Clincosm LogoSign in Get a demo

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 Disease Intervention/Treatment Phase
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

Arm Intervention/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

    Site City State Country Postal Code
    1 Birmingham Alabama United States
    2 Los Angeles California United States
    3 Stamford Connecticut United States
    4 Jacksonville Florida United States
    5 Atlanta Georgia United States
    6 Niles Illinois United States
    7 Topeka Kansas United States
    8 Westwood Kansas United States
    9 Marrero Louisiana United States
    10 Boston Massachusetts United States
    11 Lansing Michigan United States
    12 New York New York United States
    13 Chapel Hill North Carolina United States
    14 Portland Oregon United States
    15 Philadelphia Pennsylvania United States
    16 Providence Rhode Island United States
    17 Seattle Washington United States
    18 Adelaide Australia
    19 Concord Australia
    20 Fitzroy Australia
    21 Hobart Australia
    22 Melbourne Australia
    23 Nedlands Australia
    24 Woodville South Australia
    25 Barretos Brazil
    26 Porto Alegre Brazil
    27 Salvador Brazil
    28 Sao Paulo Brazil
    29 São Paulo Brazil
    30 Brno Czechia
    31 Hradec Kralove Czechia
    32 Ostrava-Poruba Czechia
    33 Praha 10 Czechia
    34 Praha 2 Czechia
    35 Bamberg Germany
    36 Berlin Germany
    37 Duesseldorf Germany
    38 Freiburg Germany
    39 Göttingen Germany
    40 Hamburg Germany
    41 Mainz Germany
    42 München Germany
    43 Stuttgart Germany
    44 Tübingen Germany
    45 Ulm Germany
    46 Würzburg Germany
    47 Budapest Hungary
    48 Debrecen Hungary
    49 Győr Hungary
    50 Pécs N/a Hungary
    51 Veszprém Hungary
    52 Busan Korea, Republic of
    53 Hwasun Korea, Republic of
    54 Seoul Korea, Republic of
    55 Suwon Korea, Republic of
    56 Ulsan Korea, Republic of
    57 Huixquilucan Mexico
    58 Monterrey Mexico
    59 Alkmaar Netherlands
    60 Amersfoort Netherlands
    61 Den Haag Netherlands
    62 Dordrecht Netherlands
    63 Groningen Netherlands
    64 Leiden Netherlands
    65 Maastricht Netherlands
    66 Nijmegen Netherlands
    67 Chorzów Poland
    68 Katowice Poland
    69 Krakow Poland
    70 Poznan Poland
    71 Warszawa Poland
    72 Krasnodar Russian Federation
    73 Moscow Russian Federation
    74 Nizhny Novgorod Russian Federation
    75 Penza Russian Federation
    76 Pyatigorsk Russian Federation
    77 Ryazan Russian Federation
    78 Samara Russian Federation
    79 Sochi Russian Federation
    80 Syktyvkar Russian Federation
    81 Madrid Spain
    82 Salamanca Spain
    83 San Sebastian de los Reyes Spain
    84 Toledo Spain
    85 Valencia Spain
    86 Linkoping Sweden
    87 Lulea Sweden
    88 Lund Sweden
    89 Orebro Sweden
    90 Sundsvall Sweden
    91 Umea Sweden
    92 Uppsala Sweden
    93 Västerås Sweden
    94 Ankara Turkey
    95 Istanbul Turkey
    96 Izmir Turkey
    97 Kayseri Turkey
    98 Kocaeli Turkey
    99 Malatya Turkey
    100 Cherkasy Ukraine
    101 Dnepropetrovsk Ukraine
    102 Ivano-Frankivsk Ukraine
    103 Kiev Ukraine
    104 Lviv Ukraine
    105 Poltava Ukraine
    106 Vinnitsa Ukraine
    107 Zaporizhzhya Ukraine

    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:
    Jul 15, 2022
    Last Verified:
    Jul 1, 2022
    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
    Multiple Myeloma
    Plasmacytoma
    Refractory Multiple Myeloma
    Relapsed Multiple Myeloma
    Daratumumab
    VELCADE
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Dexamethasone
    Bortezomib
    Daratumumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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
    STARTED 247 251
    Treated 237 243
    COMPLETED 0 0
    NOT COMPLETED 247 251

    Baseline Characteristics

    Arm/Group Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd) Total
    Arm/Group Description Participants 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 Participants 247 251 498
    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
    Title Progression-free Survival (PFS)
    Description 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.
