Clinical trial NCT02195479
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Bortezomib Velcade Melphalan Prednisone Daratumumab
Sponsor: Janssen Research & Development, LLC
Start date: 2014-12-09; Completion date: 2024-08-07
Enrollment: 706 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the addition of daratumumab to velcade (bortezomib) melphalan-prednisone (VMP) will prolong progression-free survival (PFS) compared with VMP alone in participants with previously untreated multiple myeloma who are ineligible for high dose chemotherapy and autologous stem cell transplant (ASCT).

Detailed description:
The study consists of 3 phases: Screening Phase (within 21 days prior to randomization), Treatment Phase (Cycle 1 Day 1 to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, withdrawal of consent, or the study ends, whichever occurs first). Treatment phase will include 2 treatments (Treatment A: participants will receive Velcade MelphalanPrednisone (VMP) alone and Treatment B: participants will receive daratumumab in combination with VMP).Two interim analyses are planned. The first will be to evaluate safety after a total of approximately 100 participants have been treated for at least 2 cycles or discontinued the study treatment. The second will be to evaluate cumulative interim safety and efficacy data, and will be performed when approximately 216 PFS events have been accumulated. The final OS analysis will occur when approximately 382 deaths have occurred. Efficacy will be primarily measured by comparison of PFS between the two treatment arms. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants will receive velcade (bortezomib) 1.3 milligram per square meter (mg/m\^2) as subcutaneous injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at Weeks 1, 2, 4 and 5 in Cycles 2 to 9, melphalan 9 mg/m\^2 , orally, once daily (on Days 1-4) and prednisone 60 mg/m\^2, orally, once daily, on Days 1 to 4 of each cycle up to Cycle 9. arm 2: Participants will receive velcade 1.3 mg/m\^2 as SC injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at Weeks 1, 2, 4 and 5 in Cycles 2 to 9, melphalan 9 mg/m\^2, orally, once daily (on Days 1-4) and prednisone 60 mg/m\^2, orally, once daily, on Days 1 to 4 of each cycle up to Cycle 9. In addition participants will also receive daratumumab 16 mg/kg as IV infusion, once weekly, for 6 weeks in Cycle 1 and then every 3 weeks, in Cycle 2 to 9 and thereafter, once every 4 weeks until documented progression, unacceptable toxicity, or until the end of study. On days when daratumumab is given, dexamethasone 20 mg IV or PO is given 1 hour or less prior to daratumumab administration as pre medication and prednisone substitute, and prednisone 60 mg/m2 once daily will be given on Days 2-4. Following amendment 7, participants will have the option to switch to daratumumab subcutaneous (SC) on Day 1 of any cycle, at the discretion of the investigator.
Interventions: intervention 1: Velcade intervention 2: Melphalan intervention 3: Prednisone intervention 4: Daratumumab IV intervention 5: Dexamethasone intervention 6: Daratumumab SC
Intervention descriptions: intervention 1: Participants will receive velcade 1.3 mg/m\^2, as subcutaneous injection, twice weekly at Weeks 1, 2, 4 and 5 in Cycle 1 followed by once weekly at Weeks 1, 2, 4 and 5 in Cycles 2 to 9. intervention 2: Participants will receive melphalan 9 mg/m\^2, orally, once daily on Days 1 to 4 of each cycle up to Cycle 9. intervention 3: Participants will receive prednisone 60 mg/m\^2, orally, once daily, on Days 1 to 4 of each cycle up to Cycle 9. intervention 4: Participants will receive daratumumab 16 mg/kg as intravenous infusion, once weekly, for 6 weeks in Cycle 1 and then once every 3 weeks, in Cycle 2 to 9 and thereafter, once every 4 weeks until documented progression, unacceptable toxicity, or until the end of study . intervention 5: Participants administered with dexamethasone 20 mg IV or PO is given 1 hour or less prior to daratumumab administration as pre medication and prednisone substitute. intervention 6: Daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg once every 4 weeks until documented progression, unacceptable toxicity, or until the end of study. Following amendment 7, participants can switch from daratumumab IV to daratumumab SC.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved,  Date: 14 February 2018
Janssen Research & Development*
Clinical Protocol
A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomib) 
Melphalan-Prednisone (VMP) Compared to Daratumumab in Combination with VMP 
(D-VMP), in Subjects with Previously Untreated Multiple Myeloma who are Ineligible for 
High-dose Therapy
Protocol 54767414MMY3007; Phase 3
Amendment 5
JNJ-54767414  Daratumumab
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
EudraCT NUMBER: 2014-002272-88
Status:
Approved
Date:
14 February 2018
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-83878417, 10.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 28
TIME AND EVENTS SCHEDULE .............................................................................................................. 34
TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 1 (VMP TREATMENT 
PHASE)....................................................................................................................................................... 37
TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 2 TO 9 (VMP 
TREATMENT PHASE) ............................................................................................................................... 38
TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 10+ (DARA 
TREATMENT PHASE, ARM B ONLY) ...................................................................................................... 40
ABBREVIATIONS ...................................................................................................................................... 41
1.
INTRODUCTION................................................................................................................................ 43
1.1.
Background .................................................................................................................................... 43
1.1.1.
Multiple Myeloma........................................................................................................................ 43
1.1.2.
Treatment Options for Multiple Myeloma.................................................................................... 43
1.1.3.
Transplant-ineligible Population ................................................................................................. 44
1.1.4.
Treatment Until Progression in Transplant-ineligible Patients.................................................... 44
1.2.
Daratumumab ................................................................................................................................ 45
1.2.1.
Nonclinical Studies ..................................................................................................................... 45
1.2.2.
Clinical Studies ........................................................................................................................... 47
1.2.2.1.
Single-Agent Daratumumab Studies (GEN501 and MMY2002) ............................................. 47
1.2.2.2.
Combination Daratumumab Studies ....................................................................................... 48
1.3.
Overall Rationale for the Study...................................................................................................... 50
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 51
2.1.
Objectives ...................................................................................................................................... 51
2.2.
Hypothesis ..................................................................................................................................... 51
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 52
3.1.
Overview of Study Design.............................................................................................................. 52
3.2.
Study Design Rationale.................................................................................................................. 54
4.
SUBJECT POPULATION.................................................................................................................. 58
4.1.
Inclusion Criteria ............................................................................................................................ 58
4.2.
Exclusion Criteria ........................................................................................................................... 60
4.3.
Prohibitions and Restrictions ......................................................................................................... 63
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 63
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 64
6.1.
Daratumumab (Arm B Only) .......................................................................................................... 65
6.1.1.
Daratumumab Preparation ......................................................................................................... 65
6.1.2.
Daratumumab Administration ..................................................................................................... 65
6.1.3.
Guidelines for Prevention of Infusion Reactions ........................................................................ 66
6.1.3.1.
Pre-infusion Medication........................................................................................................... 66
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6.1.3.2.
Post-Infusion Medication ......................................................................................................... 66
6.1.4.
Management of Infusion-related Reactions................................................................................ 67
6.1.4.1.
Infusion-Related Events of Grade 1 or Grade 2...................................................................... 67
6.1.4.2.
Infusion-Related Reactions of Grade 3 or Higher ................................................................... 68
6.2.
VELCADE, Melphalan, and Prednisone (Arm A and Arm B)......................................................... 68
6.2.1.
Dose Calculation of VELCADE, Melphalan, and Prednisone..................................................... 68
6.2.2.
VELCADE Administration ........................................................................................................... 68
6.2.3.
Melphalan and Prednisone Administration................................................................................. 69
6.3.
Dose Delays and Dose Modification.............................................................................................. 69
6.3.1.
