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    Clinical Trial Results:
    A Randomized, Controlled, Open-Label, Phase 3 Study of Melflufen/ Dexamethasone Compared with Pomalidomide/Dexamethasone for Patients with Relapsed Refractory Multiple Myeloma who are Refractory to Lenalidomide

    Summary
    EudraCT number
    		 2016-003517-95
    Trial protocol
    		 HU   ES   CZ   GB   GR   BE   DK   NL   NO   FR   PL   AT   EE   LT   IT   RO  
    Global end of trial date
    03 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2024
    First version publication date
    24 Jan 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OP-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03151811
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Oncopeptides AB
    Sponsor organisation address
    Luntmakargatan 46, Stockholm, Sweden, SE-111 37
    Public contact
    Clinical Trials Information Desk, Oncopeptides AB, trials@oncopeptides.se
    Scientific contact
    Clinical Trials Information Desk, Oncopeptides AB, trials@oncopeptides.se
    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
    03 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the PFS of melflufen plus dexamethasone (Arm A) versus pomalidomide plus dexamethasone (Arm B) as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC).
    Protection of trial subjects
    This clinical study was designed, implemented, and reported in accordance with the International Conference of Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations, and with the ethical principles laid down in the Declaration of Helsinki. Eligible patients were only to be included in the study after providing written, IEC-approved informed consent. The clinical study was designed based on well-established guidance for oncology studies including relapsed-refractory multiple myeloma (RRMM) management, response assessment, and National Comprehensive Cancer Network Guidelines.
    Background therapy
    		 Dexamethasone 40 mg administered orally on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged <75 years OR Dexamethasone 20 mg administered orally on Days 1, 8, 15, and 22 of each 28-day cycle for patients aged ≥75 years
    Evidence for comparator
    		 Pomalidomide is a third-generation immunomodulatory drug approved in 2013 by the US FDA and the EMA in combination with low-dose dexamethasone for multiple myeloma (MM) patients who have received at least two prior therapies (including both lenalidomide and bortezomib) and whose disease progressed after the last treatment. An expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma noted that for patients who have exhausted lenalidomide- and bortezomib-based therapies, pomalidomide plus low-dose dexamethasone is an effective treatment option, and that evidence suggests that pomalidomide is equally effective in patients whose last therapy was lenalidomide or bortezomib.
    Actual start date of recruitment
    01 Mar 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
    Netherlands: 3
    Country: Number of subjects enrolled
    Norway: 33
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Czechia: 59
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Estonia: 4
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Greece: 46
    Country: Number of subjects enrolled
    Hungary: 31
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Russian Federation: 79
    Country: Number of subjects enrolled
    Taiwan: 5
    Worldwide total number of subjects
    495
    EEA total number of subjects
    346
    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)
    181
    From 65 to 84 years
    309
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient initiated study treatment in OP-103 on 12 June 2017. A total of 495 patients were randomized in the study, 246 in the melflufen+dexamethasone group and 249 in the pomalidomide+dexamethasone group. Among the randomized patients, 21 were not treated (18 in the melflufen+dex group and 3 in the pomalidomide+dex group).

    Pre-assignment
    Screening details
    		 Key inclusion criteria: age ≥ 18 years; prior diagnosis of multiple myeloma; received 2-4 prior lines of therapy, including lenalidomide and a protease inhibitor, either sequential or in the same line; and refractory to both the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    An Independent Review Committee (IRC) assessed all tumor responses and progression. The IRC members were blinded to all treatment data and performed their reviews.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Melflufen 40 mg iv on Day 1 of each 28-day cycle via a central catheter. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Melflufen
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Melflufen 40 mg was administered as a 30-minute infusion on Day 1 of each 28-day cycle via central catheter.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was given po at the standard dose of 40 mg weekly, on Days 1, 8, 15, and 22 of each 28-day cycle. Patients ≥ 75 years of age were given dexamethasone po 20 mg weekly. On the days that both melflufen and dexamethasone were given (i.e., Day 1 of each cycle), dexamethasone was to be taken before the administration of melflufen.

