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    Clinical Trial Results:
    A randomized Phase II, 2-armed study in transplant ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM) comparing Carfilzomib + Thalidomide + dexamethasone (KTd) versus Carfilzomib + Lenalidomide + dexamethasone (KRd) induction therapy with respect to response rates and investigating a Carfilzomib (K) monotherapy maintenance strategy

    Summary
    EudraCT number
    		 2016-000475-24
    Trial protocol
    		 AT   DE  
    Global end of trial date
    28 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Oct 2024
    First version publication date
    18 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AGMT_MM-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02891811
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AGMT
    Sponsor organisation address
    Gentzgasse 60/21, Vienna, Austria, 1180
    Public contact
    Daniela Wolkersdorfer, AGMT, +43 6626404412, d.wolkersdofer@agmt.at
    Scientific contact
    Richard Greil, AGMT, +43 6626404412, office@agmt.at
    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
    24 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To show non-inferiority with respect to response rates between KTd and KRd: Overall response rate (ORR) are assessed according to International Myeloma Working Group (IMWG) criteria to determine the ORR in patients NDMM after receiving max 9 cycles induction therapy with either carfilzomib in combination with thalidomide and dexamethasone or carfilzomib in combination with lenalidomide and dexamethasone
    Protection of trial subjects
    Anti-biotic, anti-viral, and anti-thrombosis pretreatment and prophylaxis was mandatory. Guidelines for dose modifications on case of toxicities were given. In general, concomitant medications and therapies necessary for supportive care and safety of the patient were allowed. The administration of any other anticancer agent or other concurrent investigational drug was not permitted. The inclusion of women of childbearing potential (WOCBP) and male subjects with pregnant or non-pregnant WOCBP had to follow specific recommendations for contraception and pregnancy testing. Furthermore, for all participating patients special counselling regarding use of thalidomide or lenalidomide had to be done prior to each treatment cycle.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2017
    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
    Austria: 121
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    4
    From 65 to 84 years
    118
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between 20-Mar-2017 and 16-Dec-2021, 124 patients were enrolled in 16 sites in Austria and 2 sites in Germany. 1 patient withdrew concent shortly after randomization, did not receive any study treatment and is excluded from analysis.

    Pre-assignment
    Screening details
    		 Adult patients (≥18 years) with newly diagnosed, symptomatic MM not eligible or not willing to undergo autologous stem cell transplantation following induction and who are < NYHA class III/IV, ECOG PS 0-1, CrCl > 30ml/min, PN ≤ 2 (without pain).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 KTd Induction
    Arm description
    		 Induction therapy for a maximum of 9 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cycle 1: 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; Cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Cycle 3-9: 56mg/m2 on day 1, 8 and 15

    Investigational medicinal product name
    Thalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100mg/day, day 1-28 (50mg in patients aged ≥75 years)

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion, Tablet
    Routes of administration
    Infusion , Injection , Oral use
    Dosage and administration details
    40mg/week- day 1,8,15,22 (20mg in patients aged ≥75 years)

    Arm title
    		 KRd Induction
    Arm description
    		 Induction therapy for a maximum of 9 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Cycle 1: 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; Cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Cycle 3-9: 56mg/m2 on day 1, 8 and 15

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    25mg/day, day 1-21

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion, Tablet
    Routes of administration
    Infusion , Injection , Oral use
    Dosage and administration details
    40mg/week- day 1,8,15,22 (20mg in patients aged ≥75 years)

    Number of subjects in period 1 [1]
    		KTd Induction KRd Induction
    Started
    63
    60
    Completed
    46
    38
    Not completed
    17
    22
         investigator's decision
    2
    1
         severe AE/toxicity
    9
    15
         progressive disease/death
    2
    3
         patient's decision
    4
    2
         dialysis-dependent
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient withdrew concent shortly after randomization in KRd arm and did not receive any study treatment. This patient is excluded from analysis.
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 K monotherapy
    Arm description
    		 Maintenance treatment with carfilzomib for a maximum period of 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    Other name
    Kyprolis
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    day 1 and day 15 using the last tolerated dose for 12 cylces