Daratumumab Dose Modification ............................................................................................... 69
6.3.1.1.
Daratumumab-Related Toxicity Management......................................................................... 70
6.3.1.2.
Daratumumab Interruption or Missed Doses........................................................................... 71
6.3.2.
Dose Reductions (VELCADE, Melphalan, and Prednisone)...................................................... 71
6.3.3.
Dose Modification Guidelines for VELCADE, Melphalan, and Prednisone Related 
Toxicities..................................................................................................................................... 71
7.
TREATMENT COMPLIANCE............................................................................................................ 77
8.
CONCOMITANT THERAPY.............................................................................................................. 77
8.1.
Recommended Therapies.............................................................................................................. 77
8.1.1.
Bisphosphonate Therapy............................................................................................................ 77
8.1.2.
Therapy for Tumor Lysis Syndrome ........................................................................................... 77
8.1.3.
Prophylaxis for Pneumocystis carinii.......................................................................................... 78
8.1.4.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 78
8.1.5.
Prevention of Hemorrhagic Cystitis ............................................................................................ 78
8.2.
Permitted Therapies....................................................................................................................... 78
8.3.
Prohibited Therapies...................................................................................................................... 78
8.4.
Subsequent Therapies................................................................................................................... 79
9.
STUDY EVALUATIONS .................................................................................................................... 80
9.1.
Study Procedures........................................................................................................................... 80
9.1.1.
Overview..................................................................................................................................... 80
9.1.2.
Screening Phase ........................................................................................................................ 80
9.1.3.
Treatment Phase ........................................................................................................................ 81
9.1.4.
Follow-up Phase......................................................................................................................... 82
9.1.5.
Assessments Following the Positive Second Interim Analysis of PFS ...................................... 82
9.1.6.
Assessments Following the OS Interim Analysis ....................................................................... 83
9.2.
Efficacy........................................................................................................................................... 83
9.2.1.
Evaluations ................................................................................................................................. 83
9.2.1.1.
Response Categories .............................................................................................................. 83
9.2.1.2.
Myeloma Protein Measurements in Serum and Urine ............................................................ 86
9.2.1.3.
Serum Calcium Corrected for Albumin.................................................................................... 87
9.2.1.4.
β2-microglobulin and Albumin................................................................................................. 87
9.2.1.5.
Bone Marrow Examination ...................................................................................................... 87
9.2.1.6.
Minimal Residual Disease Assessment .................................................................................. 89
9.2.1.7.
Assessment of Lytic Disease................................................................................................... 89
9.2.1.8.
Documentation of Extramedullary Plasmacytomas................................................................. 89
9.2.2.
Endpoints.................................................................................................................................... 90
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 92
9.3.1.
Evaluations ................................................................................................................................. 92
9.3.2.
Analytical Procedures................................................................................................................. 92
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 92
9.3.4.
Immunogenicity Assessments (Antibodies to daratumumab) .................................................... 93
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 93
9.5.
Biomarkers ..................................................................................................................................... 93
9.6.
Patient-reported Outcomes............................................................................................................ 94
9.7.
Medical Resource Utilization.......................................................................................................... 95
9.8.
Safety Evaluations ......................................................................................................................... 95
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9.9.
Sample Collection and Handling.................................................................................................... 98
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 98
10.1.
Completion ..................................................................................................................................... 98
10.2.
Discontinuation of Study Treatment............................................................................................... 99
10.3.
Withdrawal From the Study.......................................................................................................... 100
11.
STATISTICAL METHODS............................................................................................................... 100
11.1.
Subject Information ...................................................................................................................... 100
11.2.
Sample Size Determination ......................................................................................................... 101
11.3.
Efficacy Analyses ......................................................................................................................... 101
11.4.
Pharmacokinetic Analyses........................................................................................................... 102
11.5.
Immunogenicity Analyses ............................................................................................................ 102
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 102
11.7.
Biomarker Analyses ..................................................................................................................... 102
11.8.
Patient-reported Outcomes.......................................................................................................... 103
11.9.
Safety Analyses ........................................................................................................................... 103
11.10.
Interim Analysis............................................................................................................................ 104
11.11.
Data Monitoring Committee ......................................................................................................... 105
12.
ADVERSE EVENT REPORTING .................................................................................................... 105
12.1.
Definitions .................................................................................................................................... 105
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 105
12.1.2.
Attribution Definitions................................................................................................................ 106
12.1.3.
Severity Criteria ........................................................................................................................ 107
12.2.
Special Reporting Situations........................................................................................................ 107
12.3.
Procedures................................................................................................................................... 108
12.3.1.
All Adverse Events.................................................................................................................... 108
12.3.2.
Serious Adverse Events ........................................................................................................... 109
12.3.3.
Pregnancy................................................................................................................................. 110
12.4.
Reporting, Monitoring, and Review of Safety Events in Japanese Subjects in Arm B 
(Japanese Sites Only).................................................................................................................. 110
12.5.
Contacting Sponsor Regarding Safety......................................................................................... 111
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 111
13.1.
Procedures................................................................................................................................... 111
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 111
14.
STUDY DRUG INFORMATION....................................................................................................... 111
14.1.
Physical Description of Study Drug.............................................................................................. 111
14.2.
Packaging .................................................................................................................................... 111
14.3.
Labeling........................................................................................................................................ 112
14.4.
Preparation, Handling, and Storage............................................................................................. 112
14.5.
Drug Accountability ...................................................................................................................... 112
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 112
16.
ETHICAL ASPECTS ....................................................................................................................... 113
16.1.
Study-Specific Design Considerations......................................................................................... 113
16.2.
Regulatory Ethics Compliance..................................................................................................... 114
16.2.1.
Investigator Responsibilities ..................................................................................................... 114
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 114
16.2.3.
Informed Consent ..................................................................................................................... 115
16.2.4.
Privacy of Personal Data .......................................................................................................... 116
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 117
16.2.6.
Country Selection ..................................................................................................................... 117
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 117
17.1.
Protocol Amendments.................................................................................................................. 117
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17.2.
Regulatory Documentation .......................................................................................................... 118
17.2.1.
Regulatory Approval/Notification .............................................................................................. 118
17.2.2.
Required Pre-Study Documentation......................................................................................... 118
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 119
17.4.
Source Documentation................................................................................................................. 119
17.5.
Case Report Form Completion .................................................................................................... 120
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 121
17.7.
Record Retention ......................................................................................................................... 121
17.8.
Monitoring .................................................................................................................................... 122
17.9.
Study Completion/Termination..................................................................................................... 122
17.9.1.
Study Completion ..................................................................................................................... 122
17.9.2.
Study Termination..................................................................................................................... 122
17.10.
On-Site Audits .............................................................................................................................. 123
17.11.
