Addition of Daratumumab to Combination of Bortezomib and Dexamethasone in Participants With Relapsed or Refractory Multiple Myeloma

Sponsor
Janssen Research & Development, LLC (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02136134
Collaborator
(none)
500
Enrollment
107
Locations
2
Arms
118.5
Anticipated Duration (Months)
4.7
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the effects of administration of daratumumab when combined with VELCADE (bortezomib) and dexamethasone compared with bortezomib and dexamethasone alone, for participants with relapsed or refractory multiple myeloma.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

Detailed Description

This is an open-label (physicians and participants know the identity of the assigned treatment), randomized (the study medication is assigned by chance), multicenter, active-controlled study comparing daratumumab, VELCADE, and dexamethasone (DVd) with VELCADE and dexamethasone (Vd) in participants with relapsed or refractory multiple myeloma. Approximately 480 participants will be randomly assigned in a 1:1 ratio to receive either DVd or Vd. Randomization will be stratified by International Staging System (ISS), number of prior treatment programs (1 vs. 2 or 3 vs. >3), and prior VELCADE treatment ("no" vs. "yes"). Within each stratum, participants will be randomized to one of the treatment groups.The study will consist of a Screening Phase, a Treatment Phase, and a Follow-up Phase. Participants will be treated until disease progression, unacceptable toxicity, or other reasons to discontinue the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
500 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 3 Study Comparing Daratumumab, Bortezomib and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) in Subjects With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date :
Aug 15, 2014
Actual Primary Completion Date :
Jan 11, 2016
Anticipated Study Completion Date :
Jun 30, 2024

Arms and Interventions

ArmIntervention/Treatment
Experimental: Daratumumab+VELCADE+dexamethasone

Daratumumab, VELCADE and dexamethasone

Drug: Daratumumab
Daratumumab will be administered as an IV infusion or 16 mg/kg weekly for the first 3 cycles, on Day 1 of Cycles 4-9, and then every 4 weeks thereafter. As per protocol amendment-6 participants receiving treatment with daratumumab IV will have the option to switch to daratumumab SC 1800 mg on Day 1 of any cycle, at the discretion of the investigator.

Drug: VELCADE (Bortezomib)
VELCADE will be administered at a dose of 1.3 mg/m2 subcutaneously (SC) on Days 1, 4, 8 and 11 of each 21-day cycle. Eight VELCADE treatment cycles are to be administered.
Other Names:
  • VELCADE
  • Drug: Dexamethasone
    Dexamethasone will be administered orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 VELCADE treatment cycles.

    Active Comparator: VELCADE+dexamethasone

    VELCADE and dexamethasone.

    Drug: VELCADE (Bortezomib)
    VELCADE will be administered at a dose of 1.3 mg/m2 subcutaneously (SC) on Days 1, 4, 8 and 11 of each 21-day cycle. Eight VELCADE treatment cycles are to be administered.
    Other Names:
  • VELCADE
  • Drug: Dexamethasone
    Dexamethasone will be administered orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11 and 12 of the first 8 VELCADE treatment cycles.

    Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival (PFS) [From the date of randomization to either progressive disease or death, whichever occurs first (approximately 3 years)]

      PFS was defined as duration from date of randomization to either progressive disease (PD)/death, whichever occurred first. PD was defined as meeting any one of following criteria: Increase of greater than equal to (>=)25 percent (%) in level of serum M-protein from lowest response value and absolute increase must be >=0.5 gram per deciliter (g/dL); Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be >10 mg/dL; Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.

    Secondary Outcome Measures

    1. Time to Disease Progression (TTP) [From the date of randomization to the date of first documented evidence of progression or death due to PD whichever occurs first (approximately 3 years)]

      TTP was defined as time from date of randomization to date of first documented evidence of progressive disease (PD). PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5 g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 milligram per deciliter (mg/dL); Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to Plasma Cell (PC) proliferative disorder.

    2. Percentage of Participants With a Very Good Partial Response (VGPR) or Better [Up to disease progression (approximately of 3 years)]

      Response rate of VGPR or better was defined as the percentage of participants who achieved VGPR and CR (including sCR) according to the IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >90% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry.

