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    Clinical Trial Results:
    A Phase 3 Randomized, Multicenter Study of Subcutaneous versus Intravenous Administration of Daratumumab in Subjects with Relapsed or Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2017-000206-38
    Trial protocol
    		 SE   CZ   GB   GR   ES   FR   PL   IT  
    Global end of trial date
    04 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2023
    First version publication date
    18 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54767414MMY3012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03277105
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202 South, Raritan, New Jersey, United States, 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    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 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant human hyaluronidase PH20 (Dara SC) was non-inferior to intravenous (IV) administration of daratumumab (Dara IV) in terms of the overall response rate (ORR) and maximum trough concentration (Ctrough).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2017
    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
    Australia: 28
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 36
    Country: Number of subjects enrolled
    Czechia: 36
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Russian Federation: 55
    Country: Number of subjects enrolled
    Sweden: 36
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Ukraine: 47
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    522
    EEA total number of subjects
    212
    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)
    221
    From 65 to 84 years
    293
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 522 subjects were enrolled, of which 518 subjects were treated and none of the subject completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daratumumab IV
    Arm description
    		 Subjects received daratumumab 16 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    JNJ-54767414
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daratumumab 16 milligrams per kilogram (mg/kg) was administered once weekly in Cycles 1 and 2, every 2 weeks in Cycles 3 to 6, and every 4 weeks thereafter until disease progression, unacceptable toxicity or the end of study.

    Arm title
    		 Daratumumab SC
    Arm description
    		 Subjects received daratumumab 1800 mg subcutaneous (SC) injection co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Units per millilitre (U/mL), once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    JNJ-54767414
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a fixed dose of daratumumab 1800 mg with rHuPH20 2000 U/mL, once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.

    Number of subjects in period 1
    		Daratumumab IV Daratumumab SC
    Started
    259
    263
    Treated (Safety Analysis Set)
    258
    260
    Completed
    0
    0
    Not completed
    259
    263
         Adverse event, serious fatal
    129
    124
         Consent withdrawn by subject
    10
    10
         Unspecified
    118
    125
         Lost to follow-up
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daratumumab IV
    Reporting group description
    		 Subjects received daratumumab 16 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Reporting group title
    Daratumumab SC
    Reporting group description
    		 Subjects received daratumumab 1800 mg subcutaneous (SC) injection co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Units per millilitre (U/mL), once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Reporting group values
    		 Daratumumab IV Daratumumab SC Total
    Number of subjects
    		 259 263 522
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 100 121 221
        From 65-84 years
    		 151 142 293
        85 years and over
    		 8 0 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.8 ( 10.16 ) 65.3 ( 9.11 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 110 127 237
        Male
    		 149 136 285
    Stage of Disease (ISS)
    Units: Subjects
        Stage I
    		 94 82 176
        Stage II
    		 89 101 190
        Stage III
    		 76 79 155
        Not reported
    		 0 1 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 40 32 72
        Black or African American
    		 5 9 14
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 201 207 408
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 12 14 26
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 9 14 23
        Not Hispanic or Latino
    		 227 225 452
        Unknown or Not Reported
    		 23 24 47
    Region of Enrollment
    Units: Subjects
        AUSTRALIA
    		 15 13 28
        BRAZIL
    		 10 15 25
        CANADA
    		 16 20 36
        CZECH REPUBLIC
    		 20 16 36
        FRANCE
    		 6 10 16
        GREECE
    		 1 6 7
        ISRAEL
    		 5 8 13
        ITALY
    		 10 16 26
        JAPAN
    		 24 18 42
        POLAND
    		 39 26 65
        RUSSIAN FEDERATION
    		 28 27 55
        SOUTH KOREA
    		 7 4 11
        SPAIN
    		 14 12 26
        SWEDEN
    		 18 18 36
        TAIWAN
    		 6 8 14
        UKRAINE
    		 22 25 47
        UNITED KINGDOM
    		 16 17 33
        UNITED STATES
    		 2 4 6
    Number of prior lines
    Units: Subjects
        Less than or equal to (<= 4) Lines
    		 175 174 349
        Greater than (>) 4 Lines
    		 84 89 173
    Refractory status
    Units: Subjects
        Both PI and IMiD
    		 133 125 258
        IMiD only
    		 81 67 148
        None
    		 26 41 67
        PI only
    		 19 30 49
    Weight group
    Units: Subjects
        <=65
    		 92 94 186
        >65 - 85
    		 105 102 207
        >85
    		 61 66 127
        Not Weighed
    		 1 1 2
    AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.8 ( 10.16 ) 65.3 ( 9.11 ) -