Use of Information and Publication.............................................................................................. 123
REFERENCES.......................................................................................................................................... 125
INVESTIGATOR AGREEMENT ............................................................................................................... 141
LIST OF ATTACHMENTS
Attachment 1:
Modified IMWG Diagnostic Criteria for Multiple Myeloma........................................ 128
Attachment 2:
ECOG Performance Status Scale ............................................................................ 129
Attachment 3:
Serum Calcium Corrected for Albumin..................................................................... 130
Attachment 4:
Guideline for Asthma Eligibility Criteria .................................................................... 131
Attachment 5:
Antihistamine Medications........................................................................................ 135
Attachment 6:
Conversion Table for Glucocorticosteroid Dose....................................................... 136
Attachment 7:
Body Surface Area Nomogram ................................................................................ 137
Attachment 8:
Reporting, Monitoring, and Evaluating Safety Events in Japanese Subjects in 
Arm B (Japanese Sites Only) ................................................................................... 138
Attachment 9:
International Staging System (ISS) Staging............................................................. 139
Attachment 10:
Anticipated Adverse Events...................................................................................... 140
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Daratumumab Single-Agent Studies GEN501 and MMY2002................................................. 48
Table 2:
Daratumumab Combination Studies GEN503 and MMY1001 ................................................. 49
Table 3:
Complete responses, progression-free survival and peripheral neuropathy in all 
patients and in those who received weekly infusion of VELCADE........................................... 55
Table 4:
Daratumumab-Related Toxicity Management .......................................................................... 70
Table 5:
Dose Reduction for VELCADE ................................................................................................. 71
Table 6:
Dose Reduction for Melphalan ................................................................................................. 71
Table 7:
Dose Reduction for Prednisone................................................................................................ 71
Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone .............................. 72
Table 9:
International Uniform Response Criteria Consensus Recommendations ................................ 85
Table 10:
Bone Marrow Testing................................................................................................................ 88
FIGURES
Figure 1:
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents ........................................................................................................ 46
Figure 2:
Dose-dependent Lysis of Multiple Myeloma cells in Triple Chemotherapy Treatments........... 47
Figure 3:
Schematic Overview of the Study............................................................................................. 52
Figure 4:
Daratumumab Maximal Target Suppression ............................................................................ 57
Figure 5:
Study Treatment Administration ............................................................................................... 65
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
26 June 2014
Amendment 1
24 November 2014
Amendment 2
05 November 2015
Amendment 3
26 July 2016
Amendment 4
11 November 2016
Amendment 5
14 February 2018
Amendments are listed beginning with the most recent amendment.
Amendment 5 (14 February 2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Based on the Independent Data Monitoring Committee (IDMC)
recommendation following review of data from the second interim analysis, the study is being amended to allow 
subjects in Arm A (VELCADE [bortezomib]-melphalan-prednisone [VMP] alone) access to daratumumab after
sponsor confirmation of disease progression (PD) per International Myeloma Working Group criteria.
Applicable Section(s)
Description of Change(s)
Rationale: Subjects randomized to Arm A (VMP) who have sponsor-confirmed disease progression may have 
the option to receive daratumumab provided by the sponsor (in any subsequent line of therapy) if recommended 
by the investigator. Eligibility for and administration of daratumumab must be in accordance with local 
prescribing information and local regulations. 
8.4. Subsequent 
Therapies
A new section has been added.
Rationale: To update statistical text following positive findings for the second interim analysis.
Synopsis, Overview 
of Study Design;
Synopsis, Statistical 
Methods;
3.1. Overview of 
Study Design;
9.2.2. Endpoints
Details of IDMC reviews have been removed from the Synopsis, Overview of Study 
Design.
Details of IDMC reviews, the 2 planned interim analyses, and the primary 
progression-free survival (PFS) analysis have been incorporated within the Synopsis, 
Statistical Methods.
It is explained that the interim PFS analysis will function as the primary analysis of this 
endpoint, as the superiority of daratumumab plus VMP (D-VMP) over VMP alone is 
established at the second interim analysis.
Synopsis, Overview 
of Study Design;
Synopsis, Statistical 
Methods;
Time and Events 
Schedule;
3.1. Overview of 
Study Design
Removed text which referred to reduced data collection as described in Section 9.1.4. 
Where appropriate, added references to subject monitoring as described in the new 
Sections 9.1.5 (following positive second interim analysis of PFS) and 9.1.6 (following 
overall survival [OS] interim analysis).
Synopsis, Overview 
of Study Design;
3.1. Overview of 
Study Design
Added a statement that as the superiority of daratumumab combined with VMP over 
VMP alone with respect to PFS was established at the second interim analysis, the 
interim PFS analysis will serve as the primary PFS analysis.
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Applicable Section(s)
Description of Change(s)
Synopsis, Overview 
of Study Design;
3.1. Overview of 
Study Design; 
11.10. Interim 
Analysis
Described that an interim analysis of OS is now planned to be conducted when 
200 deaths (60% of all planned events) have been accumulated, with the final analysis of 
OS to be conducted when 330 deaths are accumulated.
Time and Events 
Schedule;
9.2.2. Endpoints
Removed text which referred to disease evaluations not being required after the clinical 
cutoff date.
9.1.4. Follow-up 
Phase
Removed the following text:
A clinical cut-off will be established after the primary PFS analysis (360 PFS 
events). Following the clinical cut-off date, disease assessments will no longer be 
required and data collection will be limited to the following:
•
For subjects still receiving study treatment: study treatment administration, AEs, 
SAEs, laboratory data associated with SAEs
•
For all subjects: all subsequent anticancer treatment, PFS2 (per investigator 
judgment), second primary malignancies, and survival follow-up
9.1.5. Assessments 
Following the 
Positive Second 
Interim Analysis of 
PFS
A new section has been added.
9.1.6. Assessments 
Following the OS 
Interim Analysis
A new section has been added.
11.3. Efficacy 
Analyses
Described that the analysis of OS may be confounded by subjects from Arm A receiving 
daratumumab after their study treatment was stopped. Exploratory analysis may be 
performed to adjust for the effect daratumumab exposure may have on OS for the 
subjects who were randomized to Arm A (VMP).
11.3. Efficacy 
Analyses
Text describing secondary endpoints was revised to align with the secondary endpoints 
which were planned to be sequentially tested at the second interim analysis.
Rationale: To clarify/emphasize the requirement to wait until confirmed PD prior to starting subsequent 
anti-myeloma therapy.
Synopsis, Overview 
of Study Design;
3.1. Overview of 
Study Design
It is emphasized that for both Arm A (VMP) and Arm B (D-VMP), subjects entering the 
Follow-up Phase ‘should not be started on subsequent anti-myeloma therapy without 
confirmed disease progression’.
8.3. Prohibited 
Therapies
Clarified that the prohibition on concomitant administration of any other antineoplastic 
therapy for the intention of treating multiple myeloma applies prior to confirmation of 
disease progression.
Synopsis, Overview 
of Study Design;
3.1. Overview of 
Study Design;
9.1.4. Follow-up 
Phase;
9.2.1.1. Response 
Categories
Cross-references to the new Section 8.4 Subsequent Therapies have been added.
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Applicable Section(s)
Description of Change(s)
Rationale: Clarification of the IDMC’s role in data review following database lock for the primary analysis.
Synopsis, Statistical 
Methods;
3.1. Overview of 
Study Design;
11.11. Data 
Monitoring 
Committee
It is noted that the IDMC will no longer review study data after the database lock for the 
primary analysis has been completed.
Rationale: To clarify the daratumumab pharmacokinetics (PK) and immunogenicity assessments specific to Arm 
B (D-VMP).
Synopsis, 
Pharmacokinetic and 
Immunogenicity 
Evaluations;
9.3.1. Evaluations;
9.3.4. 
Immunogenicity 
Assessments
(Antibodies to 
daratumumab)
Added text stating that in the Follow-up Phase, for all subjects in Arm B (D-VMP), 
samples for PK and immunogenicity assessments are to be collected 8 weeks after the 
last dose of daratumumab, regardless of whether there has been confirmed disease 
progression.
Time and Events 
Schedule
Within the rows describing daratumumab PK and immunogenicity assessments, the 
‘Prior to PD’ and ‘After PD’ cells under Follow-up Phase have been merged. Samples 
are to be collected 8 weeks after the last dose of daratumumab, regardless of whether 
there has been confirmed disease progression.
Within the rows describing daratumumab PK and immunogenicity assessments, text has 
been added to emphasize that these assessments apply only to subjects in Arm B.
Rationale: To clarify quantitative immunoglobulin (Ig) assessments.
