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    Clinical Trial Results:
    A phase III trial comparing bortezomib, cyclophosphamide and dexamethasone versus lenalinomide cyclophosphamide and dexamethasone in patients with multiple myeloma at first relapse

    Summary
    EudraCT number
    		 2010-021557-40
    Trial protocol
    		 IT  
    Global end of trial date
    28 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Feb 2020
    First version publication date
    20 Feb 2020
    Other versions
    Summary report(s)
    		 Br J Haematology 2020

    Trial information

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    Trial identification
    Sponsor protocol code
    MM-Rel
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fondazione IRCCS Istituto Nazionale dei Tumori
    Sponsor organisation address
    via Venezian 1, Milano, Italy,
    Public contact
    Clinical Trials Center, Fondazione IRCCS Istituto Nazionale dei Tumori, 0039 0223903146, trialcenter@istitutotumori.mi.it
    Scientific contact
    Prof. Corradini: paolo.corradini@unimi.it; Dr Montefusco: montefusco.vittorio@sancarlo.mi.it; , Fondazione IRCCS Istituto Nazionale dei Tumori, 0039 0223902950, paolo.corradini@unimi.it
    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
    01 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the CR and VGPR rate at 6 weeks after the end of consolidation in patients treated with VCD (velcade-cyclophosphamide-dexamethasone) versus RCD (revlimid-cyclophosphamide-dexamethasone).
    Protection of trial subjects
    Each subject, or the subject's representative, signed an informed consent form prior to screening
    Background therapy
    		 All patients received acyclovir 400 mg bid for herpes viruses prophylaxis. Prophylaxis with quinolones, cotrimoxazole, and fluconazole was prescribed as clinically indicated. All subjects were allowed to receive Biphosphonates therapy (intravenous pamidronate or zolendronic acid) according to the current guidelines or when clinically indicated.
    Evidence for comparator
    		 Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma. However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we conducted a phase III randomized trial comparing cyclophosphamide and dexamethasone plus bortezomib (VCD, i.e. Test Products) or lenalidomide (RCD, i.e. Reference Therapy) in MM patients at first relapse.
    Actual start date of recruitment
    03 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 159
    Worldwide total number of subjects
    159
    EEA total number of subjects
    159
    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)
    85
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 159 patients were enrolled from March 2011 until February 2015. The study was prematurely closed due to regional regulatory issues.

    Pre-assignment
    Screening details
    		 MM patients at first symptomatic relapse were eligible. Key entry criteria were age ≥18 and ≤75 years, and measurable disease according to the International Myeloma Working Group (IMWG) criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 159
    Number of subjects completed
    		 155

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Screening failure: 2
    Reason: Number of subjects
    		 death of unknown cause: 1
    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
    not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VCD (bortezomib-cyclophosphamide-dexamethasone)
    Arm description
    		 Induction treatment: cyclophosphamide 500 mg/sqm, iv, on day 1 and 8, and dexamethasone 20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 in combination with subcutaneous bortezomib 1.3 mg/sqm on days 1, 8, 15, 22 (VCD) in six 35-day cycles. Consolidation phase: after the first six cycles, patients received consolidation with 3 further cycles of VCD therapy, administered every 2 months (i.e. the duration of the cycle was 35 days, followed by a 25 days rest). Patients who did not achieve at least a minimal response (MR) after the third cycle, or at least a PR after the sixth cycle, were allowed to go off study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/sqm, on day 1 and 8 of each 35-day cycle

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 of each 35-day cycle

    Investigational medicinal product name
    bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.3 mg/sqm on days 1, 8, 15, 22 of each 35-day cycle

    Arm title
    		 RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Arm description
    		 Induction treatment: cyclophosphamide 500 mg/sqm, iv, on day 1 and 8, and dexamethasone 20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 in combination with oral lenalidomide 15 mg on days 1 to 21 (RCD) in six 28-day cycles. Consolidation phase: after the first six cycles, patients received consolidation with 3 further cycles of RCD therapy, administered every 2 months (i.e. the duration of the cycle was 28 days, followed by a 32 days rest). Patients who did not achieve at least a minimal response (MR) after the third cycle, or at least a PR after the sixth cycle, were allowed to go off study. RCD arm patients received anti-thrombotic prophylaxis with low molecular weight heparin at 100 IU/Kg/die during the first three courses.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/sqm, iv, on day 1 and 8 of each 28 days cycle

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 of each 28 days cycle

    Investigational medicinal product name
    lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15 mg on days 1-21 of each 28 days cycle