    Arm title
    		 Arm B
    Arm description
    		 Pomalidomide 4 mg po on Days 1 to 21 of each 28-day cycle. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pomalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Pomalidomide 4 mg was administered orally on Days 1 to 28 of each 28-day cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was given po at the standard dose of 40 mg weekly, on Days 1, 8, 15, and 22 of each 28-day cycle. Patients ≥ 75 years of age were given dexamethasone po 20 mg weekly. On the days that both pomalidomide and dexamethasone were given (i.e., Day 1 of each cycle), dexamethasone was to be taken before the administration of pomalidomide.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    246
    249
    Treated
    228
    246
    Completed
    0
    0
    Not completed
    246
    249
         Physician decision
    21
    9
         Consent withdrawn by subject
    17
    7
         Study terminated by Sponsor
    5
    11
         Adverse event
    49
    40
         Randomized But Not Treated
    18
    3
         Progressive disease
    130
    170
         Lost to follow-up
    -
    1
         Lack of efficacy
    6
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Melflufen 40 mg iv on Day 1 of each 28-day cycle via a central catheter. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).

    Reporting group title
    Arm B
    Reporting group description
    		 Pomalidomide 4 mg po on Days 1 to 21 of each 28-day cycle. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 246 249 495
    Age categorical
    Units: Subjects
        <65 years
    		 96 85 181
        65 to <75 years
    		 113 125 238
        ≥75 years
    		 37 39 76
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.1 ( 8.98 ) 66.5 ( 8.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 107 109 216
        Male
    		 139 140 279
    Race
    Units: Subjects
        Asian
    		 8 13 21
        Black or African American
    		 4 4 8
        White
    		 224 222 446
        Other
    		 1 0 1
        Unknown
    		 9 9 18
        Not reported
    		 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 8 5 13
        Not Hispanic or Latino
    		 232 237 469
        Not reported
    		 6 7 13
    Baseline ECOG Performance Status
    Units: Subjects
        Score = 0
    		 90 92 182
        Score = 1
    		 130 136 266
        Score = 2
    		 26 21 47
    ISS stage at study entry
    ISS = International Staging System
    Units: Subjects
        Stage = I
    		 119 124 243
        Stage = II
    		 94 94 188
        Stage = III
    		 33 31 64
    Bone lesions present at study entry
    Units: Subjects
        Yes
    		 184 206 390
        No
    		 62 43 105
    Extramedullary disease present at study entry
    Units: Subjects
        Yes
    		 31 31 62
        No
    		 215 218 433
    R-ISS stage of disease at study entry
    R-ISS = Revised-International Staging System
    Units: Subjects
        R-I
    		 69 69 138
        R-II
    		 129 138 267
        R-III
    		 24 17 41
        Unknown/missing
    		 24 25 49
    Cytogenic risk group based on FISH at study entry
    FISH = fluorescence in situ hybridization
    Units: Subjects
        High
    		 83 86 169
        Standard
    		 128 130 258
        Unknown
    		 35 33 68
    Baseline weight
    Units: kg
        arithmetic mean (standard deviation)
    		 76.9 ( 14.71 ) 76.1 ( 14.38 ) -
    Time since initial diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 4.88 ( 3.98 ) 4.82 ( 3.88 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Melflufen 40 mg iv on Day 1 of each 28-day cycle via a central catheter. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).

    Reporting group title
    Arm B
    Reporting group description
    		 Pomalidomide 4 mg po on Days 1 to 21 of each 28-day cycle. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age).