    Time Frame From 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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 247 251
    Median (95% Confidence Interval) [months]
    7.16
    NA
    2. Secondary Outcome
    Title Time to Disease Progression (TTP)
    Description 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.
    Time Frame 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)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population included all randomized participants.
    Arm/Group Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 247 251
    Median (95% Confidence Interval) [months]
    7.29
    NA
    3. Secondary Outcome
    Title Percentage of Participants With a Very Good Partial Response (VGPR) or Better
    Description 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.
    Time Frame Up 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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 234 240
    Number (95% Confidence Interval) [percentage of participants]
    29.1
    11.8%
    59.2
    23.6%
    4. Secondary Outcome
    Title Overall Response Rate (ORR)
    Description 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.
    Time Frame Up 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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 234 240
    Number (95% Confidence Interval) [percentage of participants]
    63.2
    25.6%
    82.9
    33%
    5. Secondary Outcome
    Title Percentage of Participants With Negative Minimal Residual Disease (MRD)
    Description 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.
    Time Frame Up 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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 247 251
    Number [percentage of participants]
    2.8
    1.1%
    13.5
    5.4%
    6. Secondary Outcome
    Title Overall Survival (OS)
    Description Overall Survival was measured from the date of randomization to the date of the participant's death.
    Time Frame Up 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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 Participants 247 251
    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 Title Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Arm/Group Description Participants 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 (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 80/237 (33.8%) 102/243 (42%)
    Blood and lymphatic system disorders
    Anaemia 1/237 (0.4%) 8/243 (3.3%)
    Febrile Neutropenia 0/237 (0%) 2/243 (0.8%)
    Neutropenia 0/237 (0%) 2/243 (0.8%)
    Thrombocytopenia 1/237 (0.4%) 6/243 (2.5%)
    Cardiac disorders
    Acute Coronary Syndrome 0/237 (0%) 1/243 (0.4%)
    Acute Myocardial Infarction 0/237 (0%) 1/243 (0.4%)
    Arrhythmia Supraventricular 0/237 (0%) 1/243 (0.4%)
    Atrial Fibrillation 0/237 (0%) 5/243 (2.1%)
    Cardiac Arrest 1/237 (0.4%) 1/243 (0.4%)
    Cardiac Failure 0/237 (0%) 1/243 (0.4%)
    Cardiac Failure Congestive 1/237 (0.4%) 2/243 (0.8%)
    Cardiogenic Shock 1/237 (0.4%) 1/243 (0.4%)
    Myocardial Infarction 2/237 (0.8%) 0/243 (0%)
    Ventricular Extrasystoles 1/237 (0.4%) 0/243 (0%)
    Endocrine disorders
    Adrenal Insufficiency 1/237 (0.4%) 0/243 (0%)