    Number of subjects in period 1 [1]
    		VCD (bortezomib-cyclophosphamide-dexamethasone) RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Started
    76
    79
    Mid-Induction (after the third cycle)
    53
    61
    End of Induction (after the sixth cycle)
    41
    49
    Completed
    31
    43
    Not completed
    45
    36
         Consent withdrawn by subject
    3
    -
         Physician decision
    4
    6
         Lack of partial response after the sixth cycle
    9
    7
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    3
    3
         Progressive disease during consolidation
    6
    6
         Lack of minimal response after the third cycle
    20
    13
    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: A total number of 186 patients was required to evaluate the primary endpoint. The required sample size was increased up to 200 patients (100 for each arm) to account for about 5% drop-in and drop-outs. However, only 159 patients were enrolled as the study was prematurely closed due to regional regulatory issues. Among patients enrolled, 155 were randomized to receive VCD (n = 76) or RCD (n = 79), and were included in the ITT analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 155 155
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 83 83
        From 65-84 years
    		 72 72
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 83 83
        Male
    		 72 72

    End points

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    End points reporting groups
    Reporting group title
    VCD (bortezomib-cyclophosphamide-dexamethasone)
    Reporting group description
    		 Induction treatment: cyclophosphamide 500 mg/sqm, iv, on day 1 and 8, and dexamethasone 20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 in combination with subcutaneous bortezomib 1.3 mg/sqm on days 1, 8, 15, 22 (VCD) in six 35-day cycles. Consolidation phase: after the first six cycles, patients received consolidation with 3 further cycles of VCD therapy, administered every 2 months (i.e. the duration of the cycle was 35 days, followed by a 25 days rest). Patients who did not achieve at least a minimal response (MR) after the third cycle, or at least a PR after the sixth cycle, were allowed to go off study.

    Reporting group title
    RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Reporting group description
    		 Induction treatment: cyclophosphamide 500 mg/sqm, iv, on day 1 and 8, and dexamethasone 20 mg, oral or iv, on days 1-2, 8-9, 15-16, and 22-23 in combination with oral lenalidomide 15 mg on days 1 to 21 (RCD) in six 28-day cycles. Consolidation phase: after the first six cycles, patients received consolidation with 3 further cycles of RCD therapy, administered every 2 months (i.e. the duration of the cycle was 28 days, followed by a 32 days rest). Patients who did not achieve at least a minimal response (MR) after the third cycle, or at least a PR after the sixth cycle, were allowed to go off study. RCD arm patients received anti-thrombotic prophylaxis with low molecular weight heparin at 100 IU/Kg/die during the first three courses.

    Primary: VGPR and CR rate

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    End point title
    		 VGPR and CR rate
    End point description
    Since we compared two fixed-duration therapies and we were mainly interested in discerning the depth of response obtained with the two treatments, we chose as primary endpoint the achievement of a very good partial response (VGPR) or better (i.e. CR) at 6 weeks after the end of consolidation. Response was assessed according to the IMWG criteria.
    End point type
    Primary
    End point timeframe
    At six weeks after 9 treatment cycles
    End point values
    		 VCD (bortezomib-cyclophosphamide-dexamethasone) RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Number of subjects analysed
    31
    43
    Units: subjects
        Stringent Complete Response (sCR)
    4
    1
        Complete response (CR)
    5
    5
        Very Good Partial Response (VGPR)
    3
    8
        Partial Response (PR)
    10
    20
        Stable Disease (SD)
    3
    1
        Progressive disease (PD)
    4
    6
        Not assessable
    2
    2
    Statistical analysis title
    		 Depth of response (VGPR and CR rate)
    Statistical analysis description
    The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after 9 treatment cycles. The expected VGPR and CR rate in the VCD and RCD treatment groups were 40% and 20%, respectively. Allowing for a significance level (alpha) of 5%, and a 85% power, then a total number of 186 patients were required. Statistical analysis was performed on an Intention-To-Treat basis. Statistical analyses were conducted using SAS (version 9.4) and R (version 3.3.1) software.
    Comparison groups
    VCD (bortezomib-cyclophosphamide-dexamethasone) v RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 ≤ 0.05 [2]
    Method
    		 Regression, Cox
    Confidence interval
    Notes
    [1] - For regulatory issues on use of drugs in clinical trials, we enrolled only 159 patients, in spite of at least 186 patients being necessary to keep a statistical power of 85%. After 9 cycles of therapy, 12 VCD and 14 RCD patients achieved a VGPR or better (p=0.70); thus the primary endpoint of the study was not met.
    [2] - We planned to use a standard p-value