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS was defined as all subjects who were randomized. Subjects were analyzed according to the treatment assigned at randomization.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set was defined as all subjects who received at least one or partial dose of melflufen, pomalidomide, or dexamethasone. The Safety Analysis Set was the primary population for the summaries of all exposure and safety data. Subjects were summarized according to the treatment actually received.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    To show the superiority of PFS in patients treated with melflufen+dexamethasone (Arm A) compared to pomalidomide+dexamethasone (Arm B) as assessed by the IRC. PFS was defined as the duration in months from the date of randomization to the date of first documentation of confirmed progressive disease or death due to any cause.
    End point type
    Primary
    End point timeframe
    From date of randomization until confirmed disease progression or death due to any cause. Data cutoff date was 03 Feb 2021.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    246 [1]
    249 [2]
    Units: Months
        median (confidence interval 95%)
    6.83 (4.96 to 8.54)
    4.93 (4.24 to 5.72)
    Notes
    [1] - Patients with events: 165 Patients censored: 81 Median follow-up: 15.47 months
    [2] - Patients with events: 190 Patients censored: 59 Median follow-up: 16.26 months
    Statistical analysis title
    		 Statistical Analysis for PFS
    Statistical analysis description
    PFS analyzed using a log-rank test stratified by the randomization stratification factors to compare treatment group survival distributions based on the FAS. Kaplan-Meier (K-M) estimates of the survival distributions of the time-to-event based on log(-log[survival]) distribution were tabulated by treatment arm (including K-M estimates of medians and 95% CIs). Hazard ratio and 95% CIs were based on semiparametric Cox proportional hazards regression model stratified by randomization strata.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0319 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.792
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 0.981
    Notes
    [3] - Superiority of melflufen+dexamethasone over pomalidomide+dexamthasone with respect to the primary endpoint was claimed if the 2-sided p-value was <0.05 favoring melflufen+dexamethasone. In addition to a significant p-value for the treatment comparison based on the log-rank test, the superiority of melflufen+dexamethasone versus pomalidomide+dexamethasone was demonstrated if the upper limit of the 95% CI for the hazard ratio was < 1.0.
    [4] - Log-rank test stratified by randomization strata: age (<75, ≥75), number of lines of prior therapy (2, 3-4), and International Staging System (ISS) Score (1, ≥2).

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    To assess and compare the ORR in Arm A versus Arm B, as assessed by the IRC. ORR was defined as the proportion of patients for whom the best overall confirmed response was stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR).
    End point type
    Secondary
    End point timeframe
    From randomization until best response achieved before confirmed disease progression or death due to any cause. Median time to best response was 2.1 and 2.0 months for Arm A and B, respectively. Data cutoff date was 03 Feb 2021.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    246 [5]
    249 [6]
    Units: Percent
        number (confidence interval 95%)
    32.5 (26.71 to 38.76)
    26.9 (21.50 to 32.87)
    Notes
    [5] - Number of patients with best response ≥PR: 80
    [6] - Number of patients with best response ≥PR: 67
    Statistical analysis title
    		 Statistical Analysis for ORR
    Statistical analysis description
    The treatment groups for the FAS population were compared using the Cochran Mantel Haenszel (CMH) chi square test. The two-sided 95% exact binomial CI for ORR was calculated for each treatment arm.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1607 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - Superiority testing of melflufen+dexamethasone over pomalidomide+dexamethasone with respect to the key secondary endpoints performed using a gatekeeping procedure based on a closed fixed-sequence test, provided the primary efficacy endpoint comparison was statistically significant at an alpha level of 0.05. In case of statistical superiority on the primary endpoint, then ORR was tested for statistical superiority.
    [8] - P-value was calculated from a CMH test stratified by the following randomization strata: age (<75, ≥75), number of lines of prior therapy (2, 3-4), and International Staging System (ISS) Score (1, ≥2).

