapy (or at the end of therapy). 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    10.2 (-16.9 to 54.5)
        Percent change from baseline to 8 months
    39.9 (6.9 to 264.9)
        Percent change from baseline to 12 months
    34.0 (-19.5 to 162.1)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Resorption Marker, CTX

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    End point title
    		 % Median Changes in Bone Resorption Marker, CTX
    End point description
    Median change from baseline in bone resorption marker CTX (measured in pg/ml) after 8 and 12 months of daratumumab monotherapy. 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 8 months
    6.6 (-52.5 to 41.6)
        Percent change from baseline to 12 months
    -33.9 (-79.4 to 0.9)
    No statistical analyses for this end point

    Secondary: % Median change in Bone Resorption Marker, TRACP-5b

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    End point title
    		 % Median change in Bone Resorption Marker, TRACP-5b
    End point description
    Median change from baseline in bone resorption marker TRACP-5b (measured in mU/dL) after 8 and 12 months of daratumumab monotherapy. 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent volume/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 8 months
    10.3 (-18.6 to 45.0)
        Percent change from baseline to 12 months
    5.7 (-21.6 to 38.6)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Marker RANKL

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    End point title
    		 % Median Changes in Bone Marker RANKL
    End point description
    Median change from baseline in RANKL (measured in pg/ml) after 4, 8 and 12 months of daratumumab monotherapy. 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    20.7 (-32.9 to 100.9)
        Percent change from baseline to 8 months
    74.0 (-26.9 to 194.6)
        Percent change from baseline to 12 months
    83.0 (23.4 to 121.2)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Marker Ratio,RANKL/OPG Ratio

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    End point title
    		 % Median Changes in Bone Marker Ratio,RANKL/OPG Ratio
    End point description
    Median Change from baseline in RANKL/OPG ratio after 4, 8 and 12 months of daratumumab monotherapy. 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: Ratio RANKL/OPG
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    3.80 (-39.29 to 147.06)
        Percent change from baseline to 8 months
    48.30 (-38.62 to 270.33)
        Percent change from baseline to 12 months
    57.11 (-15.91 to 179.54)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Marker CCL3

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    End point title
    		 % Median Changes in Bone Marker CCL3
    End point description
    Median change from baseline in CCL3 (measured in pg/ml) after 4, 8 and 12 months of daratumumab monotherapy. 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    -16.0 (-34.4 to 6.0)
        Percent change from baseline to 8 months
    -22.0 (-61.9 to 34.7)
        Percent change from baseline to 12 months
    -26.1 (-63.3 to -1.9)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Marker Dkk1

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    End point title
    		 % Median Changes in Bone Marker Dkk1
    End point description
    Median change from baseline in Dkk1 (measured in ng/ml) after 4, 8 and 12 months of daratumumab monotherapy. 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    -17.5 (-42.5 to -4.9)
        Percent change from baseline to 8 months
    -27.6 (-35.6 to -11.7)
        Percent change from baseline to 12 months
    -38.3 (-54.1 to -30.4)
    No statistical analyses for this end point

    Secondary: % Median Changes in Bone Marker SOST

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    End point title
    		 % Median Changes in Bone Marker SOST
    End point description
    Median change from baseline in SOST (measured in pmol/L) after 4, 8 and 12 months of daratumumab monotherapy. 4 months, N=33 8 months, N=18 12 months, N=14
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: percent weight/volume
    median (inter-quartile range (Q1-Q3))
        Percent change from baseline to 4 months
    2.7 (-32.2 to 69.3)
        Percent change from baseline to 8 months
    -14.6 (-43.1 to 6.5)
        Percent change from baseline to 12 months
    -16.5 (-48.8 to 187.7)
    No statistical analyses for this end point

    Secondary: Median Changes in Bone Marker Activin-A

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    End point title
    		 Median Changes in Bone Marker Activin-A
    End point description
    Change from baseline in activin-A (measured in μg/L) after 4, 8 and 12 months of daratumumab monotherapy. There are no available results due to insufficient sample tissue.
    End point type
    Secondary
    End point timeframe
    From baseline up to 12 months of daratumumab monotherapy or at end of treatment.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    0 [4]
    Units: percent weight/volume
        median (standard deviation)
    ( )
    Notes
    [4] - There are no available results due to insufficient sample tissue.
    No statistical analyses for this end point

    Secondary: Immunomodulatory Effects of Daratumumab on T Cells by Comprehensive Molecular and Phenotypic Studies and Correlations With Bone Markers.