    3. Overall Response Rate (ORR) [Up to disease progression (approximately of 3 years)]

      The Overall response rate was defined as the percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) according to the International Myeloma Working Group (IMWG) criteria, during the study or during follow up. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >=90% or to <200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.

    4. Percentage of Participants With Negative Minimal Residual Disease (MRD) [Up to disease progression (approximately of 3 years)]

      The Minimal Residual Disease negativity rate was defined as the percentage of participants who had negative MRD assessment at any timepoint after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood. MRD was assessed in participants who achieved complete response or stringent complete response (CR/sCR). IMWG criteria for CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR plus normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry.

    5. Overall Survival (OS) [Up to the end of the study (approximately of 3 years)]

      Overall Survival was measured from the date of randomization to the date of the participant's death.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Must have had documented multiple myeloma

    • Must have received at least 1 prior line of therapy for multiple myeloma

    • Must have had documented evidence of progressive disease as defined based on Investigator's determination of response of International Myeloma Working Group (IMWG) criteria on or after their last regimen

    • Must have an Eastern Cooperative Oncology Group Performance Status score of 0, 1, or 2

    • Must have achieved a response (partial response [PR] or better based on investigator's determination of response by the IMWG criteria) to at least 1 prior regimen in the past

    Exclusion Criteria:
    • Has received daratumumab or other anti-CD38 therapies previously

    • Is refractory to VELCADE or another PI, like ixazomib and carfilzomib (had progression of disease while receiving VELCADE therapy or within 60 days of ending VELCADE therapy or another PI therapy, like ixazomib and carfilzomib

    • Is intolerant to VELCADE (ie, discontinued due to any adverse event while on VELCADE treatment)

    • Has received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the treatment, whichever is longer, before the date of randomization. The only exception is emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 milligram per day [mg/day] for a maximum of 4 days) before treatment. A list of anti-myeloma treatments with the corresponding pharmacokinetic half-lives is provided in the Site Investigational Product Procedures Manual (IPPM).

    • Has a history of malignancy (other than multiple myeloma) within 3 years before the date of randomization

    • Has any concurrent medical condition or disease (eg, active systemic infection) that is likely to interfere with study procedures

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1BirminghamAlabamaUnited States
    2Los AngelesCaliforniaUnited States
    3StamfordConnecticutUnited States
    4JacksonvilleFloridaUnited States
    5AtlantaGeorgiaUnited States
    6NilesIllinoisUnited States
    7TopekaKansasUnited States
    8WestwoodKansasUnited States
    9MarreroLouisianaUnited States
    10BostonMassachusettsUnited States
    11LansingMichiganUnited States
    12New YorkNew YorkUnited States
    13Chapel HillNorth CarolinaUnited States
    14PortlandOregonUnited States
    15PhiladelphiaPennsylvaniaUnited States
    16ProvidenceRhode IslandUnited States
    17SeattleWashingtonUnited States
    18AdelaideAustralia
    19ConcordAustralia
    20FitzroyAustralia
    21HobartAustralia
    22MelbourneAustralia
    23NedlandsAustralia
    24Woodville SouthAustralia
    25BarretosBrazil
    26Porto AlegreBrazil
    27SalvadorBrazil
    28Sao PauloBrazil
    29São PauloBrazil
    30BrnoCzechia
    31Hradec KraloveCzechia
    32Ostrava-PorubaCzechia
    33Praha 10Czechia
    34Praha 2Czechia
    35BambergGermany
    36BerlinGermany
    37DuesseldorfGermany
    38FreiburgGermany
    39GöttingenGermany
    40HamburgGermany
    41MainzGermany
    42MünchenGermany
    43StuttgartGermany
    44TübingenGermany
    45UlmGermany
    46WürzburgGermany
    47BudapestHungary
    48DebrecenHungary
    49GyőrHungary
    50Pécs N/aHungary
    51VeszprémHungary
    52BusanKorea, Republic of
    53HwasunKorea, Republic of
    54SeoulKorea, Republic of
    55SuwonKorea, Republic of
    56UlsanKorea, Republic of
    57HuixquilucanMexico
    58MonterreyMexico
    59AlkmaarNetherlands
    60AmersfoortNetherlands
    61Den HaagNetherlands
    62DordrechtNetherlands
    63GroningenNetherlands
    64LeidenNetherlands
    65MaastrichtNetherlands
    66NijmegenNetherlands
    67ChorzówPoland
    68KatowicePoland
    69KrakowPoland
    70PoznanPoland
    71WarszawaPoland
    72KrasnodarRussian Federation
    73MoscowRussian Federation
    74Nizhny NovgorodRussian Federation
    75PenzaRussian Federation
    76PyatigorskRussian Federation
    77RyazanRussian Federation
    78SamaraRussian Federation
    79SochiRussian Federation
    80SyktyvkarRussian Federation
    81MadridSpain
    82SalamancaSpain
    83San Sebastian de los ReyesSpain
    84ToledoSpain
    85ValenciaSpain
    86LinkopingSweden
    87LuleaSweden
    88LundSweden
    89OrebroSweden
    90SundsvallSweden
    91UmeaSweden
    92UppsalaSweden
    93VästeråsSweden
    94AnkaraTurkey
    95IstanbulTurkey
    96IzmirTurkey
    97KayseriTurkey
    98KocaeliTurkey
    99MalatyaTurkey
    100CherkasyUkraine
    101DnepropetrovskUkraine
    102Ivano-FrankivskUkraine
    103KievUkraine
    104LvivUkraine
    105PoltavaUkraine
    106VinnitsaUkraine
    107ZaporizhzhyaUkraine