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    To assess and compare DOR in patients with ≥PR (sCR, CR, VGPR, PR) as best response in Arm A versus Arm B, as assessed by the IRC. DOR was defined as the time from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression, or to death due to any cause. DOR was defined only for patients with a confirmed PR or better.
    End point type
    Secondary
    End point timeframe
    From first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause. Data cutoff date was 03 Feb 2021.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    246 [9]
    249 [10]
    Units: Months
        median (confidence interval 95%)
    11.17 (8.48 to 17.48)
    11.07 (7.62 to 15.44)
    Notes
    [9] - Patients with best response ≥PR: 80 (42 with events / 38 censored) Median follow-up: 15.84 months
    [10] - Patients with best response ≥PR: 67 (38 with events / 29 censored) Median follow-up: 16.76 months
    Statistical analysis title
    		 Statistical Analysis of DOR
    Statistical analysis description
    DOR analyzed using a log-rank test stratified by the randomization stratification factors to compare treatment group DOR distributions based on the FAS. K-M estimates of the DOR distributions of the time-to-event based on log(-log[survival]) distribution were tabulated by treatment arm (including K-M estimates of medians and 95% CIs). Hazard ratio and 95% CIs were based on semiparametric Cox proportional hazards regression model stratified by randomization strata.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.651
         upper limit
    		 1.728
    Notes
    [11] - DOR was not a key secondary endpoint. Therefore, it was not included in the multiplicity adjustment.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    To assess and compare OS in Arm A versus Arm B. OS was defined as time (months) from date of randomization to death due to any cause. Patients who were still alive at end of study, or lost to follow up, were censored at the last day the patient was known to be alive.
    End point type
    Secondary
    End point timeframe
    From randomization until up to 24 months following confirmed disease progression or initiation of subsequent therapy. Data cutoff date was 03 Feb 2023.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    246 [12]
    249 [13]
    Units: Months
        median (confidence interval 95%)
    20.24 (15.84 to 24.15)
    23.98 (18.92 to 27.86)
    Notes
    [12] - Patients with events: 180 (73.2%) Patients censored: 66 (26.8%) Median follow-up: 40.31 months
    [13] - Patients with events: 169 (67.9%) Patients censored: 80 (32.1%) Median follow-up: 38.08 months
    Statistical analysis title
    		 Overall Survival Statistical Analysis
    Statistical analysis description
    OS analyzed using a log-rank test stratified by the randomization stratification factors to compare treatment group survival distributions based on the FAS. K-M estimates of the survival distributions of the time-to-event based on log(-log[survival]) distribution were tabulated by treatment arm (including K-M estimates of medians and 95% CIs). Hazard ratio and 95% CIs were based on a semiparametric Cox proportional hazards regression model stratified by randomization strata.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.4088 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.884
         upper limit
    		 1.352
    Notes
    [14] - Superiority testing of melflufen+dexamethasone over pomalidomide+dexamethasone with respect to the key secondary endpoints performed using a gatekeeping procedure based on a closed fixed-sequence test, provided the primary efficacy endpoint comparison was statistically significant at an alpha level of 0.05. In case of statistical superiority on the primary endpoint then ORR was tested for superiority. In case of statistical superiority on ORR, then overall survival was tested for superiority.
    [15] - Log-rank test was stratified by randomization strata: age (<75, ≥75), number of lines of prior therapy (2, 3-4), and ISS Score (1, ≥2).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs): from the start of study treatment until 30 days after the last dose of study drug or initiation of subsequent therapy. Serious AEs (SAEs): from signing of ICF until 30 days after the last dose of study drug. Data cutoff: 03 Feb 2023.
    Adverse event reporting additional description
    SAEs reported in the SAE section are treatment-emergent SAEs. The frequency threshold for reporting treatment-emergent SAEs is 2%. Non-serious AEs were not calculated in this study. The data reported in the non-serious AE section include all treatment-emergent AEs (non-serious AEs and SAEs). Safety evaluations based on the Safety Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Melflufen 40 mg iv on Day 1 of each 28-day cycle via a central catheter. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age). There were 228 patients in Arm A who received at least 1 dose of study treatment.

    Reporting group title
    Arm B
    Reporting group description
    		 Pomalidomide 4 mg po on Days 1 to 21 of each 28-day cycle. Dexamethasone 40 mg po on Days 1, 8, 15 and 22 of each 28-day cycle (20 mg for patients ≥ 75 years of age). There were 246 patients in Arm B who received at least 1 dose of study treatment.

