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    Clinical Trial Results:
    A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been Previously Treated with Daratumumab to Evaluate Daratumumab Retreatment

    Summary
    EudraCT number
    		 2018-004185-34
    Trial protocol
    		 BE   DE   DK   NL   FR   ES   PL   GR   IT  
    Global end of trial date
    10 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2023
    First version publication date
    28 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54767414MMY2065
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03871829
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    Antwerpseweg 15-17, Beerse, Belgium, B-2340
    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
    10 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to compare the efficacy (rate of very good partial response [VGPR] or better as best response as defined by the International Myeloma Working Group [IMWG] criteria) of daratumumab subcutaneous (Dara-SC) in combination with carfilzomib and dexamethasone (Kd) with the efficacy of Kd in subjects with relapsed refractory multiple myeloma who were previously exposed to daratumumab to evaluate daratumumab retreatment.
    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
    19 Jul 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    88
    EEA total number of subjects
    58
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    31
    From 65 to 84 years
    54
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 88 subjects were enrolled and treated, and none had completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Carfilzomib+Dexamethasone (Kd)
    Arm description
    		 Subjects received carfilzomib 20 milligram per metre square (mg/m^2) intravenously (IV) on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and thereafter on Days 1, 8, 15 from Cycle 2 onwards. Subjects received dexamethasone 20 milligrams (mg) on Cycle 1 Days 1 and 2, and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2. Subjects received 40 mg on Days 1, 8, 15 and 22 for Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards.

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carfilzomib 20 mg/m^2 on Cycle 1 Day 1 and 70 mg/m^2 on Cycle 1 Days 8 and 15, and thereafter on Days 1, 8, 15 from Cycle 2 onwards.

    Arm title
    		 Arm B: Dara-SC in combination with Kd (DKd)
    Arm description
    		 Subjects received daratumumab 1800 mg by SC injection (Dara-SC) on Days 1, 8, 15, 22 of Cycles 1 and 2, Days 1 and 15 of Cycle 3-6, and on Day 1 from Cycle 7 onwards. Subjects received carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and Days 1, 8 and 15 from Cycle 2 onwards. Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed PD, death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received daratumumab 1800 mg on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 from Cycle 7 onwards.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Subjects received dexamethasone 40 mg IV or orally on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards.

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received carfilzomib 20 mg/m^2 on Cycle 1 Day 1 and 70 mg/m^2 on Cycle 1 Days 8 and 15 and Days 1, 8 and 15 from Cycle 2 onwards.

    Number of subjects in period 1
    		Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Started
    44
    44
    Completed
    0
    0
    Not completed
    44
    44
         Adverse event, serious fatal
    12
    8
         Consent withdrawn by subject
    1
    1
         Study terminated by sponsor
    31
    34
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Carfilzomib+Dexamethasone (Kd)
    Reporting group description
    		 Subjects received carfilzomib 20 milligram per metre square (mg/m^2) intravenously (IV) on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and thereafter on Days 1, 8, 15 from Cycle 2 onwards. Subjects received dexamethasone 20 milligrams (mg) on Cycle 1 Days 1 and 2, and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.

    Reporting group title
    Arm B: Dara-SC in combination with Kd (DKd)
    Reporting group description
    		 Subjects received daratumumab 1800 mg by SC injection (Dara-SC) on Days 1, 8, 15, 22 of Cycles 1 and 2, Days 1 and 15 of Cycle 3-6, and on Day 1 from Cycle 7 onwards. Subjects received carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and Days 1, 8 and 15 from Cycle 2 onwards. Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed PD, death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.

    Reporting group values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd) Total
    Number of subjects
    		 44 44 88
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 15 16 31
        From 65 to 84 years
    		 26 28 54
        85 years and over
    		 3 0 3
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.4 ± 8.56 66.7 ± 9.72 -
    Title for Gender
    Units: subjects
        Female
    		 21 18 39
        Male
    		 23 26 49

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Carfilzomib+Dexamethasone (Kd)
    Reporting group description
    		 Subjects received carfilzomib 20 milligram per metre square (mg/m^2) intravenously (IV) on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and thereafter on Days 1, 8, 15 from Cycle 2 onwards. Subjects received dexamethasone 20 milligrams (mg) on Cycle 1 Days 1 and 2, and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.

    Reporting group title
    Arm B: Dara-SC in combination with Kd (DKd)
    Reporting group description
    		 Subjects received daratumumab 1800 mg by SC injection (Dara-SC) on Days 1, 8, 15, 22 of Cycles 1 and 2, Days 1 and 15 of Cycle 3-6, and on Day 1 from Cycle 7 onwards. Subjects received carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Cycle 1 Days 8 and 15, and Days 1, 8 and 15 from Cycle 2 onwards. Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 of Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 of Cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed PD, death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first. Each cycles were of 28 days.