    Sponsors and Collaborators

    • Janssen Research & Development, LLC

    Investigators

    • Study Director: Janssen Research & Development, LLC Clinical trial, Janssen Research & Development, LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Janssen Research & Development, LLC
    ClinicalTrials.gov Identifier:
    NCT02136134
    Other Study ID Numbers:
    • CR103995
    • 2014-000255-85
    • 54767414MMY3004
    • NCT01620879
    First Posted:
    May 12, 2014
    Last Update Posted:
    Nov 5, 2021
    Last Verified:
    Nov 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Janssen Research & Development, LLC
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Period Title: Overall Study
    STARTED247251
    Treated237243
    COMPLETED00
    NOT COMPLETED247251

    Baseline Characteristics

    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)Total
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Total of all reporting groups
    Overall Participants247251498
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    63.9
    (9.81)
    62.8
    (9.66)
    63.3
    (9.74)
    Sex: Female, Male (Count of Participants)
    Female
    100
    40.5%
    114
    45.4%
    214
    43%
    Male
    147
    59.5%
    137
    54.6%
    284
    57%
    Region of Enrollment (participants) [Number]
    Australia
    20
    8.1%
    23
    9.2%
    43
    8.6%
    Brazil
    9
    3.6%
    13
    5.2%
    22
    4.4%
    Czech Republic
    19
    7.7%
    16
    6.4%
    35
    7%
    Germany
    21
    8.5%
    21
    8.4%
    42
    8.4%
    Hungary
    14
    5.7%
    16
    6.4%
    30
    6%
    Italy
    25
    10.1%
    24
    9.6%
    49
    9.8%
    Korea, Republic of
    8
    3.2%
    10
    4%
    18
    3.6%
    Mexico
    1
    0.4%
    2
    0.8%
    3
    0.6%
    Netherlands
    14
    5.7%
    11
    4.4%
    25
    5%
    Poland
    18
    7.3%
    16
    6.4%
    34
    6.8%
    Russian Federation
    13
    5.3%
    21
    8.4%
    34
    6.8%
    Spain
    19
    7.7%
    10
    4%
    29
    5.8%
    Sweden
    9
    3.6%
    10
    4%
    19
    3.8%
    Turkey
    14
    5.7%
    14
    5.6%
    28
    5.6%
    Ukraine
    22
    8.9%
    28
    11.2%
    50
    10%
    United States
    21
    8.5%
    16
    6.4%
    37
    7.4%
    Stage of Disease (ISS) (participants) [Number]
    I
    96
    38.9%
    98
    39%
    194
    39%
    II
    100
    40.5%
    94
    37.5%
    194
    39%
    III
    51
    20.6%
    59
    23.5%
    110
    22.1%
    No. of Prior Lines of Therapy (participants) [Number]
    1
    113
    45.7%
    122
    48.6%
    235
    47.2%
    2
    74
    30%
    70
    27.9%
    144
    28.9%
    3
    32
    13%
    37
    14.7%
    69
    13.9%
    >3
    28
    11.3%
    22
    8.8%
    50
    10%