Time and Events 
Schedule
Within the quantitative Ig row, the ‘Cycle 10+’ text has been revised to replace ‘C12D1 
and every 3 cycles thereafter until PD’ with ‘every 4 months until PD’. It is emphasized 
that assessments of quantitative Ig for Cycle 10+ apply to Arm B (D-VMP) only. Within 
this same row, within the Follow-up Phase/Prior to PD cell, the following text has been 
added: ‘Every 3 months in Year 1, then every 4 months after Year 1 until PD’.
Rationale: To clarify that Eastern Cooperative Oncology Group (ECOG) and patient-reported outcomes (PRO) 
assessments that occur at Week 8 and Week 16 post-PD should be scheduled relative to the date of confirmation 
of disease progression.
9.1.4. Follow-up 
Phase
Text in bold has been added: ‘Every 16-week follow-up contacts, as well as Week 8 
post-PD and Week 16 post-PD ECOG and ePRO assessments, should be scheduled 
from the date of confirmed progression (ie, the date of the confirmatory laboratory 
assessment, not the date of confirmation by the sponsor).’
Rationale: Replaced time qualifier of ‘1-3 weeks later’ because in urgent situations, a repeat investigation may 
be needed sooner. ‘At least 1 day later’ is used to make clear that the confirmatory test cannot happen on the 
same day as the initial test.
9.2.1.2. Myeloma 
Protein 
Measurements in 
Serum and Urine
Text in strikethrough has been deleted, text in bold has been added: ‘Disease 
progression based on 1 of the laboratory tests alone must be confirmed by at least 1 a
repeat investigation performed at least 1 day 1 to 3 weeks later’.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
10
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify that sites should continue to monitor extramedullary plasmacytomas for PD following 
complete response (CR).
9.2.1.8. 
Documentation of 
Extramedullary 
Plasmacytomas
Text in strikethrough has been deleted: ‘Assessment of measurable sites of 
extramedullary disease will be performed and evaluated locally every 6 weeks (by 
physical examination) or every 12 weeks by imaging (if required) for subjects with a 
history of plasmacytomas or as clinically indicated during treatment for other subjects, 
until development of confirmed CR or confirmed disease progression.’
Rationale: To clarify required chemistry assessments at End-of-Treatment.
9.8. Safety 
Evaluations
Text in bold has been added: ‘Screening, Cycles 1-9 and End-of-Treatment’
Rationale: To clarify definitions for study end.
10.1. Completion 
Text added that the study end is defined as when 330 deaths have occurred or 5 years 
after the last subject is randomized, whichever comes first.
Rationale: To clarify definitions for completion of treatment.
10.1. Completion 
Separate definitions are provided for treatment completion for Arm A (VMP) and Arm 
B (D-VMP).
Rationale: Alignment of text with recent protocol template changes.
Title page
Added ‘Janssen Pharmaceutica NV’ to the list of legal entities.
10.3. Withdrawal 
from the Study
Revised the text related to subjects withdrawing from the study.
12.3.1. All Adverse 
Events
Added a sentence related to sponsor's responsibility for reporting anticipated events.
12.3.3. Pregnancy
Deleted text related to the unknown effect of study drug on sperm, and consolidated to a 
single paragraph the guidance for all initial reports of pregnancy in female subjects or 
partners of male subjects.
17.3. Subject 
Identification,
Enrollment, and 
Screening Logs
Added ‘(as allowed by local regulations)’ following 2 instances of ‘date of birth’.
17.11. Use of 
Information and 
Publication
Added the text in bold: ‘key assessment parameters of the study will be used to 
determine a coordinating investigator for the study’.
Changed the time for submitting combined results from the completed study for 
publication from ‘within 12 months of the availability of the final data (tables, listings, 
graphs)’ to ‘within 18 months after study end date’.
Revised the text beginning ‘Authorship of publications...’
Abbreviations
ICMJE has been added to the list of abbreviations.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Throughout the 
protocol
‘anticancer’ has been replaced with ‘anti-myeloma’
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
11
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
6.3.1.1. 
Daratumumab-
Related Toxicity 
Management
Added ‘other’ to describe ‘components of the chemotherapy regimen’.
9.2.1.5. Bone Marrow 
Examination, 
Table 10 Bone 
Marrow Testing
Within the cell that describes local testing for CR, stringent CR (sCR), the text in bold
has been added, to clarify that a separate biopsy is not needed: ‘If sCR is not met, repeat 
local testing for sCR with subsequent bone marrow examinations will be done at the 
time of the next protocol-required bone marrow examination’.
10.3. Withdrawal 
from the Study
‘When a subject withdraws before completing the study’ has been revised to ‘When a 
subject withdraws from the study’.
Amendment 4 (11 November 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The International Myeloma Working Group (IMWG) has recently defined 
new categories of MRD–negativity and has clarified several aspects of disease response assessment along with 
clinical trial endpoints (Kumar, 2016). In order for Protocol MMY3007 to be aligned with the new categories of 
MRD-negativity, the time points for collection of bone marrow for MRD assessment must be revised.
Applicable Section(s)
Description of Change(s)
Rationale: Addition of Kumar 2016 reference to support IMWG recommendations for multiple myeloma treatment 
response criteria.
Amendment table; 
9.2.1.1 Response 
Categories; 
References 
Reference added to Amendment table, Section 9.2.1.1, and References
Rationale: Clarification of the minimal residual disease (MRD) secondary objective for cross protocol consistency. 
Synopsis, Secondary 
Objectives; 2.1 
Secondary Objectives
Text modified to clarify objective to be the assessment of MRD negativity rate. Text 
moved to clinical outcome objective and text noting time point of “after treatment” was 
deleted.
Rationale: Inclusion of objective “time to response” for cross-protocol consistency.
Synopsis, Secondary 
Objectives; 2.1 
Secondary Objectives
“Time to response” included under clinical outcomes objective. 
Rationale: New objective added to provide cross protocol consistency and to explore durability of MRD negativity.
Synopsis, Exploratory 
Objectives; 2.1 
Exploratory 
Objectives; 9.2.2 
Endpoints
Exploratory objective added to assess durability of MRD negativity. 
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
12
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Whole blood samples for MRD assessment obtained with bone marrow aspirates will no longer be 
collected. 
Synopsis, Overview 
of Study Design; 
Time and Event 
Schedule: Disease: 
Evaluations: Blood 
sample for MRD; 3.1 
Overview of Study 
Design ;9.2.1.6 
Minimal Residual
Disease Assessment
Text and requirement for whole blood samples to be obtained at 14, 20, and 26 months 
(+/-1 month) for MRD assessment deleted. 
Rationale: Revision of endpoint presentation for protocol consistency.
Synopsis, Efficacy 
Evaluation/Endpoints; 
9.2.2 Endpoints
Secondary efficacy endpoint for sCR rate moved below overall response rate endpoint. 
Rationale: Revision of the definition of MRD negativity required to align with IMWG.
Synopsis, Efficacy 
Evaluation/Endpoints; 
9.2.2 Endpoints
Text modified to define the MRD negativity rate as the proportion of subjects with 
negative MRD at any time point after the date of randomization. Text defining rate as 
measurement of subjects who achieve CR/sCR at 14, 20, and 26 months after first dose 
deleted.
Rationale: Text correction to include exploratory endpoints to align with exploratory endpoints in Section 9.2.2.
Synopsis, Efficacy 
Evaluation/Endpoints
Exploratory endpoints added to synopsis.
Rationale: Text correction to include a time to response secondary efficacy endpoint to align with secondary 
objectives.
Synopsis, Efficacy 
Evaluation/Endpoints; 
9.2.2 Endpoints
Time to response, defined as the time between the randomization and the first efficacy 
evaluation that the subject has met all criteria for PR or better” included as secondary 
efficacy endpoint. 