    End points

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    End points reporting groups
    Reporting group title
    Daratumumab IV
    Reporting group description
    		 Subjects received daratumumab 16 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Reporting group title
    Daratumumab SC
    Reporting group description
    		 Subjects received daratumumab 1800 mg subcutaneous (SC) injection co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Units per millilitre (U/mL), once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Primary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR) [1]
    End point description
    ORR was defined as the percentage of subjects who achieved partial response (PR) or better according to International Myeloma Working Group (IMWG) criteria, during or after study treatment. IMWG criteria for PR: greater than or equal to (>=) 50 percent (%) reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to less than (<) 200 milligrams (mg)/24 hours. Intent-to-treat (ITT) analysis set included subjects randomised into the study.
    End point type
    Primary
    End point timeframe
    Up to 3 years
    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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Percentage of subjects
        number (confidence interval 95%)
    39.8 (33.8 to 46.0)
    43.7 (37.6 to 50.0)
    No statistical analyses for this end point

    Primary: Maximum Trough Concentration (Ctrough) of Daratumumab

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    End point title
    		 Maximum Trough Concentration (Ctrough) of Daratumumab [2]
    End point description
    Maximum Ctrough was defined as the serum predose concentration of daratumumab on Cycle 3 Day 1. Pharmacokinetics-evaluable analysis set included subjects who received all 8 weekly full doses of daratumumab IV or daratumumab SC in Cycle 1 and Cycle 2 and provided a pre-dose pharmacokinetic sample on Cycle 3 Day 1 within the sampling window of 8 hours prior to the start of dose administration. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Predose on Cycle 3 Day 1 (each cycle of 28 days)
    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: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    146
    149
    Units: micrograms per millilitre (mcg/mL)
        arithmetic mean (standard deviation)
    496 ( 231 )
    581 ( 315 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-emergent Infusion-related Reactions (IRR)

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    End point title
    		 Percentage of Subjects With Treatment-emergent Infusion-related Reactions (IRR)
    End point description
    Percentage of subjects with treatment-emergent infusion-related reactions were reported. Safety analysis set included all randomised subjects who receive at least 1 dose of study drug and were analysed according to the actual treatment that they received.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    258
    260
    Units: Percentage of subjects
        number (confidence interval 95%)
    34.5 (28.7 to 40.6)
    12.7 (8.9 to 17.4)
    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
    PFS was defined as time from date of randomisation to either progression of disease (PD), death due to any cause, whichever occurs first. IMWG criteria for PD: Increase of 25% from lowest response value in Serum M component (absolute increase [AI] must be >=0.5 grams per decilitre (g/dL), Urine M-component (AI must be >=200 mg/24 hours), Subjects without measurable serum and urine M-protein levels: difference between involved and uninvolved free light chain (FLC) levels (AI must be >10 milligrams per decilitre (mg/dL), subjects without measurable serum and urine M-protein levels and without measurable disease by FLC levels, bone marrow PC% (absolute percentage must be >=10%), definite development of new bone lesions or soft tissue plasmacytomas or increase in size of bone lesions or tissue plasmacytomas and development of hypercalcemia (serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder. ITT analysis set included subjects randomised into the study.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Months
        median (confidence interval 95%)
    6.08 (4.73 to 7.43)
    5.62 (4.70 to 7.49)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Very Good Partial Response (VGPR) or Better