    Outcome Measures

    1. Primary Outcome
    TitleProgression-free Survival (PFS)
    DescriptionPFS was defined as duration from date of randomization to either progressive disease (PD)/death, whichever occurred first. PD was defined as meeting any one of following criteria: Increase of greater than equal to (>=)25 percent (%) in level of serum M-protein from lowest response value and absolute increase must be >=0.5 gram per deciliter (g/dL); Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved FLC levels from lowest response value and absolute increase must be >10 mg/dL; Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to PC proliferative disorder.
    Time FrameFrom the date of randomization to either progressive disease or death, whichever occurs first (approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all randomized participants.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants247251
    Median (95% Confidence Interval) [months]
    7.16
    NA
    2. Secondary Outcome
    TitleTime to Disease Progression (TTP)
    DescriptionTTP was defined as time from date of randomization to date of first documented evidence of progressive disease (PD). PD was defined as meeting any one of following criteria: Increase of >=25% in level of serum M-protein from lowest response value and absolute increase must be >=0.5 g/dL; Increase of >=25% in 24-hour urinary light chain excretion (urine M-protein) from lowest response value and absolute increase must be >=200 mg/24hours; Only in participants without measurable serum and urine M-protein levels: increase of >=25% in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase must be >10 milligram per deciliter (mg/dL); Definite increase in size of existing bone lesions or soft tissue plasmacytomas; Definite development of new bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to Plasma Cell (PC) proliferative disorder.
    Time FrameFrom the date of randomization to the date of first documented evidence of progression or death due to PD whichever occurs first (approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all randomized participants.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants247251
    Median (95% Confidence Interval) [months]
    7.29
    NA
    3. Secondary Outcome
    TitlePercentage of Participants With a Very Good Partial Response (VGPR) or Better
    DescriptionResponse rate of VGPR or better was defined as the percentage of participants who achieved VGPR and CR (including sCR) according to the IMWG criteria during or after the study treatment. IMWG criteria for VGPR: Serum and urine M-component detectable by immunofixation but not on electrophoresis, or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >90% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required; CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry.
    Time FrameUp to disease progression (approximately of 3 years)

    Outcome Measure Data

    Analysis Population Description
    The response evaluable analysis set is defined as participants who have a confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit, received at least 1 administration of study treatment, and had at least 1 post baseline disease assessment.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants234240
    Number (95% Confidence Interval) [percentage of participants]
    29.1
    11.8%
    59.2
    23.6%
    4. Secondary Outcome
    TitleOverall Response Rate (ORR)
    DescriptionThe Overall response rate was defined as the percentage of participants who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) according to the International Myeloma Working Group (IMWG) criteria, during the study or during follow up. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >=90% or to <200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required.
    Time FrameUp to disease progression (approximately of 3 years)

    Outcome Measure Data

    Analysis Population Description
    The response-evaluable analysis set is defined as participants who have confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit, received at least 1 administration of study treatment and had at least 1 post baseline disease assessment.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants234240
    Number (95% Confidence Interval) [percentage of participants]
    63.2
    25.6%
    82.9
    33%
    5. Secondary Outcome
    TitlePercentage of Participants With Negative Minimal Residual Disease (MRD)
    DescriptionThe Minimal Residual Disease negativity rate was defined as the percentage of participants who had negative MRD assessment at any timepoint after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood. MRD was assessed in participants who achieved complete response or stringent complete response (CR/sCR). IMWG criteria for CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR plus normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2 to 4 color flow cytometry.
    Time FrameUp to disease progression (approximately of 3 years)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all randomized participants.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants247251
    Number [percentage of participants]
    2.8
    1.1%
    13.5
    5.4%
    6. Secondary Outcome
    TitleOverall Survival (OS)
    DescriptionOverall Survival was measured from the date of randomization to the date of the participant's death.
    Time FrameUp to the end of the study (approximately of 3 years)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all randomized participants.
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    Measure Participants247251
    Median (95% Confidence Interval) [months]
    NA
    NA