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Median follow-up was 34 months, specifically 34 months in the VCD group, and 32 months in the RCD group. One-year PFS was 60%(95% CI: 50–72%) and 64% (95% CI: 53–75%), two-year PFS was 34% (95% CI: 25–47%) and 40% (95% CI: 30–53%), and median PFS was 16.3 (95% CI: 12.1–22.4) and 18.6 (95% CI: 14.7–25.5), in the VCD and in RCD arms respectively. No statistically significan tdifferences in PFS were observed with VCD and RCD according to age(<65 or ≥65 years), first-line therapy (chemotherapy or bortezomib-based regimen), ISS stage (I vs. II–III), and time-to-progression with first-line therapy (>3 years vs. ≤3 years).
    End point type
    Secondary
    End point timeframe
    PFS was calculated as the time from randomization to the date of first evidence of PD or death without evidence of PD or to the last date the patient was known to be progression-free. Median follow-up was calculated by the reverse Kaplan–Meier method.
    End point values
    		 VCD (bortezomib-cyclophosphamide-dexamethasone) RCD (lenalidomide-cyclophosphamide-dexamethasone)
    Number of subjects analysed
    76
    79
    Units: not progressed living patients
        1-year not progressed living patients
    45
    49
        2-year not progressed living patients
    21
    26
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization up to 6 weeks after the end of consolidation
    Adverse event reporting additional description
    Toxicities are graded according to the Common Terminology Criteria for Adverse Events v.3.0 (CTCAE)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    All treated patients
    Reporting group description
    		 A total of 52 patients, 26 in each arm, experienced at least one toxicity. All deaths occurred during follow-up and were not recorded as serious adverse events. No toxicity related deaths were observed. The majority of patients in both study groups (n = 42) died from relapse or progression: 25 in the VCD and 17 in the RCD arm respectively. Among others, 9 patients died for other causes: 2 in the VCD arm and 7 in the RCD arm respectively. For 6 patients (3 in each arm) the cause of death is unknown.

    Serious adverse events
    		 All treated patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 155 (21.94%)
         number of deaths (all causes)
    57
         number of deaths resulting from adverse events
    0
    Investigations
    Neutropenia
    Additional description: Grade 3-4 neutropenia was observed in 4 VCD patients and 9 RCD patients
         subjects affected / exposed
    13 / 155 (8.39%)
         occurrences causally related to treatment / all
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
    Additional description: Grade 3-4 Thrombocytopenia occurred in 3 VCD patients and in 5 RCD patients
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Second primary malignancy
         subjects affected / exposed
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
    Additional description: Grade 3-4 infections occurred in 9 VCD patients and in 3 RCD patients
         subjects affected / exposed
    12 / 155 (7.74%)
         occurrences causally related to treatment / all
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All treated patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 155 (30.32%)
    Investigations
    Neutropenia
    Additional description: Grade 1-2 neutropenia occurred in 8 RCD patients (none in VCD patients)
         subjects affected / exposed
    8 / 155 (5.16%)
         occurrences all number
    8
    Nervous system disorders
    Peripheral sensory neuropathy
    Additional description: any grade peripheral sensory neuropathy occurred in a total of 12 VCD and 4 RCD patients
         subjects affected / exposed
    16 / 155 (10.32%)
         occurrences all number
    16
    Infections and infestations
    Infection
    Additional description: Grade 1-2 infections were observed in 7 VCD patients and in 16 RCD patients
         subjects affected / exposed
    23 / 155 (14.84%)
         occurrences all number
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2011
    Amendment 1: clarifications on the evaluation of the response after the third cycle; increase in the number of participating sites.
    16 Jul 2012
    Amendment 2: changes in exclusion criteria to specify that “active hepatitis B virus (HBV DNA positivity) or hepatitis C virus (HCV RNA positivity) are not, per se, a contraindication to the study, unless, in the opinion of the treating physician, these conditions can be predicted to interfere with treatment administration”; clarifications on the consolidation phase; increase in the number of participating sites.
    27 Jan 2014
    Amendment 3: extension of study enrolment (from 2 to 4 years); change in the route of bortezomib administration (from intravenous to subcutaneous).

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Jul 2015
    Amendment 4: early termination of enrolment due to regional regulatory issues, leading the National Healthcare System to stop bortezomib and lenalidomide free supply for the study.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Our results should be considered with caution, since, for regulatory issues on use of drugs in clinical trials, we enrolled only 159 patients, in spite of at least 186 patients being necessary to keep a statistical power of 85%.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31898319
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