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    End point title
    		 Percentage of Subjects With Very Good Partial Response (VGPR) or Better
    End point description
    VGPR or better was defined as the percentage of subjects who achieved VGPR or better (VGPR, complete response (CR) or stringent complete response [sCR]), based on computerized algorithm as per IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >=90 percent (%) reduction in serum M-protein plus urine M-protein <100 milligrams (mg)/24 hours, CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells (PCs) in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescencea or 2 to 4 color flow cytometry. ITT analysis set included subjects randomised into the study
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Percentage of subjects
        number (confidence interval 95%)
    21.6 (16.8 to 27.1)
    23.6 (18.6 to 29.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Complete Response (Including sCR) or Better

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    End point title
    		 Percentage of Subjects With Complete Response (Including sCR) or Better
    End point description
    CR or better was defined as percentage of subjects with a CR or better (CR or stringent complete response [sCR]) based on computerized algorithm as per IMWG criteria. IMWG criteria for CR- negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow. sCR: CR plus normal FLC ratio, and absence of clonal PCs by IHC, immunofluorescencea or 2- to 4 color flow cytometry. ITT analysis set included subjects randomised into the study.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Percentage of subjects
        number (confidence interval 95%)
    5.4 (3.0 to 8.9)
    4.6 (2.4 to 7.8)
    No statistical analyses for this end point

    Secondary: Time to Next Therapy

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    End point title
    		 Time to Next Therapy
    End point description
    Time to next therapy was defined as the time from randomisation to the start of the first subsequent anti-cancer therapy. ITT analysis set included subjects randomised into the study.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Months
        median (confidence interval 95%)
    9.43 (8.15 to 10.71)
    8.80 (7.59 to 10.91)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomisation to the date of the subject's death due to any cause. ITT analysis set included subjects randomised into the study. Here, 99999 signifies lower limit of 95% CI were not estimable due to lower number of events.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    259
    263
    Units: Months
        median (confidence interval 95%)
    25.56 (22.05 to 99999)
    28.19 (22.77 to 99999)
    No statistical analyses for this end point

    Secondary: Patient-Reported Satisfaction With Therapy as Assessed with Cancer Therapy Satisfaction Questionnaire (CTSQ) at Specified Timepoints