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    End point title
    		 Immunomodulatory Effects of Daratumumab on T Cells by Comprehensive Molecular and Phenotypic Studies and Correlations With Bone Markers.
    End point description
    The evaluation of the immunomodulatory effects of daratumumab on T cells by comprehensive molecular and phenotypic studies and correlations with bone markers. This was not a measurable outcome.
    End point type
    Secondary
    End point timeframe
    Measured at baseline and after 3 and 6 months after initiation of daratumumab monotherapy.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    0 [5]
    Units: Count
        number (not applicable)
    Notes
    [5] - This was not a measurable outcome.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression free survival is defined as the time, in months, from recruitment to the date of the first documented PD or death due to any cause, whichever comes first. PD was assessed by the investigator based on the analysis of serum and urine protein electrophoresis (sPEP and uPEP), serum free light chain protein (sFLC), Corrected serum calcium assessment, imaging and bone marrow assessments as per modified IMWG guidelines.
    End point type
    Secondary
    End point timeframe
    From recruitment to the date of the first documented PD or death due to any cause, whichever comes first (approximately up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: Months
    median (confidence interval 95%)
        Median (95% Confidence Interval)
    4.66 (2.98 to 7.15)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time, in months, from treatment start to the date of death from any cause.
    End point type
    Secondary
    End point timeframe
    Time from first dose of study treatment to death (approximately up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: Months
    median (confidence interval 95%)
        Median (95% Confidence Interval)
    10.46 (8.33 to 16.59)
    No statistical analyses for this end point

    Secondary: Time to Next Treatment

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    End point title
    		 Time to Next Treatment
    End point description
    Time to next therapy will be defined as the time, in months, from treatment start to the date of next anti-neoplastic therapy or death from any cause, whichever comes first.
    End point type
    Secondary
    End point timeframe
    From first dose until the date to next anti-neoplastic therapy or death from any cause, whichever comes first (approximately up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: Months
    median (confidence interval 95%)
        Median (95% Confidence Interval)
    7.10 (3.80 to 9.10)
    No statistical analyses for this end point

    Secondary: The Incidence of Pathological Fractures (Skeletal Surveys-Skeletal Related Events)

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    End point title
    		 The Incidence of Pathological Fractures (Skeletal Surveys-Skeletal Related Events)
    End point description
    The incidence of pathological fractures will be evaluated in terms of number (and percentage) of patients with events and number of events per patient. No skeletal-related events were observed during the study period.
    End point type
    Secondary
    End point timeframe
    From baseline to 24 months (up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    0 [6]
    Units: Count
        number (not applicable)
    Notes
    [6] - No skeletal-related events were observed during the study period.
    No statistical analyses for this end point

    Secondary: Need for Radiotherapy or Surgery to the Bones (Skeletal Surveys-Skeletal Related Events)

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    End point title
    		 Need for Radiotherapy or Surgery to the Bones (Skeletal Surveys-Skeletal Related Events)
    End point description
    Need for radiotherapy or surgery to the bones will be evaluated in terms of number (and percentage) of patients with events and number of events per patient. No skeletal-related events were observed during the study period.
    End point type
    Secondary
    End point timeframe
    From baseline to 24 months (up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    0 [7]
    Units: Count
        number (not applicable)
    Notes
    [7] - No skeletal-related events were observed during the study period.
    No statistical analyses for this end point

    Secondary: Spinal Cord Compression (Skeletal Surveys-Skeletal Related Events)

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    End point title
    		 Spinal Cord Compression (Skeletal Surveys-Skeletal Related Events)
    End point description
    Spinal cord compression will be evaluated in terms of number (and percentage) of patients with events and number of events per patient. No skeletal-related events were observed during the study period.
    End point type
    Secondary
    End point timeframe
    From baseline to 24 months (up to 2 years).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    0 [8]
    Units: Count
        number (not applicable)
    Notes
    [8] - No skeletal-related events were observed during the study period.
    No statistical analyses for this end point