Rationale: Clarification of use for collected whole blood samples. 
Synopsis, Biomarker 
Evaluation; 9.5 
Biomarkers 
Text modified to indicate that whole blood samples will be collected to process to plasma 
and PBMCs. Text indicating use for assessment of MRD deleted. 
Rationale: Modification of disease evaluation prior to PD time points in the Follow-up Phase to align with 
evaluation time points in the Treatment Phase.
Time and Events
Schedule: Follow-up 
Phase
Every 4-week designation for follow-up prior to PD deleted.
Rationale: Addition of ±2 weeks window to allow for flexible scheduling for follow-up visits after PD. 
Time and Events
Schedule: Follow-up 
Phase
Visit window of ±2 weeks added to the every-16 week visit after PD in the Follow-up 
Phase.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
13
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of visit time points to ensure consistent timing of assessments for both ECOG and ePRO.
Time and Events 
Schedule: ECOG, 
Disease Evaluations, 
PRO 
Text modified to define ‘every 3 months’ as ‘every 12 weeks’ in Year 1 and ‘every 
6 months thereafter’ as ‘every 24 weeks thereafter’.
Rationale: Reinstatement of the 2-hour collection window for the pre-infusion daratumumab PK sample for 
subjects in Arm B.
Time and Events
Schedule: Laboratory 
Assessment: 
Daratumumab PK
Text added to clarify that collection of the pre-infusion daratumumab PK sample is 
allowed up to 2 hours prior to the start of infusion.
Rationale: Align bone marrow aspirate/biopsy collection time points in the Time and Events Schedule with new 
MRD guidelines and across daratumumab protocols.
Time and Events
Schedule: Disease: 
Evaluations: Bone 
marrow 
aspirate/biopsy
Text modified to indicate that for subjects with CR/sCR, additional bone marrow samples 
will be obtained 12, 18, 24, and 30 months (+2 months) after first dose. Text added 
indicating information including time points located in Section 9.2.1.5 and Table 10.
Rationale: Inclusion of antihistamine medication listing to align with daratumumab protocols.
Time and Events
Schedule for Study 
Treatment, Cycle 1; 
Time and Events
Schedule for Study 
Treatment, Cycles 2-
9; Time and Events
Schedule for Study 
Treatment, Cycle 
10+; 6.1.3.1 
Pre-infusion 
Medication
Text indicating inclusion of new attachment included in Time and Events Schedules and 
Section 6.1.3.1. Listing provided in Attachment 5. Previous Attachments 5-8 renumbered 
throughout protocol.
Rationale: Clarification that order of combination drug administration applies to subjects in Arm B only.
6 Dosage and 
Administration
Text added to clarify that the protocol-specified order of study drugs given in combination 
is applicable to subjects in Arm B only.
Rationale: Clarification that criteria required for VMP administration are applicable for Cycles 2-9 only. Minor text 
modifications to align with VELCADE SmPC.
6 Dosage and 
Administration
Text added to clarify that criteria required for VMP administration are applicable for 
Cycles 2-9 only. Text wording “must” replaced with “should” for VELCADE SmPC 
alignment.
Rationale: Clarification that text within Table 4 is applicable to “within cycle” administration only. 
6.3.1.1 
Daratumumab-
Related Toxicity 
Management, Table 4
Text added to clarify that the information for Table 4 “Daratumumab-Related Toxicity 
Management” is applicable to “within cycle” administration only and not Day 1. The dose 
on Day 1 can be delayed but may not be skipped. 
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
14
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of VELCADE dose reduction. 
6.3.2 Dose 
Reductions 
(VELCADE, 
Melphalan, and 
Prednisone)
Text added to clarify that VELCADE dose reduction is only required in cases of held 
doses due to VELCADE-related toxicity. 
Rationale: Clarification of text regarding re-escalation of melphalan after dose reduction post toxicity to align with 
melphalan dose-modification guidelines.
6.3.2 Dose 
Reductions 
(VELCADE, 
Melphalan, and 
Prednisone)
Text added to indicate that re-escalation after dose reduction post toxicity is permitted for 
melphalan following recovery of renal function.
Rationale: Clarification of toxicity guidelines provided for the administration of VELCADE, Melphalan, and 
Prednisone.
6.3.3 Dose 
Modification 
Guidelines for 
VELCADE, 
Melphalan, and 
Prednisone Related 
Toxicities 
Text added to indicate that protocol provided management guidelines are applicable for 
toxicities deemed related to the administration of VELCADE, melphalan, and prednisone. 
Rationale:  Clarification of dose modification category for Grade 3 or Grade 4 neutropenia.
6.3.3 Dose 
Modification 
Guidelines for 
VELCADE, 
Melphalan, and 
Prednisone Related 
Toxicities, Table 8 
Hematological
Text revised to emphasize that this dose modification is applicable to Grade 3 neutropenia 
with associated fever and to all Grade 4 neutropenia (with or without associated fever).
Rationale: Dose modification for melphalan in the event of Grade 3 thrombocytopenia should be implemented in 
the subsequent treatment cycle. 
6.3.3 Dose 
Modification 
Guidelines for 
VELCADE, 
Melphalan, and 
Prednisone Related 
Toxicities, Table 8 
Hematological
Text indicating that reduction of melphalan by 1 dose-level for the remainder of the cycle 
has been deleted.
Rationale: Prophylaxis text revision to align with daratumumab label
8.1.4 Prophylaxis for 
Herpes Zoster 
Reactivation
Text providing detailed information on herpes zoster prophylaxis deleted. Prophylaxis 
recommended during Treatment Phase as per institutional guidelines. 
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
15
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of the use of study drug during or after emergency orthopedic surgery or radiotherapy.
8.3 Prohibited 
Therapies 
Text modified to indicate use of study drug or components of VMP regimen during or after 
emergency orthopedic surgery or radiotherapy are for conditions related to multiple 
myeloma. Text indicating “subject benefit” deleted.
Rationale: Clarification to provide additional scheduling flexibility for subject follow-up visits after PD and to 
clarify follow-up intervals for subjects not continuing disease evaluations after PD.
9.1.4 Follow-up 
Phase
Time points from Time and Events schedule added.
Text added to expand the protocol-specified information collection period after PD to 
every 16 weeks (±2 weeks). Clarification included indicating that in subjects not 
continuing disease evaluation, an every-16-week follow-up visit should be scheduled from 
the date of the End of Treatment visit.
Rationale: Highlight that increases in serum free light chains or the FLC ratio alone do not meet IMWG criteria for 
progressive disease in patients with measurable disease by SPEP and/or UPEP at baseline.
9.2.1.1 Response 
Categories 
Text modified to indicate that for patients with measurable disease by SPEP and/or UPEP 
at baseline, increases in serum free light chains or the FLC ratio alone do not meet criteria 
for progressive disease.
Rationale: Inclusion of text for protocol consistency to Section 9.1.4.
9.2.1.1 Response 
Categories
Text “lost to follow-up” included in 
“For subjects who discontinue study treatment before disease progression, disease 
evaluations should continue to be performed per the Time and Events Schedule until 
confirmed disease progression, death, the start of a new treatment for multiple myeloma, 
withdrawal of consent for study participation, lost to follow-up, or the end of study, 
whichever occurs first” to be consistent with text in Section 9.1.4.
Rationale: Bone Marrow Examination Table modified to align with new MRD guidelines and daratumumab 
protocols. 