    Primary: Percentage of Subjects Achieving Very Good Partial Response (VGPR) or Better Response

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    End point title
    		 Percentage of Subjects Achieving Very Good Partial Response (VGPR) or Better Response [1]
    End point description
    VGPR or better rate was defined as the percentage of subjects achieving VGPR, complete response (CR), or stringent complete response (sCR) in accordance with the International Myeloma Working Group (IMWG) criteria, during/after the study treatment but before the start of subsequent anti-myeloma therapy. IMWG criteria: VGPR: Serum and urine M-component detected by immunofixation but not on electrophoresis, or greater than or equal to (>=)90 percent (%) reduction in serum Mprotein plus urine M-protein less than (<)100 milligram (mg)/24hours; CR: Negative immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas (PCs), and <5% PCs in bone marrow; sCR: CR plus normal free light chain (FLC) ratio, and Absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry. The response-evaluable analysis set included subjects who had confirmed diagnosis of multiple myeloma (MM) and measurable disease at baseline or screening visit.
    End point type
    Primary
    End point timeframe
    Up to 3 years and 7 months
    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
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    39
    41
    Units: Percentage of subjects
        number (confidence interval 90%)
    46.2 (32.3 to 60.4)
    48.8 (35.1 to 62.6)
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as the proportion of subjects who achieved partial response [PR] or better responses based on the computerized algorithm, in accordance with the IMWG criteria. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or <200 mg/24 hours; If the serum and urine M-protein were not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria; If serum and urine M-protein were not measurable, and serum free light assay is also not measurable, >=50% reduction in bone marrow plasma cells (PCs) was required in place of M-protein, provided baseline bone marrow plasma cell percentage was >=30%; additionally, if present at baseline, >=50% reduction in the size of soft tissue PCs was also required. The response-evaluable analysis set included subjects who had confirmed diagnosis of MM and measurable disease at baseline or screening visit.
    End point type
    Secondary
    End point timeframe
    Up to 3 years and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    39
    41
    Units: Percentage of subjects
        number (confidence interval 90%)
    64.1 (49.7 to 76.8)
    75.6 (62.1 to 86.1)
    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 the duration from the date of randomisation to either progressive disease (PD) or death, whichever comes first. IMWG criteria: PD: >=25% from lowest response level in serum M-component and/or in urine M-component; only in subjects without measurable serum and urine M-protein levels: increase of >=25% in the difference between involved and uninvolved FLC levels and the absolute increase must be >10 mg/dL. BMPC%: the absolute % must be >=10%; definite increase in size of existing bone lesions or soft tissue plasmacytomas; definite development of new bone lesions or soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5 milligrams per deciliter (mg/dL) or 2.65 millimoles per liter [mmol/L]) that can be attributed solely to PC proliferative disorder. Intent-to-treat (ITT) analysis set included all subjects who were randomised in 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 and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    27
    24
    Units: months
        median (confidence interval 90%)
    10.61 (4.70 to 19.88)
    10.74 (7.49 to 16.16)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Complete Response (CR) or Better

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    End point title
    		 Percentage of Subjects Achieving Complete Response (CR) or Better
    End point description
    Percentage of subjects achieving CR or better were reported. CR or better rate was defined as the proportion of subjects achieving CR or sCR based on the computerized algorithm, according to IMWG response criteria. IMWG criteria for CR: Negative immunofixation on the serum and urine, and Disappearance of any soft tissue plasmacytomas (PCs), and <5% PCs in bone marrow. The response-evaluable analysis set included subjects who had confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit.
    End point type
    Secondary
    End point timeframe
    Up to 3 years and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    39
    41
    Units: Percentage of subjects
        number (confidence interval 90%)
    25.6 (14.6 to 39.6)
    12.2 (4.9 to 23.9)
    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 analysis set included all subjects who were randomised in the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this outcome measure. Here, 99999 signifies data was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 3 years and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    12
    8
    Units: months
        median (confidence interval 90%)
    99999 (25.40 to 99999)
    99999 (27.10 to 99999)
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Daratumumab