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    End point title
    		 Patient-Reported Satisfaction With Therapy as Assessed with Cancer Therapy Satisfaction Questionnaire (CTSQ) at Specified Timepoints
    End point description
    Modified-CTSQ contain 9 items (2 items for Thoughts about Cancer Therapy and 7 items in a defined domain of Satisfaction with Therapy) specific to satisfaction with therapy and for comparison of SC and IV administration. Satisfaction with therapy was calculated based on 7-items using 5-point verbal rating scale, where 1= never and 5= always. Scores were averaged and transformed to a 0-100 scale; higher scores represent better health. At least 5 of the 7 items within the Satisfaction with Therapy domain had to be completed to calculate a domain score. No domain score was calculated for Thoughts about Cancer Therapy. ITT analysis set included subjects randomised into the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint and 'n' (number of subjects analysed) signifies the number of subjects analysed at a specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Days 8,15 and 22), Cycle 2 (Days 1,8,15 and 22), Cycle 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22 (Day 1)
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    239
    239
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n=227,230)
    70.5 ( 15.98 )
    76.9 ( 14.64 )
        Cycle 1 Day 15 (n=226,238)
    72.1 ( 16.72 )
    78.8 ( 14.94 )
        Cycle 1 Day 22 (n=226,239)
    72.8 ( 16.20 )
    78.7 ( 15.75 )
        Cycle 2 Day 1 (n=239,238)
    74.2 ( 16.44 )
    79.7 ( 16.58 )
        Cycle 2 Day 8 (n=227,232)
    74.8 ( 15.57 )
    80.1 ( 17.24 )
        Cycle 2 Day 15 (n=228,224)
    74.3 ( 16.94 )
    80.0 ( 17.37 )
        Cycle 2 Day 22 (n-221,214)
    75.2 ( 16.47 )
    79.3 ( 18.65 )
        Cycle 3 Day 1 (n=217, 224)
    76.0 ( 17.39 )
    80.4 ( 17.78 )
        Cycle 4 Day 1 (n=205,209)
    76.6 ( 17.22 )
    79.5 ( 19.88 )
        Cycle 5 Day 1 (n=187,188)
    77.1 ( 17.11 )
    79.6 ( 18.95 )
        Cycle 6 Day 1 (n=168,159)
    76.1 ( 17.79 )
    81.9 ( 18.34 )
        Cycle 7 Day 1 (n=150,137)
    78.6 ( 16.01 )
    85.0 ( 16.87 )
        Cycle 8 Day 1 (n=135,127)
    79.2 ( 15.54 )
    85.0 ( 15.18 )
        Cycle 9 Day 1 (n=121,113)
    79.8 ( 15.27 )
    85.2 ( 15.03 )
        Cycle 10 Day 1 (n=111,103)
    79.4 ( 14.73 )
    85.8 ( 13.31 )
        Cycle 11 Day 1 (n=96,94)
    79.1 ( 15.55 )
    84.8 ( 13.05 )
        Cycle 12 Day 1 (n=83, 81)
    80.3 ( 15.88 )
    85.4 ( 14.70 )
        Cycle 13 Day 1 (n=77,76)
    79.6 ( 16.57 )
    84.4 ( 15.09 )
        Cycle 14 Day 1 (n=60,61)
    80.6 ( 14.62 )
    83.5 ( 15.54 )
        Cycle 15 Day 1 (n=44,40)
    80.2 ( 15.22 )
    86.2 ( 13.51 )
        Cycle 16 Day 1 (n=29,29)
    79.4 ( 14.84 )
    88.5 ( 13.10 )
        Cycle 17 Day 1 (n=15,20)
    79.0 ( 14.34 )
    90.9 ( 11.26 )
        Cycle 18 Day 1 (n=8,10)
    84.8 ( 14.13 )
    91.4 ( 11.57 )
        Cycle 19 Day 1 (n=2,8))
    92.9 ( 10.10 )
    89.3 ( 13.36 )
        Cycle 20 Day 1 (n=0,4)
    99999 ( 99999 )
    86.6 ( 18.53 )
        Cycle 21 Day 1 (n=0,3)
    99999 ( 99999 )
    84.5 ( 20.93 )
        Cycle 22 Day 1 (n=0,1)
    99999 ( 99999 )
    96.4 ( 99999 )
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was defined as the duration from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG criteria. PD was defined as an increase of 25% from the lowest response value in one of the following: serum and urine M-component (AI must be >=0.5g/dL and >=200mg/24 hours respectively); Only in subjects without measurable serum and urine M-protein levels the difference between involved and uninvolved FLC levels (AI must be >10mg/dL); Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5mg/dL) that can be attributed solely to PC proliferative disorder. ITT analysis set included subjects randomised into the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    103
    115
    Units: months
        median (confidence interval 95%)
    10.64 (9.23 to 15.64)
    10.15 (9.23 to 13.77)
    No statistical analyses for this end point

    Secondary: Time to Partial Response (PR) or Better

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    End point title
    		 Time to Partial Response (PR) or Better
    End point description
    Time to PR or better was defined as the time from randomisation until onset of first response of PR or better. ITT analysis set included subjects randomised into the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    103
    115
    Units: months
        median (full range (min-max))
    1.02 (0.9 to 24.8)
    1.02 (0.9 to 9.4)
    No statistical analyses for this end point

    Secondary: Time to Very Good Partial Response (VGPR) or Better

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    End point title
    		 Time to Very Good Partial Response (VGPR) or Better
    End point description
    Time to VGPR or better was defined as the time from randomisation until onset of first VGPR or better. ITT analysis set included subjects randomised into the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    56
    62
    Units: months
        median (full range (min-max))
    1.92 (0.9 to 22.8)
    1.95 (1.0 to 19.4)
    No statistical analyses for this end point