    Adverse Events

    Time Frame
    Adverse Event Reporting Description Safety population included all randomized participants who had at least 1 administration of any of the study treatment (partial or complete).
    Arm/Group TitleBortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group DescriptionParticipants received bortezomib subcutaneously (SC) on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally (PO) at 20 milligram (mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.Participants received daratumumab 16 milligram per kilogram (mg/kg) intravenous (IV) infusion weekly for the first 3 cycles, on Day 1 of Cycles 4-8, and then every 4 weeks thereafter, bortezomib SC administration on Days 1, 4, 8, and 11 of each 21-day cycle (8 treatment cycles) and dexamethasone orally at 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles.
    All Cause Mortality
    Bortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total/ (NaN) / (NaN)
    Serious Adverse Events
    Bortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total80/237 (33.8%) 102/243 (42%)
    Blood and lymphatic system disorders
    Anaemia1/237 (0.4%) 8/243 (3.3%)
    Febrile Neutropenia0/237 (0%) 2/243 (0.8%)
    Neutropenia0/237 (0%) 2/243 (0.8%)
    Thrombocytopenia1/237 (0.4%) 6/243 (2.5%)
    Cardiac disorders
    Acute Coronary Syndrome0/237 (0%) 1/243 (0.4%)
    Acute Myocardial Infarction0/237 (0%) 1/243 (0.4%)
    Arrhythmia Supraventricular0/237 (0%) 1/243 (0.4%)
    Atrial Fibrillation0/237 (0%) 5/243 (2.1%)
    Cardiac Arrest1/237 (0.4%) 1/243 (0.4%)
    Cardiac Failure0/237 (0%) 1/243 (0.4%)
    Cardiac Failure Congestive1/237 (0.4%) 2/243 (0.8%)
    Cardiogenic Shock1/237 (0.4%) 1/243 (0.4%)
    Myocardial Infarction2/237 (0.8%) 0/243 (0%)
    Ventricular Extrasystoles1/237 (0.4%) 0/243 (0%)
    Endocrine disorders
    Adrenal Insufficiency1/237 (0.4%) 0/243 (0%)
    Hyperthyroidism0/237 (0%) 1/243 (0.4%)
    Eye disorders
    Diplopia0/237 (0%) 1/243 (0.4%)
    Gastrointestinal disorders
    Abdominal Pain3/237 (1.3%) 0/243 (0%)
    Abdominal Pain Upper0/237 (0%) 1/243 (0.4%)
    Constipation3/237 (1.3%) 0/243 (0%)
    Diarrhoea0/237 (0%) 4/243 (1.6%)
    Diverticular Perforation0/237 (0%) 1/243 (0.4%)
    Duodenal Ulcer0/237 (0%) 1/243 (0.4%)
    Faecaloma1/237 (0.4%) 0/243 (0%)
    Gastritis0/237 (0%) 1/243 (0.4%)
    Incarcerated Umbilical Hernia1/237 (0.4%) 0/243 (0%)
    Intestinal Obstruction0/237 (0%) 1/243 (0.4%)
    Melaena0/237 (0%) 1/243 (0.4%)
    Pancreatitis Acute0/237 (0%) 1/243 (0.4%)
    Pancreatitis Chronic0/237 (0%) 1/243 (0.4%)
    Small Intestinal Obstruction0/237 (0%) 1/243 (0.4%)
    General disorders
    Asthenia3/237 (1.3%) 0/243 (0%)
    Condition Aggravated3/237 (1.3%) 0/243 (0%)
    Fatigue0/237 (0%) 2/243 (0.8%)
    General Physical Health Deterioration3/237 (1.3%) 1/243 (0.4%)
    Influenza Like Illness1/237 (0.4%) 0/243 (0%)