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    End point title
    		 Serum Concentrations of Daratumumab [2]
    End point description
    Serum concentrations of daratumumab were assessed. Pharmacokinetic (PK) analysis set included all subjects who had received at least 1 dose of daratumumab subcutaneous (dara-SC) and had at least 1 post-dose PK sample. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints. This outcome measure was planned to be analysed for specified arm only.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 3 Day 1, Cycle 7 Day 1 (each cycle of 28 days) and Follow Up (post treatment Week 8)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure was planned to be analysed for specified arm only.
    End point values
    		 Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    22
    Units: microgram per millilitres (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day1 (n=6)
    39.1 ± 44.1
        Cycle 3 Day 1 (n=22)
    849 ± 329
        Cycle 7 Day 1 (n=19)
    715 ± 381
        Post-treatment Week 8 (n=4)
    85.5 ± 131
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Negative Minimal Residual Disease (MRD)

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    End point title
    		 Percentage of Subjects With Negative Minimal Residual Disease (MRD)
    End point description
    Percentage of subjects with negative MRD were reported. MRD negativity rate, defined as the proportion of subjects who had MRD negative status at 10^-5 by bone marrow aspirate after the date of randomisation and prior to PD or subsequent anti-myeloma therapy. MRD negativity rate, defined as the proportion of subjects who have MRD negative status at 10-5 by bone marrow aspirate after the date of randomization and prior to PD or subsequent anti-myeloma therapy. ITT analysis set analysis set included all subjects who were randomised in the study.
    End point type
    Secondary
    End point timeframe
    Up to 3 years and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    44
    44
    Units: Percentage of subjects
        number (confidence interval 95%)
    11.4 (3.8 to 24.6)
    6.8 (1.4 to 18.7)
    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 treatment was defined as the time from randomisation to the start of the next-line treatment. ITT analysis set analysis set included all subjects who were randomised in the study. Here, 'N' (number of subjects analysed) signifies subjects who were evaluable for this endpoint. Here, 99999 signifies data was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 3 years and 7 months
    End point values
    		 Arm A: Carfilzomib+Dexamethasone (Kd) Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    21
    15
    Units: months
        median (confidence interval 90%)
    20.60 (14.06 to 25.40)
    20.14 (11.33 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-recombinant Human Hyaluronidase (rHuPH20) Antibodies

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    End point title
    		 Number of Subjects with Anti-recombinant Human Hyaluronidase (rHuPH20) Antibodies [3]
    End point description
    Number of subjects with rHuPH20 antibodies were reported. The immunogenicity analysis set for dara-SC included all randomised subjects who had appropriate samples for detection of the antibodies. This outcome measure was planned to be analysed for specified arm only.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 3 Day 1, Cycle 7 Day 1 (each cycle of 28 days) and Follow Up (post treatment Week 8)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure was planned to be analysed for specified arm only.
    End point values
    		 Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    35
    Units: subjects
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Daratumumab Antibodies

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    End point title
    		 Number of Subjects with Anti-Daratumumab Antibodies [4]
    End point description
    Number of subjects who test positive for anti-daratumumab antibodies were reported. The immunogenicity analysis set for dara-SC included all randomised subjects who had appropriate samples for detection of the antibodies. This outcome measure was planned to be analysed for specified arm only.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 3 Day 1, Cycle 7 Day 1 (each cycle of 28 days) and Follow Up (post treatment Week 8)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This outcome measure was planned to be analysed for specified arm only.
    End point values
    		 Arm B: Dara-SC in combination with Kd (DKd)
    Number of subjects analysed
    35
    Units: subjects
    0
    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 and 7 months
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least 1 dose of study treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Arm B: Dara-SC in combination with Kd (DKd)
    Reporting group description
    		 Subjects received daratumumab subcutaneous (Dara-SC) 1800 mg by SC injection on Days 1, 8, 15, 22 for Cycle 1 and 2, Days 1 and 15 for Cycle 3-6, Day 1 from Cycle 7 onwards. Subjects received carfilzomib 20 mg/m^2 IV on Cycle 1 Day 1 and then 70 mg/m^2 on Day 8 and 15 of Cycle 1 and Days 1, 8 and 15 of Cycle 2. Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Subjects then received dexamethasone 40 mg on days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed PD, death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first.

    Reporting group title
    Arm A: Carfilzomib+Dexamethasone (Kd)
    Reporting group description
    		 Subjects received carfilzomib 20 milligram per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1 and then 70 mg/m^2 on Days 8 and 15 of Cycle 1 and thereafter on Days 1, 8, 15 from Cycle 2 onwards. Subjects received dexamethasone 20 mg on Cycle 1 Days 1 and 2 and 40 mg IV or orally on Days 8, 15, 22 for Cycle 1. Subjects then received dexamethasone 40 mg IV or orally on Days 1, 8, 15 and 22 for cycles 2-9, then on Days 1, 8, 15 from Cycle 10 onwards, until confirmed progressive disease (PD), death, intolerable toxicity, start of a new treatment for multiple myeloma, withdrawal of consent, or end of the study, whichever occurs first.