    Arm title
    		 Observation
    Arm description
    		 Observation for 12 months
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		K monotherapy Observation
    Started
    42
    42
    Completed
    28
    26
    Not completed
    14
    16
         investigator's decision
    2
    2
         ongoing at primary endpoint analysis
    1
    1
         progressive disease/death
    7
    13
         severe AE/toxicity
    2
    -
         patient's decision
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    KTd Induction
    Reporting group description
    		 Induction therapy for a maximum of 9 cycles

    Reporting group title
    KRd Induction
    Reporting group description
    		 Induction therapy for a maximum of 9 cycles

    Reporting group values
    		 KTd Induction KRd Induction Total
    Number of subjects
    		 63 60 123
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 75 (58 to 84) 75 (55 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 31 24 55
        Male
    		 32 36 68

    End points

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    End points reporting groups
    Reporting group title
    KTd Induction
    Reporting group description
    		 Induction therapy for a maximum of 9 cycles

    Reporting group title
    KRd Induction
    Reporting group description
    		 Induction therapy for a maximum of 9 cycles
    Reporting group title
    K monotherapy
    Reporting group description
    		 Maintenance treatment with carfilzomib for a maximum period of 12 months.

    Reporting group title
    Observation
    Reporting group description
    		 Observation for 12 months

    Primary: Response

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    End point title
    		 Response
    End point description
    Response in patients treated with KTd or KRd during induction therapy. Patients who received study medication for at least 4 weeks were evaluable for response.
    End point type
    Primary
    End point timeframe
    Response assessment was done at day 1 of each cylce (except cycle 1) and at the end of K combination treatment
    End point values
    		 KTd Induction KRd Induction
    Number of subjects analysed
    61
    55
    Units: Subjects
        stringent complete response (sCR)
    7
    4
        complete response (CR)
    20
    17
        very good partial response (VGPR)
    21
    19
        partial response (PR)
    8
    8
        minimal response (MR)
    3
    2
        stable disease (SD)
    2
    4
        progressive disease (PD)
    0
    1
    Statistical analysis title
    		 Overall response rates
    Statistical analysis description
    Response rates were similiar during induction therapy with KTd (91.8%) and KRd (87.3%), meeting the requirements for non-inferiority.
    Comparison groups
    KTd Induction v KRd Induction
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17
         upper limit
    		 7.1
    Notes
    [1] - Non-inferiority is postulated if the CI of the differences does not cross 11%. CI was calculated using the Miettinen-Nurminen method