    Hyperthyroidism 0/237 (0%) 1/243 (0.4%)
    Eye disorders
    Diplopia 0/237 (0%) 1/243 (0.4%)
    Gastrointestinal disorders
    Abdominal Pain 3/237 (1.3%) 0/243 (0%)
    Abdominal Pain Upper 0/237 (0%) 1/243 (0.4%)
    Constipation 3/237 (1.3%) 0/243 (0%)
    Diarrhoea 0/237 (0%) 4/243 (1.6%)
    Diverticular Perforation 0/237 (0%) 1/243 (0.4%)
    Duodenal Ulcer 0/237 (0%) 1/243 (0.4%)
    Faecaloma 1/237 (0.4%) 0/243 (0%)
    Gastritis 0/237 (0%) 1/243 (0.4%)
    Incarcerated Umbilical Hernia 1/237 (0.4%) 0/243 (0%)
    Intestinal Obstruction 0/237 (0%) 1/243 (0.4%)
    Melaena 0/237 (0%) 1/243 (0.4%)
    Pancreatitis Acute 0/237 (0%) 1/243 (0.4%)
    Pancreatitis Chronic 0/237 (0%) 1/243 (0.4%)
    Small Intestinal Obstruction 0/237 (0%) 1/243 (0.4%)
    General disorders
    Asthenia 3/237 (1.3%) 0/243 (0%)
    Condition Aggravated 3/237 (1.3%) 0/243 (0%)
    Fatigue 0/237 (0%) 2/243 (0.8%)
    General Physical Health Deterioration 3/237 (1.3%) 1/243 (0.4%)
    Influenza Like Illness 1/237 (0.4%) 0/243 (0%)
    Oedema Peripheral 0/237 (0%) 1/243 (0.4%)
    Pain 0/237 (0%) 1/243 (0.4%)
    Pyrexia 4/237 (1.7%) 4/243 (1.6%)
    Infections and infestations
    Bacterial Infection 1/237 (0.4%) 0/243 (0%)
    Brain Abscess 1/237 (0.4%) 0/243 (0%)
    Bronchitis 1/237 (0.4%) 5/243 (2.1%)
    Bronchopneumonia 1/237 (0.4%) 3/243 (1.2%)
    Cellulitis 0/237 (0%) 1/243 (0.4%)
    Epididymitis 1/237 (0.4%) 0/243 (0%)
    Fungal Oesophagitis 0/237 (0%) 1/243 (0.4%)
    Gangrene 1/237 (0.4%) 0/243 (0%)
    Gastroenteritis 3/237 (1.3%) 2/243 (0.8%)
    Herpes Zoster 2/237 (0.8%) 1/243 (0.4%)
    Influenza 2/237 (0.8%) 0/243 (0%)
    Lobar Pneumonia 1/237 (0.4%) 0/243 (0%)
    Lower Respiratory Tract Infection 2/237 (0.8%) 2/243 (0.8%)
    Lung Infection 1/237 (0.4%) 1/243 (0.4%)
    Metapneumovirus Infection 0/237 (0%) 1/243 (0.4%)
    Nocardiosis 1/237 (0.4%) 0/243 (0%)
    Ophthalmic Herpes Simplex 1/237 (0.4%) 0/243 (0%)
    Peritonitis 0/237 (0%) 1/243 (0.4%)
    Pneumocystis Jirovecii Pneumonia 0/237 (0%) 1/243 (0.4%)
    Pneumonia 22/237 (9.3%) 19/243 (7.8%)
    Pneumonia Cytomegaloviral 0/237 (0%) 2/243 (0.8%)
    Pneumonia Pneumococcal 0/237 (0%) 1/243 (0.4%)
    Pulmonary Sepsis 0/237 (0%) 2/243 (0.8%)
    Pyelonephritis 0/237 (0%) 1/243 (0.4%)
    Pyelonephritis Chronic 1/237 (0.4%) 0/243 (0%)
    Respiratory Syncytial Virus Infection 0/237 (0%) 1/243 (0.4%)
    Respiratory Tract Infection 1/237 (0.4%) 0/243 (0%)
    Rhinovirus Infection 0/237 (0%) 1/243 (0.4%)
    Sepsis 2/237 (0.8%) 2/243 (0.8%)
    Septic Shock 1/237 (0.4%) 0/243 (0%)
    Sinusitis 0/237 (0%) 1/243 (0.4%)
    Tracheobronchitis 1/237 (0.4%) 0/243 (0%)
    Upper Respiratory Tract Infection 2/237 (0.8%) 4/243 (1.6%)
    Urinary Tract Infection 1/237 (0.4%) 0/243 (0%)
    Injury, poisoning and procedural complications
    Contusion 1/237 (0.4%) 0/243 (0%)
    Femur Fracture 0/237 (0%) 2/243 (0.8%)
    Hip Fracture 1/237 (0.4%) 1/243 (0.4%)
    Humerus Fracture 0/237 (0%) 2/243 (0.8%)
    Rib Fracture 1/237 (0.4%) 1/243 (0.4%)
    Spinal Fracture 0/237 (0%) 1/243 (0.4%)
    Subdural Haematoma 1/237 (0.4%) 0/243 (0%)
    Thoracic Vertebral Fracture 1/237 (0.4%) 0/243 (0%)