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 228 (43.42%)
    124 / 246 (50.41%)
         number of deaths (all causes)
    168
    167
         number of deaths resulting from adverse events
    32
    37
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 228 (2.19%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 228 (0.88%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Sudden cardiac death
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 228 (1.75%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 228 (1.75%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 228 (0.44%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    4 / 228 (1.75%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 228 (0.44%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 228 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 228 (0.44%)
    9 / 246 (3.66%)
         occurrences causally related to treatment / all
    0 / 1
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 228 (0.88%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 228 (3.51%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    9 / 11
    11 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    11 / 228 (4.82%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    15 / 15
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 228 (2.19%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 228 (1.75%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal mass
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    2 / 228 (0.88%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Acute kidney injury
         subjects affected / exposed
    2 / 228 (0.88%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 228 (0.44%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    2 / 228 (0.88%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    14 / 228 (6.14%)
    23 / 246 (9.35%)
         occurrences causally related to treatment / all
    7 / 17
    10 / 26
         deaths causally related to treatment / all
    0 / 4
    2 / 4
    COVID-19 pneumonia
         subjects affected / exposed
    12 / 228 (5.26%)
    14 / 246 (5.69%)
         occurrences causally related to treatment / all
    0 / 13
    1 / 14
         deaths causally related to treatment / all
    0 / 8
    1 / 5
    Urinary tract infection
         subjects affected / exposed
    2 / 228 (0.88%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
    3 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 228 (1.32%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 228 (0.44%)
    6 / 246 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    0 / 228 (0.00%)
    5 / 246 (2.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 228 (0.44%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 228 (0.44%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 228 (1.32%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 228 (0.44%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 228 (0.00%)
    3 / 246 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Infection
         subjects affected / exposed
    2 / 228 (0.88%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 228 (0.00%)
    4 / 246 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    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 A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    227 / 228 (99.56%)
    243 / 246 (98.78%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    30 / 228 (13.16%)
    28 / 246 (11.38%)
         occurrences all number
    154
    88
    Platelet count decreased
         subjects affected / exposed
    40 / 228 (17.54%)
    11 / 246 (4.47%)
         occurrences all number
    198
    25
    SARS-CoV-2 test positive
         subjects affected / exposed
    16 / 228 (7.02%)
    22 / 246 (8.94%)
         occurrences all number
    17
    26
    White blood cell count decreased
         subjects affected / exposed
    22 / 228 (9.65%)
    6 / 246 (2.44%)
         occurrences all number
    86
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 228 (3.51%)
    16 / 246 (6.50%)
         occurrences all number
    9
    21
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    137 / 228 (60.09%)
    115 / 246 (46.75%)
         occurrences all number
    795
    421
    Anaemia
         subjects affected / exposed
    154 / 228 (67.54%)
    97 / 246 (39.43%)
         occurrences all number
    487
    238
    Thrombocytopenia
         subjects affected / exposed
    161 / 228 (70.61%)
    50 / 246 (20.33%)
         occurrences all number
    918
    149
    Leukopenia
         subjects affected / exposed
    24 / 228 (10.53%)
    11 / 246 (4.47%)
         occurrences all number
    89
    18
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    33 / 228 (14.47%)
    44 / 246 (17.89%)
         occurrences all number
    52
    57
    Asthenia
         subjects affected / exposed
    33 / 228 (14.47%)
    32 / 246 (13.01%)
         occurrences all number
    50
    47
    Pyrexia
         subjects affected / exposed
    33 / 228 (14.47%)
    18 / 246 (7.32%)
         occurrences all number
    43
    25
    Oedema peripheral
         subjects affected / exposed
    12 / 228 (5.26%)
    24 / 246 (9.76%)
         occurrences all number
    17
    24
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    32 / 228 (14.04%)
    24 / 246 (9.76%)
         occurrences all number
    46
    32
    Nausea
         subjects affected / exposed
    31 / 228 (13.60%)
    18 / 246 (7.32%)
         occurrences all number
    44
    20
    Constipation
         subjects affected / exposed
    17 / 228 (7.46%)
    29 / 246 (11.79%)
         occurrences all number
    19
    33
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    22 / 228 (9.65%)