    Secondary: Time to Complete Response (CR) or Better

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    End point title
    		 Time to Complete Response (CR) or Better
    End point description
    Time to CR or better was defined as the time from randomisation until onset of first CR or better. ITT analysis set included subjects randomised into the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Daratumumab IV Daratumumab SC
    Number of subjects analysed
    14
    12
    Units: months
        median (full range (min-max))
    7.23 (1.1 to 14.9)
    9.26 (1.2 to 23.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3 years
    Adverse event reporting additional description
    Safety analysis set included as all randomised subjects who received at least 1 dose of study drug and were analysed according to the actual treatment that they received.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Daratumumab 1800 mg SC Injection
    Reporting group description
    		 Subjects received daratumumab 1800 mg subcutaneous (SC) injection co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Unit per milliliter (U/mL), once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Reporting group title
    Daratumumab 16 mg/kg IV Infusion
    Reporting group description
    		 Subjects received daratumumab 16 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly in Cycles 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks thereafter until disease progression, unacceptable toxicity, withdrawal of consent, the investigator decides to stop treatment, or the start of subsequent anticancer therapy. The duration for each cycle was 28 days.

    Serious adverse events
    		 Daratumumab 1800 mg SC Injection Daratumumab 16 mg/kg IV Infusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 260 (31.92%)
    89 / 258 (34.50%)
         number of deaths (all causes)
    126
    130
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer Recurrent
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to Liver
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of Colon
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid Neoplasm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Associated Fever
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory Collapse
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 260 (1.54%)
    6 / 258 (2.33%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance Status Decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    4 / 260 (1.54%)
    6 / 258 (2.33%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Fatigue
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Thrombosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Condition Abnormal
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atrial Fibrillation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iiird Nerve Paralysis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Insufficiency
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Brain Oedema
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Hyperviscosity Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 260 (2.31%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deafness Neurosensory
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival Bleeding
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Varices Haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Kidney Injury
         subjects affected / exposed
    4 / 260 (1.54%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myeloma Cast Nephropathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myofascial Pain Syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    5 / 260 (1.92%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute Hepatitis B
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    5 / 260 (1.92%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower Respiratory Tract Infection
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B Reactivation
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Furuncle
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona Virus Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Campylobacter Gastroenteritis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Cryptococcal
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis Pneumococcal
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 258 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia
         subjects affected / exposed
    12 / 260 (4.62%)
    13 / 258 (5.04%)
         occurrences causally related to treatment / all
    4 / 12
    4 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory Syncytial Virus Bronchitis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 260 (1.54%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    1 / 5
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Septic Shock
         subjects affected / exposed
    3 / 260 (1.15%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Staphylococcal Sepsis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 258 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 258 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 258 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 260 (0.77%)
    4 / 258 (1.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daratumumab 1800 mg SC Injection Daratumumab 16 mg/kg IV Infusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    217 / 260 (83.46%)
    216 / 258 (83.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 260 (6.15%)
    23 / 258 (8.91%)
         occurrences all number