    Upper Limb Fracture 0/237 (0%) 1/243 (0.4%)
    Investigations
    Alanine Aminotransferase Increased 0/237 (0%) 1/243 (0.4%)
    Electrocardiogram QT Interval Abnormal 0/237 (0%) 1/243 (0.4%)
    Gamma-Glutamyltransferase Increased 0/237 (0%) 1/243 (0.4%)
    Metabolism and nutrition disorders
    Dehydration 2/237 (0.8%) 1/243 (0.4%)
    Hypercalcaemia 0/237 (0%) 2/243 (0.8%)
    Hyperglycaemia 2/237 (0.8%) 2/243 (0.8%)
    Hypoglycaemia 1/237 (0.4%) 0/243 (0%)
    Hyponatraemia 2/237 (0.8%) 0/243 (0%)
    Metabolic Acidosis 1/237 (0.4%) 1/243 (0.4%)
    Tumour Lysis Syndrome 0/237 (0%) 1/243 (0.4%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/237 (0%) 1/243 (0.4%)
    Back Pain 2/237 (0.8%) 1/243 (0.4%)
    Bone Pain 1/237 (0.4%) 2/243 (0.8%)
    Flank Pain 0/237 (0%) 1/243 (0.4%)
    Musculoskeletal Chest Pain 0/237 (0%) 1/243 (0.4%)
    Neck Pain 1/237 (0.4%) 0/243 (0%)
    Osteonecrosis of Jaw 1/237 (0.4%) 0/243 (0%)
    Pain in Extremity 2/237 (0.8%) 0/243 (0%)
    Pathological Fracture 0/237 (0%) 2/243 (0.8%)
    Spinal Pain 1/237 (0.4%) 1/243 (0.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of Colon 0/237 (0%) 1/243 (0.4%)
    Breast Cancer 0/237 (0%) 1/243 (0.4%)
    Breast Cancer Recurrent 1/237 (0.4%) 0/243 (0%)
    Gastrointestinal Tract Adenoma 0/237 (0%) 1/243 (0.4%)
    Liposarcoma 0/237 (0%) 1/243 (0.4%)
    Plasmacytoma 0/237 (0%) 1/243 (0.4%)
    Squamous Cell Carcinoma of Skin 0/237 (0%) 1/243 (0.4%)
    Transitional Cell Carcinoma 0/237 (0%) 1/243 (0.4%)
    Nervous system disorders
    Cerebral Infarction 0/237 (0%) 1/243 (0.4%)
    Cerebrovascular Accident 1/237 (0.4%) 0/243 (0%)
    Embolic Stroke 0/237 (0%) 1/243 (0.4%)
    Headache 0/237 (0%) 1/243 (0.4%)
    Ischaemic Stroke 0/237 (0%) 2/243 (0.8%)
    Monoparesis 1/237 (0.4%) 0/243 (0%)
    Radicular Syndrome 0/237 (0%) 1/243 (0.4%)
    Restless Legs Syndrome 1/237 (0.4%) 0/243 (0%)
    Syncope 2/237 (0.8%) 1/243 (0.4%)
    Transient Ischaemic Attack 0/237 (0%) 1/243 (0.4%)
    Vith Nerve Paralysis 0/237 (0%) 1/243 (0.4%)
    Psychiatric disorders
    Confusional State 0/237 (0%) 1/243 (0.4%)
    Depressed Mood 0/237 (0%) 1/243 (0.4%)
    Depression 1/237 (0.4%) 0/243 (0%)
    Renal and urinary disorders
    Acute Kidney Injury 1/237 (0.4%) 3/243 (1.2%)
    Chronic Kidney Disease 1/237 (0.4%) 1/243 (0.4%)
    Haematuria 0/237 (0%) 1/243 (0.4%)
    Myeloma Cast Nephropathy 1/237 (0.4%) 0/243 (0%)
    Renal Impairment 0/237 (0%) 1/243 (0.4%)
    Urinary Retention 1/237 (0.4%) 0/243 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/237 (0%) 1/243 (0.4%)
    Chronic Obstructive Pulmonary Disease 1/237 (0.4%) 1/243 (0.4%)
    Epistaxis 0/237 (0%) 2/243 (0.8%)
    Hydrothorax 0/237 (0%) 1/243 (0.4%)
    Hyperventilation 0/237 (0%) 1/243 (0.4%)
    Laryngeal Oedema 0/237 (0%) 1/243 (0.4%)
    Organising Pneumonia 0/237 (0%) 1/243 (0.4%)
    Oropharyngeal Swelling 0/237 (0%) 1/243 (0.4%)
    Pleural Effusion 0/237 (0%) 2/243 (0.8%)
    Pneumonia Aspiration 0/237 (0%) 1/243 (0.4%)
    Pulmonary Alveolar Haemorrhage 1/237 (0.4%) 0/243 (0%)
    Pulmonary Artery Thrombosis 0/237 (0%) 1/243 (0.4%)
    Pulmonary Embolism 2/237 (0.8%) 1/243 (0.4%)
    Pulmonary Haemorrhage 0/237 (0%) 1/243 (0.4%)