    Serious adverse events
    		 Arm B: Dara-SC in combination with Kd (DKd) Arm A: Carfilzomib+Dexamethasone (Kd)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 43 (27.91%)
    20 / 43 (46.51%)
         number of deaths (all causes)
    7
    12
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         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
    0 / 43 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         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
    Pulmonary embolism
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 43 (0.00%)
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 43 (0.00%)
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia sepsis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         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
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 43 (9.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm B: Dara-SC in combination with Kd (DKd) Arm A: Carfilzomib+Dexamethasone (Kd)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 43 (86.05%)
    39 / 43 (90.70%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 43 (25.58%)
    7 / 43 (16.28%)
         occurrences all number
    34
    13
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 43 (11.63%)
    4 / 43 (9.30%)
         occurrences all number
    9
    4
    Oedema peripheral
         subjects affected / exposed
    5 / 43 (11.63%)
    3 / 43 (6.98%)
         occurrences all number
    6
    3
    Malaise
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    4
    Fatigue
         subjects affected / exposed
    7 / 43 (16.28%)
    3 / 43 (6.98%)
         occurrences all number
    11
    4
    Catheter site pain
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    3
    Asthenia
         subjects affected / exposed
    5 / 43 (11.63%)
    6 / 43 (13.95%)
         occurrences all number
    7
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 43 (6.98%)
         occurrences all number
    0
    4
    Dyspnoea
         subjects affected / exposed
    7 / 43 (16.28%)
    4 / 43 (9.30%)
         occurrences all number
    13
    6
    Cough
         subjects affected / exposed
    6 / 43 (13.95%)
    5 / 43 (11.63%)
         occurrences all number
    7
    5
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
         occurrences all number
    4
    2
    Insomnia
         subjects affected / exposed
    2 / 43 (4.65%)
    6 / 43 (13.95%)
         occurrences all number
    2
    11
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 43 (4.65%)
         occurrences all number
    7
    2
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 43 (6.98%)
         occurrences all number
    2
    3
    Headache
         subjects affected / exposed
    2 / 43 (4.65%)
    7 / 43 (16.28%)
         occurrences all number
    2
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 43 (25.58%)
    14 / 43 (32.56%)
         occurrences all number
    20
    37
    Leukopenia
         subjects affected / exposed
    4 / 43 (9.30%)
    1 / 43 (2.33%)
         occurrences all number
    5
    2
    Lymphopenia
         subjects affected / exposed
    3 / 43 (6.98%)
    8 / 43 (18.60%)
         occurrences all number
    15
    14
    Neutropenia
         subjects affected / exposed
    8 / 43 (18.60%)
    4 / 43 (9.30%)
         occurrences all number
    18
    6
    Thrombocytopenia
         subjects affected / exposed
    16 / 43 (37.21%)
    8 / 43 (18.60%)
         occurrences all number
    77
    32
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
         occurrences all number
    3
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 43 (11.63%)
    5 / 43 (11.63%)
         occurrences all number
    9
    5
    Nausea
         subjects affected / exposed
    6 / 43 (13.95%)
    7 / 43 (16.28%)
         occurrences all number
    14
    7
    Diarrhoea
         subjects affected / exposed
    4 / 43 (9.30%)
    11 / 43 (25.58%)
         occurrences all number
    8
    14
    Constipation
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 43 (9.30%)
         occurrences all number
    2
    5
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 43 (0.00%)
         occurrences all number
    5
    0
    Renal impairment
         subjects affected / exposed
    1 / 43 (2.33%)
    5 / 43 (11.63%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 43 (2.33%)
         occurrences all number
    5
    1
    Back pain
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 43 (9.30%)
         occurrences all number
    5
    6
    Arthralgia
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 43 (9.30%)
         occurrences all number
    2
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 43 (4.65%)
    9 / 43 (20.93%)
         occurrences all number
    3
    12
    Nasopharyngitis
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 43 (6.98%)
         occurrences all number
    2
    4
    COVID-19
         subjects affected / exposed
    9 / 43 (20.93%)
    9 / 43 (20.93%)
         occurrences all number
    9
    10
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 43 (6.98%)
    4 / 43 (9.30%)
         occurrences all number
    4
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2019
    The purpose of the amendment was to include the language clarifying the need for contraception for all subjects to continue for 3 months after the end of study treatment as well as the caution for women who are at high risk for thrombosis to use other means of birth control other than hormonal birth control which carries the highest risk of thrombosis.
    13 Jun 2021
    The purpose of this amendment was to expand eligibility.

    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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