    Oedema Peripheral0/237 (0%) 1/243 (0.4%)
    Pain0/237 (0%) 1/243 (0.4%)
    Pyrexia4/237 (1.7%) 4/243 (1.6%)
    Infections and infestations
    Bacterial Infection1/237 (0.4%) 0/243 (0%)
    Brain Abscess1/237 (0.4%) 0/243 (0%)
    Bronchitis1/237 (0.4%) 5/243 (2.1%)
    Bronchopneumonia1/237 (0.4%) 3/243 (1.2%)
    Cellulitis0/237 (0%) 1/243 (0.4%)
    Epididymitis1/237 (0.4%) 0/243 (0%)
    Fungal Oesophagitis0/237 (0%) 1/243 (0.4%)
    Gangrene1/237 (0.4%) 0/243 (0%)
    Gastroenteritis3/237 (1.3%) 2/243 (0.8%)
    Herpes Zoster2/237 (0.8%) 1/243 (0.4%)
    Influenza2/237 (0.8%) 0/243 (0%)
    Lobar Pneumonia1/237 (0.4%) 0/243 (0%)
    Lower Respiratory Tract Infection2/237 (0.8%) 2/243 (0.8%)
    Lung Infection1/237 (0.4%) 1/243 (0.4%)
    Metapneumovirus Infection0/237 (0%) 1/243 (0.4%)
    Nocardiosis1/237 (0.4%) 0/243 (0%)
    Ophthalmic Herpes Simplex1/237 (0.4%) 0/243 (0%)
    Peritonitis0/237 (0%) 1/243 (0.4%)
    Pneumocystis Jirovecii Pneumonia0/237 (0%) 1/243 (0.4%)
    Pneumonia22/237 (9.3%) 19/243 (7.8%)
    Pneumonia Cytomegaloviral0/237 (0%) 2/243 (0.8%)
    Pneumonia Pneumococcal0/237 (0%) 1/243 (0.4%)
    Pulmonary Sepsis0/237 (0%) 2/243 (0.8%)
    Pyelonephritis0/237 (0%) 1/243 (0.4%)
    Pyelonephritis Chronic1/237 (0.4%) 0/243 (0%)
    Respiratory Syncytial Virus Infection0/237 (0%) 1/243 (0.4%)
    Respiratory Tract Infection1/237 (0.4%) 0/243 (0%)
    Rhinovirus Infection0/237 (0%) 1/243 (0.4%)
    Sepsis2/237 (0.8%) 2/243 (0.8%)
    Septic Shock1/237 (0.4%) 0/243 (0%)
    Sinusitis0/237 (0%) 1/243 (0.4%)
    Tracheobronchitis1/237 (0.4%) 0/243 (0%)
    Upper Respiratory Tract Infection2/237 (0.8%) 4/243 (1.6%)
    Urinary Tract Infection1/237 (0.4%) 0/243 (0%)
    Injury, poisoning and procedural complications
    Contusion1/237 (0.4%) 0/243 (0%)
    Femur Fracture0/237 (0%) 2/243 (0.8%)
    Hip Fracture1/237 (0.4%) 1/243 (0.4%)
    Humerus Fracture0/237 (0%) 2/243 (0.8%)
    Rib Fracture1/237 (0.4%) 1/243 (0.4%)
    Spinal Fracture0/237 (0%) 1/243 (0.4%)
    Subdural Haematoma1/237 (0.4%) 0/243 (0%)
    Thoracic Vertebral Fracture1/237 (0.4%) 0/243 (0%)
    Upper Limb Fracture0/237 (0%) 1/243 (0.4%)
    Investigations
    Alanine Aminotransferase Increased0/237 (0%) 1/243 (0.4%)
    Electrocardiogram QT Interval Abnormal0/237 (0%) 1/243 (0.4%)
    Gamma-Glutamyltransferase Increased0/237 (0%) 1/243 (0.4%)
    Metabolism and nutrition disorders
    Dehydration2/237 (0.8%) 1/243 (0.4%)
    Hypercalcaemia0/237 (0%) 2/243 (0.8%)
    Hyperglycaemia2/237 (0.8%) 2/243 (0.8%)
    Hypoglycaemia1/237 (0.4%) 0/243 (0%)
    Hyponatraemia2/237 (0.8%) 0/243 (0%)
    Metabolic Acidosis1/237 (0.4%) 1/243 (0.4%)
    Tumour Lysis Syndrome0/237 (0%) 1/243 (0.4%)
    Musculoskeletal and connective tissue disorders
    Arthralgia0/237 (0%) 1/243 (0.4%)
    Back Pain2/237 (0.8%) 1/243 (0.4%)
    Bone Pain1/237 (0.4%) 2/243 (0.8%)
    Flank Pain0/237 (0%) 1/243 (0.4%)