    27 / 246 (10.98%)
         occurrences all number
    27
    28
    Cough
         subjects affected / exposed
    20 / 228 (8.77%)
    20 / 246 (8.13%)
         occurrences all number
    24
    30
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    21 / 228 (9.21%)
    21 / 246 (8.54%)
         occurrences all number
    23
    29
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    19 / 228 (8.33%)
    26 / 246 (10.57%)
         occurrences all number
    20
    33
    Bone pain
         subjects affected / exposed
    16 / 228 (7.02%)
    13 / 246 (5.28%)
         occurrences all number
    18
    19
    Arthralgia
         subjects affected / exposed
    16 / 228 (7.02%)
    8 / 246 (3.25%)
         occurrences all number
    20
    9
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 228 (0.88%)
    14 / 246 (5.69%)
         occurrences all number
    2
    15
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    21 / 228 (9.21%)
    36 / 246 (14.63%)
         occurrences all number
    26
    47
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 228 (12.72%)
    27 / 246 (10.98%)
         occurrences all number
    33
    43
    Bronchitis
         subjects affected / exposed
    13 / 228 (5.70%)
    29 / 246 (11.79%)
         occurrences all number
    16
    42
    Urinary tract infection
         subjects affected / exposed
    12 / 228 (5.26%)
    16 / 246 (6.50%)
         occurrences all number
    17
    24
    Respiratory tract infection
         subjects affected / exposed
    8 / 228 (3.51%)
    20 / 246 (8.13%)
         occurrences all number
    12
    24
    COVID-19 pneumonia
         subjects affected / exposed
    12 / 228 (5.26%)
    14 / 246 (5.69%)
         occurrences all number
    15
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2017
    Protocol Amendment 2.0: - Consolidated all of the country-specific changes into a global amendment. - Clarified that IV dexamethasone was only an option for use in the USA. - Clarified that pregnancy tests must be medically supervised pregnancy test with a sensitivity consistent with the regional REMS or PPP program. - Excluded the use of live vaccines prior to, during and following treatment with study drug Extended the duration of contraception required following treatment with melflufen. - Clarified the definition of abstinence. - Recommended that men consider cryopreservation of semen prior to initiation of therapy. - Added precautionary statements regarding the re-activation of HBV infection during treatment with pomalidomide. - Added precaution regarding the use of erythropoietic agents and other agents that may have increased the risk of thromboembolic events. - Added the precautionary statement regarding the risk of renal dysfunction with cyclosporine in combination with melflufen. - Added alpha interferon to the list of agents with possible therapeutic effect against MM. - Changed the dose modification guidelines for pomalidomide to be consistent with the SmPC. - Added the option of performing an additional CBC just prior to randomization. - Clarified the required disease assessments relative to the patient’s disease characteristics and compliance with IMWG criteria. - Clarified the timing of response assessments at end of treatment and start of PFS assessments. - Provided clarification on the reference documents used to determine unexpected AE. - Informed patients regarding the availability of the study drug following study discontinuation.
    30 May 2018
    Protocol Amendment 3.0: - Increased the number of sites to approximately 100 and added the Asia/Pacific region. - Changed entry criterion #4 to allow patients refractory to lenalidomide within 18 months of randomization, in addition to last line, to improve accrual in the study. - Allowed longer time for BMA and imaging studies done prior to randomization. - Allowed M-protein assessments to be performed locally during PFS-FU. - Permitted OS follow-up beyond 24 months.
    24 May 2019
    Protocol Amendment 4.1: - Changed the name of the Oncopeptides project physician. - Updated the summary of the now completed 012-M1 study. - Changed entry criteria # 4 to allow patients that received lenalidomide and a proteasome inhibitor during the first line of therapy and were refractory to lenalidomide in the first line to potentially enroll in the study to improve accrual. - Change the coagulation studies from required at every cycle day 1 to as clinically indicated. - Increased the time from signing consent from 21 days to 28 days prior to initiation of therapy. - Changed the instructions for preparation of melflufen solution for infusion to allow for dilution with saline, which increases the shelf-life of the solution. - Added patient reported outcomes as an exploratory study objective with the purpose of supporting European pricing and reimbursement activities. - Updated the references. - Added an exploratory objective to evaluate functional status and well-being based on PRO assessments and added a description of the endpoints to evaluate this objective. - Changed the drug preparation procedures to allow for the use of saline for the dilution of melflufen which increased the shelf life of the prepared solution.
    24 Mar 2020
    Protocol Amendment 5.0: - Implemented changes to reduce the number of on-site visits and thus the risk to patients following the COVID-19 pandemic as part of an urgent safety measure released in response to the COVID-19 pandemic.
    20 Apr 2021
    Protocol Amendment 6.1: - Consolidated all safety reporting to one vendor, hence new routine for SAE reporting was implemented.

    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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