    Secondary: Safety (Adverse Events)

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    End point title
    		 Safety (Adverse Events)
    End point description
    The incidence of Adverse Events will be assessed according to the common Terminology Criteria for Adverse Events.
    End point type
    Secondary
    End point timeframe
    Continuously throughout the study, starting from informed consent until 30 days after last study treatment (approximately up to 30 months).
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: Count
    number (not applicable)
        Any (N)SAE
    47
        Any NSAE
    45
        Any SAE
    19
        Any (N)SADR related to daratumumab
    10
        Any NSADR related to daratumumab
    7
        Any SADR related to daratumumab
    4
        Any (N)SAE of Grade >=3
    31
        Any (N)SAE of Grade 3 or 4
    30
        Any fatal SAE
    12
        At least one IRR
    3
    No statistical analyses for this end point

    Secondary: % Median Change in Bone Mineral Density (BMD) of lumbar spine

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    End point title
    		 % Median Change in Bone Mineral Density (BMD) of lumbar spine
    End point description
    Median change in Bone Mineral Density (BMD) of lumbar spine measured by DXA after 6 and 12 months of daratumumab monotherapy.
    End point type
    Secondary
    End point timeframe
    Measured at baseline and after 6 and 12 months after initiation of daratumumab monotherapy.
    End point values
    		 Daratumuamb
    Number of subjects analysed
    57
    Units: score
    median (inter-quartile range (Q1-Q3))
        % change in T-score from baseline to 6 months
    -3.2 (-192.3 to 10.5)
        % change in T-score from baseline to 12 months
    3.2 (-47.4 to 28.0)
        % change in Z-score from baseline to 6 months
    -186.4 (-200.0 to -15.4)
        % change in Z-score from baseline to 12 months
    -81.8 (-333.3 to 0.0)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 years.
    Adverse event reporting additional description
    All patients who received at least one dose of study treatment were considered for data analysis. The incidence of adverse events (AEs) was tabulated by MedDRA System Organ Class (SOC) and Preferred Term (PT), overall and by maximum Common Terminology Criteria for Adverse Events (CTCAE) grade.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Serious adverse events
    		 Overall Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 57 (33.33%)
         number of deaths (all causes)
    38
         number of deaths resulting from adverse events
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    General disorders and administration site conditions
    Febrile neutropenia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 4
    Pneumonia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia influenza
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 57 (1.75%)
         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
    		 Overall Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 57 (78.95%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Vein rupture
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    3
    Chills
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    13 / 57 (22.81%)
         occurrences all number
    14
    Influenza like illness
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    3
    Dyspnoea
         subjects affected / exposed
    4 / 57 (7.02%)
         occurrences all number
    4
    Psychiatric disorders
    Dementia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Blood bilirubin increased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Neutrophil count decreased
         subjects affected / exposed
    8 / 57 (14.04%)
         occurrences all number
    8
    Platelet count decreased
         subjects affected / exposed
    10 / 57 (17.54%)
         occurrences all number
    14
    Serum ferritin decreased
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac asthma
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Coronary artery disease
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    25 / 57 (43.86%)
         occurrences all number
    36
    Thrombocytopenia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Xeroderma
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Bone pain
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Muscle spasms
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Muscular weakness
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    9 / 57 (15.79%)
         occurrences all number
    9
    Otitis media
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Tooth infection
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    4
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Hyperglycaemia
         subjects affected / exposed
    2 / 57 (3.51%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 57 (5.26%)
         occurrences all number
    3
    Hyponatraemia
         subjects affected / exposed
    5 / 57 (8.77%)
         occurrences all number
    5
    Iron deficiency
         subjects affected / exposed
    1 / 57 (1.75%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2018
    Amendment 1 The overall reason for the amendment was to clarify the timing of assessments.
    02 Jul 2019
    Amendment 2 The overall reason for the amendment was to include the new guidelines regarding HBV reactivation risk in patients receiving daratumumab treatment, and to clarify/update certain parts of the protocol.
    08 Jun 2020
    Amendment 3 The overall reason for the amendment was to update the protocol regarding the overall study duration from 30 to 36 months.

    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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