    Musculoskeletal Chest Pain0/237 (0%) 1/243 (0.4%)
    Neck Pain1/237 (0.4%) 0/243 (0%)
    Osteonecrosis of Jaw1/237 (0.4%) 0/243 (0%)
    Pain in Extremity2/237 (0.8%) 0/243 (0%)
    Pathological Fracture0/237 (0%) 2/243 (0.8%)
    Spinal Pain1/237 (0.4%) 1/243 (0.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon0/237 (0%) 1/243 (0.4%)
    Breast Cancer0/237 (0%) 1/243 (0.4%)
    Breast Cancer Recurrent1/237 (0.4%) 0/243 (0%)
    Gastrointestinal Tract Adenoma0/237 (0%) 1/243 (0.4%)
    Liposarcoma0/237 (0%) 1/243 (0.4%)
    Plasmacytoma0/237 (0%) 1/243 (0.4%)
    Squamous Cell Carcinoma of Skin0/237 (0%) 1/243 (0.4%)
    Transitional Cell Carcinoma0/237 (0%) 1/243 (0.4%)
    Nervous system disorders
    Cerebral Infarction0/237 (0%) 1/243 (0.4%)
    Cerebrovascular Accident1/237 (0.4%) 0/243 (0%)
    Embolic Stroke0/237 (0%) 1/243 (0.4%)
    Headache0/237 (0%) 1/243 (0.4%)
    Ischaemic Stroke0/237 (0%) 2/243 (0.8%)
    Monoparesis1/237 (0.4%) 0/243 (0%)
    Radicular Syndrome0/237 (0%) 1/243 (0.4%)
    Restless Legs Syndrome1/237 (0.4%) 0/243 (0%)
    Syncope2/237 (0.8%) 1/243 (0.4%)
    Transient Ischaemic Attack0/237 (0%) 1/243 (0.4%)
    Vith Nerve Paralysis0/237 (0%) 1/243 (0.4%)
    Psychiatric disorders
    Confusional State0/237 (0%) 1/243 (0.4%)
    Depressed Mood0/237 (0%) 1/243 (0.4%)
    Depression1/237 (0.4%) 0/243 (0%)
    Renal and urinary disorders
    Acute Kidney Injury1/237 (0.4%) 3/243 (1.2%)
    Chronic Kidney Disease1/237 (0.4%) 1/243 (0.4%)
    Haematuria0/237 (0%) 1/243 (0.4%)
    Myeloma Cast Nephropathy1/237 (0.4%) 0/243 (0%)
    Renal Impairment0/237 (0%) 1/243 (0.4%)
    Urinary Retention1/237 (0.4%) 0/243 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma0/237 (0%) 1/243 (0.4%)
    Chronic Obstructive Pulmonary Disease1/237 (0.4%) 1/243 (0.4%)
    Epistaxis0/237 (0%) 2/243 (0.8%)
    Hydrothorax0/237 (0%) 1/243 (0.4%)
    Hyperventilation0/237 (0%) 1/243 (0.4%)
    Laryngeal Oedema0/237 (0%) 1/243 (0.4%)
    Organising Pneumonia0/237 (0%) 1/243 (0.4%)
    Oropharyngeal Swelling0/237 (0%) 1/243 (0.4%)
    Pleural Effusion0/237 (0%) 2/243 (0.8%)
    Pneumonia Aspiration0/237 (0%) 1/243 (0.4%)
    Pulmonary Alveolar Haemorrhage1/237 (0.4%) 0/243 (0%)
    Pulmonary Artery Thrombosis0/237 (0%) 1/243 (0.4%)
    Pulmonary Embolism2/237 (0.8%) 1/243 (0.4%)
    Pulmonary Haemorrhage0/237 (0%) 1/243 (0.4%)
    Pulmonary Oedema1/237 (0.4%) 0/243 (0%)
    Respiratory Failure2/237 (0.8%) 2/243 (0.8%)
    Vascular disorders
    Hypertension0/237 (0%) 1/243 (0.4%)
    Hypertensive Crisis0/237 (0%) 1/243 (0.4%)
    Orthostatic Hypotension2/237 (0.8%) 0/243 (0%)
    Peripheral Artery Aneurysm0/237 (0%) 1/243 (0.4%)
    Other (Not Including Serious) Adverse Events
    Bortezomib + Dexamethasone (Vd)Daratumumab + Bortezomib and Dexamethasone (DVd)
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total224/237 (94.5%) 238/243 (97.9%)
    Blood and lymphatic system disorders