    22
    33
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 260 (5.77%)
    25 / 258 (9.69%)
         occurrences all number
    15
    26
    Dizziness
         subjects affected / exposed
    15 / 260 (5.77%)
    11 / 258 (4.26%)
         occurrences all number
    20
    12
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    49 / 260 (18.85%)
    50 / 258 (19.38%)
         occurrences all number
    137
    180
    Neutropenia
         subjects affected / exposed
    52 / 260 (20.00%)
    34 / 258 (13.18%)
         occurrences all number
    110
    87
    Lymphopenia
         subjects affected / exposed
    21 / 260 (8.08%)
    17 / 258 (6.59%)
         occurrences all number
    34
    31
    Leukopenia
         subjects affected / exposed
    18 / 260 (6.92%)
    10 / 258 (3.88%)
         occurrences all number
    35
    20
    Anaemia
         subjects affected / exposed
    71 / 260 (27.31%)
    64 / 258 (24.81%)
         occurrences all number
    143
    143
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 260 (5.77%)
    17 / 258 (6.59%)
         occurrences all number
    20
    21
    Pyrexia
         subjects affected / exposed
    36 / 260 (13.85%)
    34 / 258 (13.18%)
         occurrences all number
    56
    48
    Oedema Peripheral
         subjects affected / exposed
    10 / 260 (3.85%)
    15 / 258 (5.81%)
         occurrences all number
    10
    21
    Fatigue
         subjects affected / exposed
    33 / 260 (12.69%)
    26 / 258 (10.08%)
         occurrences all number
    43
    29
    Chills
         subjects affected / exposed
    15 / 260 (5.77%)
    32 / 258 (12.40%)
         occurrences all number
    16
    32
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    16 / 260 (6.15%)
    22 / 258 (8.53%)
         occurrences all number
    17
    26
    Diarrhoea
         subjects affected / exposed
    41 / 260 (15.77%)
    32 / 258 (12.40%)
         occurrences all number
    64
    50
    Nausea
         subjects affected / exposed
    24 / 260 (9.23%)
    31 / 258 (12.02%)
         occurrences all number
    29
    37
    Vomiting
         subjects affected / exposed
    16 / 260 (6.15%)
    21 / 258 (8.14%)
         occurrences all number
    17
    24
    Respiratory, thoracic and mediastinal disorders
    Nasal Congestion
         subjects affected / exposed
    10 / 260 (3.85%)
    13 / 258 (5.04%)
         occurrences all number
    11
    13
    Dyspnoea
         subjects affected / exposed
    15 / 260 (5.77%)
    28 / 258 (10.85%)
         occurrences all number
    19
    34
    Cough
         subjects affected / exposed
    25 / 260 (9.62%)
    36 / 258 (13.95%)
         occurrences all number
    39
    37
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 260 (5.38%)
    14 / 258 (5.43%)
         occurrences all number
    15
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 260 (12.69%)
    18 / 258 (6.98%)
         occurrences all number
    40
    20
    Back Pain
         subjects affected / exposed
    31 / 260 (11.92%)
    36 / 258 (13.95%)
         occurrences all number
    48
    42
    Bone Pain
         subjects affected / exposed
    17 / 260 (6.54%)
    10 / 258 (3.88%)
         occurrences all number
    17
    12
    Musculoskeletal Chest Pain
         subjects affected / exposed
    19 / 260 (7.31%)
    16 / 258 (6.20%)
         occurrences all number
    27
    19
    Musculoskeletal Pain
         subjects affected / exposed
    15 / 260 (5.77%)
    13 / 258 (5.04%)
         occurrences all number
    16
    16
    Pain in Extremity
         subjects affected / exposed
    19 / 260 (7.31%)
    13 / 258 (5.04%)
         occurrences all number
    21
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    14 / 260 (5.38%)
    9 / 258 (3.49%)
         occurrences all number
    14
    9
    Nasopharyngitis
         subjects affected / exposed
    28 / 260 (10.77%)
    21 / 258 (8.14%)
         occurrences all number
    41
    30
    Upper Respiratory Tract Infection
         subjects affected / exposed
    44 / 260 (16.92%)
    30 / 258 (11.63%)
         occurrences all number
    73
    41
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    13 / 260 (5.00%)
    17 / 258 (6.59%)
         occurrences all number
    13
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2017
    The purpose of this amendment was to address feedback from regulatory health authorities including updating inclusion criteria for measurable disease and hepatitis B virus (HBV) status, to provide additional instruction in the event of infusion-related reactions, and to clarify methodology of local bone marrow testing.
    13 Aug 2018
    The purpose of this amendment was to made an update to the regulatory strategy, including an update to the statistical plan, is being implemented to allow Japan to enroll beyond the initially planned 480 subjects in order to meet a health authority commitment. Clarifications had also been made to ensure accuracy and clarity throughout the protocol.
    21 Jan 2020
    The purpose of this amendment was to define the end of the data collection period and to clarify access to drug treatment after data collection in the study electronic case report form (eCRF) had ended.
    01 Apr 2020
    The purpose of this amendment was to provide flexibility for study investigators to prioritize the safety of their patients during the global coronavirus (COVID-19) pandemic.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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