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All patients having received at least one dose of the study medication were followed for adverse events for at least 28 days after discontinuing study treatment or completion of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population includes all enrolled patients who received at least one dose of the study treatment. SARs are assessed as related to carfilzomib.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    86 / 123 (69.92%)
         number of deaths (all causes)
    23
         number of deaths resulting from adverse events
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 123 (4.07%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion site reaction
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Dyspnoea
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences causally related to treatment / all
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 123 (3.25%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Urinary retention
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 123 (2.44%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone lesion
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic spinal stenosis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    15 / 123 (12.20%)
         occurrences causally related to treatment / all
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 123 (3.25%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Febrile infection
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    2 / 123 (1.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypokalaemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 123 (95.93%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 123 (9.76%)
         occurrences all number
    20
    Hypotension
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    8
    Thrombophlebitis
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    63 / 123 (51.22%)
         occurrences all number
    110
    Oedema peripheral
         subjects affected / exposed
    44 / 123 (35.77%)
         occurrences all number
    71
    Pyrexia
         subjects affected / exposed
    19 / 123 (15.45%)
         occurrences all number
    29
    Pain
         subjects affected / exposed
    12 / 123 (9.76%)
         occurrences all number
    18
    Chills
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    9
    Asthenia
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    9
    Chest pain
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    7
    Influenza like illness
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    7
    Oedema
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    23 / 123 (18.70%)
         occurrences all number
    29
    Cough
         subjects affected / exposed
    13 / 123 (10.57%)
         occurrences all number
    15
    Oropharyngeal pain
         subjects affected / exposed
    10 / 123 (8.13%)
         occurrences all number
    10
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    10 / 123 (8.13%)
         occurrences all number
    11
    Insomnia
         subjects affected / exposed
    9 / 123 (7.32%)
         occurrences all number
    12
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    19 / 123 (15.45%)
         occurrences all number
    22
    Platelet count decreased
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    27
    Neutrophil count decreased
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    18
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    22 / 123 (17.89%)
         occurrences all number
    27
    Tremor
         subjects affected / exposed
    15 / 123 (12.20%)
         occurrences all number
    17
    Paraesthesia
         subjects affected / exposed
    11 / 123 (8.94%)
         occurrences all number
    12
    Neuropathy peripheral
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    9
    Headache
         subjects affected / exposed
    14 / 123 (11.38%)
         occurrences all number
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 123 (16.26%)
         occurrences all number
    33
    Thrombocytopenia
         subjects affected / exposed
    17 / 123 (13.82%)
         occurrences all number
    34
    Neutropenia
         subjects affected / exposed
    11 / 123 (8.94%)
         occurrences all number
    17
    Leukopenia
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    27 / 123 (21.95%)
         occurrences all number
    35
    Tinnitus
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    9
    Eye disorders
    Visual impairment
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    7
    Cataract
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    37 / 123 (30.08%)
         occurrences all number
    67
    Constipation
         subjects affected / exposed
    32 / 123 (26.02%)
         occurrences all number
    40
    Diarrhoea
         subjects affected / exposed
    27 / 123 (21.95%)
         occurrences all number
    43
    Vomiting
         subjects affected / exposed
    14 / 123 (11.38%)
         occurrences all number
    21
    Abdominal pain upper
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    7
    Dry mouth
         subjects affected / exposed
    6 / 123 (4.88%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    25 / 123 (20.33%)
         occurrences all number
    39
    Pruritus
         subjects affected / exposed
    9 / 123 (7.32%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 123 (14.63%)
         occurrences all number
    22
    Arthralgia
         subjects affected / exposed
    18 / 123 (14.63%)
         occurrences all number
    25
    Muscle spasms
         subjects affected / exposed
    17 / 123 (13.82%)
         occurrences all number
    27
    Bone pain
         subjects affected / exposed
    10 / 123 (8.13%)
         occurrences all number
    15
    Pain in extremity
         subjects affected / exposed
    9 / 123 (7.32%)
         occurrences all number
    12
    Myalgia
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 123 (15.45%)
         occurrences all number
    20
    Urinary tract infection
         subjects affected / exposed
    14 / 123 (11.38%)
         occurrences all number
    15
    Bronchitis
         subjects affected / exposed
    11 / 123 (8.94%)
         occurrences all number
    14
    Infection
         subjects affected / exposed
    8 / 123 (6.50%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    17 / 123 (13.82%)
         occurrences all number
    19
    Hypokalaemia
         subjects affected / exposed
    9 / 123 (7.32%)
         occurrences all number
    9
    Hypocalcaemia
         subjects affected / exposed
    7 / 123 (5.69%)
         occurrences all number
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2017
    Based on data from Biran et al. 2016, presented at ASH 2016, increased cardiotoxicity and thrombotic microangiopathy were seen in elderly patients receiving 70 mg carfilzomib in combination with dexamethasone and lenalidomide. Due to these observations, the dose and scheduling of carfilzomib was adapted for this trial. Also frail patients and those with an ECOG PS status ≥2 were excluded from this study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38895059
    http://www.ncbi.nlm.nih.gov/pubmed/38425185
    For support, Contact us.
    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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