    Pulmonary Oedema 1/237 (0.4%) 0/243 (0%)
    Respiratory Failure 2/237 (0.8%) 2/243 (0.8%)
    Vascular disorders
    Hypertension 0/237 (0%) 1/243 (0.4%)
    Hypertensive Crisis 0/237 (0%) 1/243 (0.4%)
    Orthostatic Hypotension 2/237 (0.8%) 0/243 (0%)
    Peripheral Artery Aneurysm 0/237 (0%) 1/243 (0.4%)
    Other (Not Including Serious) Adverse Events
    Bortezomib + Dexamethasone (Vd) Daratumumab + Bortezomib and Dexamethasone (DVd)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 224/237 (94.5%) 238/243 (97.9%)
    Blood and lymphatic system disorders
    Anaemia 74/237 (31.2%) 58/243 (23.9%)
    Leukopenia 11/237 (4.6%) 19/243 (7.8%)
    Lymphopenia 9/237 (3.8%) 32/243 (13.2%)
    Neutropenia 22/237 (9.3%) 42/243 (17.3%)
    Thrombocytopenia 104/237 (43.9%) 143/243 (58.8%)
    Gastrointestinal disorders
    Abdominal Pain Upper 7/237 (3%) 13/243 (5.3%)
    Constipation 36/237 (15.2%) 48/243 (19.8%)
    Diarrhoea 53/237 (22.4%) 76/243 (31.3%)
    Dyspepsia 13/237 (5.5%) 5/243 (2.1%)
    Nausea 26/237 (11%) 34/243 (14%)
    Vomiting 9/237 (3.8%) 26/243 (10.7%)
    General disorders
    Asthenia 36/237 (15.2%) 21/243 (8.6%)
    Fatigue 58/237 (24.5%) 52/243 (21.4%)
    Oedema 9/237 (3.8%) 14/243 (5.8%)
    Oedema Peripheral 19/237 (8%) 40/243 (16.5%)
    Pyrexia 25/237 (10.5%) 35/243 (14.4%)
    Infections and infestations
    Bronchitis 12/237 (5.1%) 26/243 (10.7%)
    Conjunctivitis 7/237 (3%) 21/243 (8.6%)
    Herpes Zoster 5/237 (2.1%) 13/243 (5.3%)
    Nasopharyngitis 9/237 (3.8%) 17/243 (7%)
    Pneumonia 7/237 (3%) 17/243 (7%)
    Upper Respiratory Tract Infection 41/237 (17.3%) 57/243 (23.5%)
    Investigations
    Alanine Aminotransferase Increased 10/237 (4.2%) 17/243 (7%)
    Weight Decreased 3/237 (1.3%) 13/243 (5.3%)
    Metabolism and nutrition disorders
    Decreased Appetite 12/237 (5.1%) 22/243 (9.1%)
    Hyperglycaemia 17/237 (7.2%) 19/243 (7.8%)
    Hypokalaemia 11/237 (4.6%) 22/243 (9.1%)
    Hypophosphataemia 7/237 (3%) 13/243 (5.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 11/237 (4.6%) 22/243 (9.1%)
    Back Pain 24/237 (10.1%) 32/243 (13.2%)
    Bone Pain 13/237 (5.5%) 13/243 (5.3%)
    Muscle Spasms 5/237 (2.1%) 19/243 (7.8%)
    Musculoskeletal Chest Pain 5/237 (2.1%) 15/243 (6.2%)
    Pain in Extremity 15/237 (6.3%) 22/243 (9.1%)
    Nervous system disorders
    Dizziness 24/237 (10.1%) 24/243 (9.9%)
    Headache 14/237 (5.9%) 24/243 (9.9%)
    Neuralgia 26/237 (11%) 33/243 (13.6%)
    Paraesthesia 14/237 (5.9%) 11/243 (4.5%)
    Peripheral Sensory Neuropathy 89/237 (37.6%) 115/243 (47.3%)
    Psychiatric disorders
    Insomnia 35/237 (14.8%) 41/243 (16.9%)
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm 1/237 (0.4%) 23/243 (9.5%)
    Cough 30/237 (12.7%) 58/243 (23.9%)
    Dyspnoea 21/237 (8.9%) 45/243 (18.5%)
    Epistaxis 12/237 (5.1%) 11/243 (4.5%)
    Skin and subcutaneous tissue disorders
    Rash 7/237 (3%) 13/243 (5.3%)
    Vascular disorders
    Hypertension 8/237 (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/Title Director, Clinical Research
    Organization Janssen R&D US
    Phone
    Email ClinicalTrialDisclosure@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:
    Jul 15, 2022
    Last Verified:
    Jul 1, 2022