    Anaemia74/237 (31.2%) 58/243 (23.9%)
    Leukopenia11/237 (4.6%) 19/243 (7.8%)
    Lymphopenia9/237 (3.8%) 32/243 (13.2%)
    Neutropenia22/237 (9.3%) 42/243 (17.3%)
    Thrombocytopenia104/237 (43.9%) 143/243 (58.8%)
    Gastrointestinal disorders
    Abdominal Pain Upper7/237 (3%) 13/243 (5.3%)
    Constipation36/237 (15.2%) 48/243 (19.8%)
    Diarrhoea53/237 (22.4%) 76/243 (31.3%)
    Dyspepsia13/237 (5.5%) 5/243 (2.1%)
    Nausea26/237 (11%) 34/243 (14%)
    Vomiting9/237 (3.8%) 26/243 (10.7%)
    General disorders
    Asthenia36/237 (15.2%) 21/243 (8.6%)
    Fatigue58/237 (24.5%) 52/243 (21.4%)
    Oedema9/237 (3.8%) 14/243 (5.8%)
    Oedema Peripheral19/237 (8%) 40/243 (16.5%)
    Pyrexia25/237 (10.5%) 35/243 (14.4%)
    Infections and infestations
    Bronchitis12/237 (5.1%) 26/243 (10.7%)
    Conjunctivitis7/237 (3%) 21/243 (8.6%)
    Herpes Zoster5/237 (2.1%) 13/243 (5.3%)
    Nasopharyngitis9/237 (3.8%) 17/243 (7%)
    Pneumonia7/237 (3%) 17/243 (7%)
    Upper Respiratory Tract Infection41/237 (17.3%) 57/243 (23.5%)
    Investigations
    Alanine Aminotransferase Increased10/237 (4.2%) 17/243 (7%)
    Weight Decreased3/237 (1.3%) 13/243 (5.3%)
    Metabolism and nutrition disorders
    Decreased Appetite12/237 (5.1%) 22/243 (9.1%)
    Hyperglycaemia17/237 (7.2%) 19/243 (7.8%)
    Hypokalaemia11/237 (4.6%) 22/243 (9.1%)
    Hypophosphataemia7/237 (3%) 13/243 (5.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia11/237 (4.6%) 22/243 (9.1%)
    Back Pain24/237 (10.1%) 32/243 (13.2%)
    Bone Pain13/237 (5.5%) 13/243 (5.3%)
    Muscle Spasms5/237 (2.1%) 19/243 (7.8%)
    Musculoskeletal Chest Pain5/237 (2.1%) 15/243 (6.2%)
    Pain in Extremity15/237 (6.3%) 22/243 (9.1%)
    Nervous system disorders
    Dizziness24/237 (10.1%) 24/243 (9.9%)
    Headache14/237 (5.9%) 24/243 (9.9%)
    Neuralgia26/237 (11%) 33/243 (13.6%)
    Paraesthesia14/237 (5.9%) 11/243 (4.5%)
    Peripheral Sensory Neuropathy89/237 (37.6%) 115/243 (47.3%)
    Psychiatric disorders
    Insomnia35/237 (14.8%) 41/243 (16.9%)
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm1/237 (0.4%) 23/243 (9.5%)
    Cough30/237 (12.7%) 58/243 (23.9%)
    Dyspnoea21/237 (8.9%) 45/243 (18.5%)
    Epistaxis12/237 (5.1%) 11/243 (4.5%)
    Skin and subcutaneous tissue disorders
    Rash7/237 (3%) 13/243 (5.3%)
    Vascular disorders
    Hypertension8/237 (3.4%) 21/243 (8.6%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.

    Results Point of Contact

    Name/TitleDirector, Clinical Research
    OrganizationJanssen R&D US
    Phone
    EmailClinicalTrialDisclosure@its.jnj.com
    Responsible Party:
    Janssen Research & Development, LLC
    ClinicalTrials.gov Identifier:
    NCT02136134
    Other Study ID Numbers:
    • CR103995
    • 2014-000255-85
    • 54767414MMY3004
    • NCT01620879
    First Posted:
    May 12, 2014
    Last Update Posted:
    Nov 5, 2021
    Last Verified:
    Nov 1, 2021