9.2.1.5 Bone Marrow 
Examination, Table 
10
Text modifications:
CR/sCR
Local testing: Text modified to indicate preference of 2-4 color flow cytometry for 
detection of kappa/lambda ratio. Immunohistochemistry and immunofluorescence 
allowed but a kappa/lambda ratio from ≥100 plasma cells required to confirm 
sCR. Subjects who achieved CR but not sCR will have additional sCR 
evaluations to coincide with MRD bone marrow time points until sCR is 
achieved. 
Central testing: For subjects with CR/sCR additional samples to be obtained at 12, 
18, 24, and 30 months after first dose. A window of 2 months after the 12, 18, 24 
and 30-month time points is allowed.
Maintained CR/sCR:
Text deleted 
Disease Progression: 
Text modified to indicate that a bone marrow sample is requested from subjects in 
both treatment arms at disease progression to evaluate mechanism of resistance.
Rationale: Revision of time points for bone marrow collection for MRD assessment.
9.2.1.6 Minimal 
Residual Disease 
Assessment
Text indicating collection time points of baseline, CR confirmation, 14, 20 and 26 months 
(+/-1 month) deleted. Please see Table 10 for updated time points.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
16
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Clarification of collection points for the Serum Chemistry Panel.
9.8 Safety 
Evaluations: Clinical 
Laboratory Tests
Text added to indicate that the serum chemistry panel is to be obtained at Screening and 
Cycles 1-9. Text added to clarify that sodium and potassium, added in Amendment 2, will 
be retrospectively evaluated from the date of subject consent if collected as part of routine 
care. Urea added to the serum chemistry panel for Cycles 10+. 
Rationale: Addition of Chapuy 2016 reference to support processes to eliminate daratumumab IAT interference.
9.8 Safety 
Evaluations:
Daratumumab 
Interference with 
Indirect Antiglobulin 
Test (IAT) Results;
References
Reference added to Section 9.8 and References
Rationale: Although vital signs are performed at multiple time points as specified in the Time and Events Schedule, 
only vital signs obtained at Screening or associated with an adverse event are captured in the eCRFs.
9.8 Safety 
Evaluations; 
References: Vital 
Signs
Text modified to indicate that only vital signs obtained at Screening or associated with an 
AE will be entered in the eCRF; all measurements will be recorded in the source 
documents.
Rationale: Clarification that subjects do not have to discontinue all components of the VMP regimen if only one 
component requires a third dose reduction for toxicity.
10.2 Discontinuation 
of Study Treatment
Text modified to indicate that subjects do not have to discontinue all components of the 
VMP regimen if only one component requires a third dose reduction for toxicity. Bullet 
outlining discontinuation of study treatment if any component of VMP requires dose 
reduction for the third time deleted.
Rationale: Realignment of the testing order of the major secondary endpoints for the control of familywise type 1 
error during the second interim analysis.
11.3 Efficacy 
Analyses, Secondary 
Endpoints 
Text modifications
Major secondary endpoints revised as TTP, CR rate, MRD negativity rate, PFS2, 
and OS.
Secondary time to event efficacy endpoints: time to treatment added as endpoint.
Rationale: Changes from baseline cannot be summarized since vital signs are only captured in the eCRF at 
Screening and when associated with an adverse event.
11.9 Safety Analysis
Text modified to indicate that descriptive statistics for baseline temperature, heart rate, and 
blood pressure will be summarized. Text indicating providing changes from baseline for 
these parameters deleted.
Rationale: Inclusion of anticipated adverse events guidelines to align daratumumab protocols.
12.3.1 All Adverse 
Events; Attachment 
10
Text added to Section 12.3.1 indicating inclusion of new attachment. New guidelines 
provided in Attachment 10. 
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
17
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Alignment of text with recent protocol template changes.
12.3.1 All Adverse 
Events
Text modified to indicate that the sponsor will report incidences of suspected unexpected 
serious adverse events to the investigator. Text added to indicate that the sponsor will 
periodically evaluate the data independent of the investigator and will, in the event of a 
drug-related serious anticipated event, submit appropriate documentation to the 
investigator. 
Rationale: Alignment of text with recent protocol template changes.
17.5 Case Report 
Form Completion
Text specifying that all data related to the study must be recorded on eCRFs prepared by 
the sponsor was deleted.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 (25 July 2016)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The Safety Evaluations included in Protocol Amendment 2 (dated 
05 Nov 2015) for the chemistry panel (ie, the analysis of sodium and potassium levels) will require the collection of 
results to be done retrospectively from the date of subject consent for the duration of the study, if collected as part of 
routine care. The baseline data, if available, are needed in order to effectively analyze safety with respect to changes 
in sodium/potassium levels while on treatment with respect to the investigational agent daratumumab in this 
combination with VMP in the frontline setting of treatment for multiple myeloma in an elderly population. This 
does not require any additional testing nor does it require a change to the Informed Consent Form or the request for 
additional consent from the subjects.
Applicable Section(s)
Description of Change(s)
Rationale: This nonsubstantial amendment is required to include a clarification statement regarding collection of 
sodium and potassium. No changes to the text have been made.
Amendment 2 (05 November 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To provide updated guidance with respect to VELCADE dose 
modifications (per the Summary of Product Characteristics [SmPC] and United Sates Package Insert [USPI]) and to 
align with the VELCADE label regarding dose modifications, to incorporate investigator feedback into the protocol, 
and to revise operational aspects of the study and provide clarifications on study procedures.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
18
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: To provide updated guidance with respect to VELCADE dose modifications (per SmPC and USPI) and 
to add a window for within-cycle VELCADE and daratumumab treatments for site and subject convenience
Time and Events 
Schedules for Study 
Treatment, Cycle 1
(VMP treatment 
Phase) and Cycle 2 to 
9 (VMP Treatment 
Phase);
6.2.2 VELCADE 
Administration
VELCADE doses should must be at least 72 hours apart. Doses that need to be withheld 
are skipped and will not be made up later in the cycle. Individual doses within a cycle 
have a ±1 day window. 
6 Dosage and 
Administration; 
9.1.3 Treatment Phase
Text has been added or revised as follows:
Before initiating a new cycle of therapy, subjects must meet the following criteria:
•
Platelet count ≥70 x 109/L
•
ANC ≥1.0 x 109/L
•
Non-hematological toxicities resolved to Grade 1 or baseline
The start of each cycle may occur within ±3 days of the scheduled day in order to 
accommodate the schedule of the site or subject. If the start of a cycle is delayed, Day 1 
of subsequent cycles should be adjusted accordingly to maintain the 42-day cycle 
duration. In Cycles 1 through 9, weekly or every-three-week daratumumab infusions 
may be given within ±1 day of the scheduled day in order to accommodate the 
schedule of the site or subject. Additionally, weekly or twice weekly VELCADE doses 
may be given within ±1 day of the scheduled day in order to accommodate the 
schedule of the site or subject. Changes to within-cycle dosing should not impact 
Day 1 of the next cycle. The start of each cycle should be scheduled relative to Cycle 1 
Day 1 and should not change if visits have shifted within the allowed window.
6.3.2 Dose 
Reductions 
(VELCADE, 
Melphalan, and 
Prednisone)
VELCADE will be reduced or discontinued according to the guidelines presented in 
Table 5. In addition to the VELCADE dose modification guidelines presented in 
Section 6.3.3, Table 8, if several VELCADE doses in a cycle are withheld (≥3 doses 
during twice weekly administration or ≥2 doses during weekly administration), 
VELCADE dose should be reduced by 1 dose level. Once reduced due to toxicity, 
doses of VELCADE, melphalan, or prednisone should not be re-escalated.
6.3.3 Dose 
Modification 
Guidelines for 
VELCADE, 
Melphalan, and 
Prednisone 
Moved all footnotes in Table 8 to the end of the table. 
Updated Table 8 to align with VELCADE SmPC and USPI.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
19
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale:  To allow flexibility in the administration of pre-infusion medications, to clarify allowable pre-infusion 
medications, and to be consistent with other daratumumab protocols.
Time and Events 
Schedules for Study 
Treatment, Cycle 1
(VMP treatment 
Phase) and Cycle 2 to 
9 (VMP Treatment 
Phase), and Cycle 
10+ (Dara treatment 
Phase, Arm B only) 
Administer pre-infusion medications approximately 1 hour before daratumumab infusion. 
Pre-infusion medications given by mouth (PO) may be administered within 3 hours before 
the infusion.
Time and Events 
Schedules for Study 
Treatment, Cycle 1
(VMP treatment 
Phase) and Cycle 2 to 
9 (VMP Treatment 
Phase); and Cycle 
10+ (Dara treatment 
Phase, Arm B only);
6.1.3.1 Pre-infusion 
Medication
Because it is acceptable to give dexamethasone PO or intravenously (IV) regardless of 
availability of IV dexamethasone, text was revised for clarity: Dexamethasone 20 mg IV 
or PO.
To specify that only equivalent H1 blockers are acceptable, clarified: An antihistamine 
(diphenhydramine 25-50 mg IV or PO, or equivalent H1 blocker)
Time and Events 
Schedules for Study 
Treatment, Cycle 1
(VMP Treatment 
Phase);
6.1.3.1 Pre-infusion 
Medication
Added allowance of administration of leukotriene inhibitor, montelukast 10 mg PO or 
equivalent, at C1D1 approximately 1 hour or less before the daratumumab infusion.
6.1.3.2 Post-Infusion 
Medication
Added leukotriene inhibitor (montelukast or equivalent) as allowable post-infusion 
medication
Attachment 5 
Conversion Table for 
Glucocorticosteroid 
Dose
Revised table to remove hydrocortisone, as it’s a short acting corticosteroid and should not 
be used as a pre-infusion medication substitute for dexamethasone. Added the allowance 
of bethamethasone (0.6 mg), which can be used as a substitute for dexamethasone 
pre-infusion medication. 
Rationale: To provide additional guidance as to acceptable methods of bone marrow preparation and indicate that 
flow cytometry is also an acceptable method of confirming multiple myeloma diagnosis.
Time and Events 
Schedule
For screening (up to 42 days before randomization) fresh aspirate or biopsy preferred. If 
not available, obtain non-decalcified slides (bone marrow aspirate, touch preparation 
or clot selection) or FFPE block (clot section only, no bone marrow biopsy).
9.2.1.5 Bone Marrow 
Examination
Updated Table 10 to provide additional guidance on the acceptable methods of bone 
marrow preparation.
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
20
Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: To clarify assessments and procedures, and timing thereof, and allow flexibility, as applicable, for some 
assessments and procedures, in relation to Screening.
Time and Events 
Schedule;
9.1.2 Screening 
Phase;
9.2.1.8 
Documentation of 
Extramedullary 
Plasmacytomas
Disease evaluations, including chest X-ray (or full chest CT scan), 12-lead ECG, lytic 
disease assessment, and extramedullary plasmacytomas are performed as part of SOC, are 
acceptable to be used for screening, as long as the assessments are done within 42 days 
before randomization. 
For subjects with history of plasmacytomas assessed by physical exam, a repeat 
assessment should be performed on C1D1 if not done within 14 days prior to 
randomization
Time and Events 
Schedule
12-lead ECG assessments can be performed within ±7 days of the planned assessment 
date.
Hematology and chemistry values are acceptable for screening to meet CRAB criteria, if 
performed as part of SOC within 42 days before randomization but must be performed 
within 21 days before randomization for other eligibility requirements.  
Clarification for analysis of daratumumab PK. For Arm B only, on daratumumab infusion 
days, 1 sample is to be collected before the start of infusion, and 1 sample is to be 
collected after the end of infusion (up to 2 hours after the end of infusion).  
Clarified that for SPEP and IFE, 24-hour UPEP and IFE; serum FLC; and calcium and 
albumin that the time frame is based on when the samples were collected, not when results 
were received.
Clarified timing of assessments for Quantitative Ig to indicate that during Cycles 1-9, 
assessments are at C3D1, C5D1, C7D1, and C9D1.  For Cycles 10+, assessments are at 
C12D1 and every 3 cycles thereafter until PD. 
Rationale: Modified language and guidance pertaining to the indirect antiglobulin test (IAT).
Time and Events 
Schedule
Added text indicating that a wallet card is to be given to all subjects (in Arm A and in 
Arm B) at C1D1.
4.3 Prohibitions and 
Restrictions
Removed the Blood Type IAT results language, as this is now limited to Section 9.8 Safety 
Evaluations.
9.8 Safety 
Evaluations
Updated the daratumumab IAT results text to align with other daratumumab protocols. 
12.3.1 All Adverse 
Events
Added text specifying that wallet cards must be carried for the duration of the study by 
subjects in Arm A and for at least 6 months after the study treatment is discontinued for 
subjects in Arm B.
Rationale: To clarify inclusion and exclusion criteria.
Synopsis, Subject 
Population; 
4.1 Inclusion Criteria, 
Criterion #2.2
Eligible subjects must satisfy the calcium elevation, renal insufficiency, anemia, and 
bone abnormalities (CRAB) diagnostic criteria, monoclonal plasma cells in the bone 
marrow ≥10% or presence of a biopsy proven plasmacytomas, and measurable 
secretory disease, as assessed by the central laboratory.
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Applicable Section(s)
Description of Change(s)
4.2 Exclusion 
Criteria, Criterion 
12.2
Because subjects with pacemakers, which is classified as NCI CTCAE Grade 3 atrial 
fibrillation, are eligible for the study, criterion was revised to clarify: “Subjects are to be 
excluded if they have uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥2)
or clinically significant ECG abnormalities”, because subjects with pacemakers, which is 
classified as NCI-CTCAE Grade 3 atrial fibrillation, are allowed to be enrolled in the 
study.
As the intent is to exclude any subjects with prolonged QT and not to have sites converting 
ECG output using different correction formulas, criterion was revised to state “screening 
12-lead ECG showing a baseline corrected QT interval as corrected by Fridericia’s 
formula (QTcF) (QTc)>470 msec.
Rationale: To align with updated Investigator’s Brochure (IB) and risk language wording, updated the timeframe 
associated with birth control use.
4.2 Exclusion 
Criteria, Criterion 
#16.1
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study or within 3 months 4 months after the last dose of any 
component of the treatment regimen. Or, subject is a man who plans to father a child while 
enrolled in this study or within 3 months 4 months after the last dose of any component of 
the treatment regimen.
4.3 Prohibitions and 
Restrictions, #1 and 
#2
1. For women of childbearing potential, adequate contraception as specified in Section 4.1 
must continue during the Treatment Phase, during any dose interruptions, and for 3 
months 4 months after the last dose of daratumumab. In addition, women must not donate 
ova during the study and for 3 months 4 months after the last dose of daratumumab.
2. A man who is sexually active with a woman of childbearing potential must always use a 
latex or synthetic condom during the study and for 3 months 4 months after discontinuing 
daratumumab. All men must not donate sperm during the study and for 3 months
4 months after the last dose of daratumumab. 
Rationale: To clarify if assessments are to be analyzed by the local or central laboratory and to provide the 
reference for determination of ISS Stage.
Synopsis, Overview 
of the Study Design; 
Time and Events 
Schedule;
5 Treatment 
Allocation and 
Blinding; 
9.2.1.4 β2 
Microglobulin and 
Albumin
Eligible subjects will be stratified by International Staging System (I vs II vs III based on 
central laboratory results at Screening).
Time and Events 
Schedule
Indirect Antiglobulin Test (IAT) is to be assessed locally.
Randomization based on SPEP and IFE and 24-hour UPEP and IFE is based on central 
laboratory values. 
New Attachment 8
International Staging 
System (ISS) Staging
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JNJ-54767414 Daratumumab
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Applicable Section(s)
Description of Change(s)
Rationale: To update recommended and prohibited therapies.
8.1 Recommended 
Therapies
Removed Section 8.1.1 Prevention of Deep Vein Thrombosis because none of the study 
treatments are associated with increased incidence of veno-thromboembolic disease.
8.1.1 Bisphosphonate 
Therapy
After Cycle 1, investigators should not prescribe bisphosphonates to subjects who have not 
received them before as this would be considered a sign of disease progression, unless 
approved by the sponsor after confirming that the subject does not have disease 
progression at the time of bisphosphonate initiation.
8.3 Prohibited 
Therapies 
Nonsteroidal anti-inflammatory agents should be used with caution avoided in order to 
prevent myeloma-related kidney disease.
Rationale: To update serum chemistry panel assessments to allow urea to be performed instead of BUN as some 
centers do not assess BUN; to add sodium and potassium to the chemistry panel; and to clarify that direct bilirubin 
assessment is only necessary if total bilirubin is >1.5xULN.
9.8 Safety 
Evaluations
Cycles 1-9
Blood urea nitrogen (BUN) or urea
total bilirubin (direct bilirubin if total bilirubin >1.5xULN)
sodium
potassium
Cycle 10+
Sodium
Potassium
Rationale: Clarify procedure for management of infusion-related reactions.
6.1.4 Management of 
Infusion-related 
Reactions
Subjects in Arm B should be carefully observed during daratumumab infusions. Trained 
study staff at the clinic should be prepared to intervene in case of any infusion-related 
reactions occurring, and resources necessary for resuscitation (eg, agents such as 
epinephrine and aerosolized bronchodilator, also medical equipment such as oxygen tanks, 
tracheostomy equipment, and a defibrillator) must be available at the bedside. Attention to 
staffing should be considered when multiple subjects will be dosed at the same time. 
If an infusion-related reaction develops, then the infusion should be temporarily 
interrupted or slowed down.
If an infusion is paused or the infusion rate is decreased, then a longer-than-anticipated 
infusion time may occur.
Rationale: To align with updated protocol template language.
4 Subject Population
Specified that “…the investigator must consult with the appropriate sponsor representative 
and resolve any issues before enrolling a subject in the study.  Waivers are not allowed.”
Rationale: Miscellaneous updates and clarifications made throughout the protocol. 
Synopsis, Objectives 
and Hypothesis;
2.1 Objectives;
9.2.2 Endpoints
Clarified that ORR includes all subjects with PR or better (not just those with CR and PR).
Synopsis, Objectives 
and Hypothesis;
2.1 Objectives
Clarified secondary objective as “very good partial response (VGPR) or better rate.
Synopsis, Overview 
of Study Design;
3.1 Overview of 
Study Design
Measures to prevent infusion-related reactions cytokine release syndrome will include...
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Applicable Section(s)
Description of Change(s)
Synopsis, Overview 
of Study Design;
3.1 Overview of 
Study Design;
9.3.3 Pharmacokinetic 
Parameters
Blood samples will be drawn for assessment of pharmacokinetics and immunogenicity 
parameters.
Changes were made to further clarify the pharmacokinetic data analysis plans.
Synopsis, Efficacy 
Evaluations and 
Endpoints;
9.2.1.2 Myeloma 
Protein Measurements 
in Serum and Urine;
9.2.2 Endpoints
Updated the DIRA interference language to specify “For those subjects with negative or 
low SPEP (≤0.2 g/L) and suspected daratumumab interference on immunofixation, a 
reflex assay using anti-idiotype antibody will be utilized…”
For subjects with suspected daratumumab interference on SPEP and/or serum IFE…
Time and Events 
Schedule; 
9.8 Safety 
Evaluations
Removed asthma as a condition for measurement of FEV1, as subjects with asthma are 
excluded from study participation. 
Time and Events 
Schedule
Added that it is allowable to accept results of a FEV1 assessment that was done as part of 
SOC within 42 days before randomization and not require repeat assessment within 
21 days before randomization. Also, clarified the timing of the ECOG assessments in 
year 1.
Time and Events 
Schedules for Study 
Treatment, Cycle 1
(VMP treatment 
Phase) and Cycle 2 to 
9 (VMP Treatment 
Phase)
Clarified that hematology and chemistry assessments are required for subjects in both 
treatment arms. Testing may be performed for up to 2 days before other treatment days, 
and results of hematology tests must be evaluated before treatment. 
Vital signs assessments are required for subjects in both treatment arms; additional vital 
sign assessments before, during, and after the daratumumab infusion are required for 
subjects in Arm B only.
3.1 Overview of 
Study Design
Updated Figure 3 to accurately reflect that in the Follow-up Phase, prior to PD, disease 
evaluations will be conducted as per the T&E schedule (rather than q4wks).
6.1.3.2 Post-Infusion 
Medication
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol salbutanol± inhaled corticosteroids for subjects with COPD)
6.3.1.1 
Daratumumab-
Related Toxicity 
Management
Updated Table 4 to specifically refer to “Cycle 1” and “Cycles 2-9” and delete “VMP” 
clarifier.
9.2.1.8 
Documentation of 
Extramedullary 
Plasmacytomas
Correct erroneous text to indicate that to quality for PR, the sum of products of the 
perpendicular diameters of the existing extramedullary plasmacytomas must have 
decreased by at least 50% or 25%, respectively, and new plasmacytomas must not have 
developed.
9.3.2 Analytical 
Procedures
Due to the evolving need for pharmacokinetic/immunogenicity data in this study to 
support daratumumab program decisions, it is not necessary to specify bioanalysis timing 
in the protocol, so removed text describing the specific detailed timing of the bioanalysis.
12.3.1 All Adverse 
Events
Reiterated statement that only clinically relevant laboratory abnormalities (ie, those 
causing a treatment intervention or need for concomitant therapy) should be recorded on 
the adverse event eCRF. All other laboratory abnormalities need not be recorded as 
adverse events.
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JNJ-54767414 Daratumumab
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Applicable Section(s)
Description of Change(s)
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 1 (24 November 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To incorporate investigator feedback into the protocol, to further clarify 
MRD monitoring, to clarify safety reporting requirements for sites in Japan, to incorporate updated IMWG criteria
Applicable Section(s)
Description of Change(s)
Rationale: To align the definition of multiple myeloma with the updated IMWG criteria (Lancet Oncol 2014; 15: 
e538–48.
Attachment 1
Replaced contents of Attachment with new guidelines adapted from the newly published 
criteria
Rationale: To provide instructions for preventing interference of daratumumab in determining blood type for future 
transfusions.
Time and Events 
Schedule, 
12.3.1, All Adverse 
Events
Blood type and IAT results will be included on wallet card for subjects in Arm B.
4.3, Prohibitions
9.8, Safety 
Evaluations
Added text to explain daratumumab interference and recommendations for which tests to 
perform.
Rationale: To clarify details of bone marrow collection for MRD monitoring.
Time and Events 
Schedule, 
9.2.1.5, Bone Marrow 
Examination
9.2.1.6, MRD 
Assessment
Clarified that a fresh bone marrow aspirate or biopsy is preferred at screening, and a fresh 
aspirate or biopsy (or both) required to confirm CR/sCR; changed timing of bone marrow 
sample and blood sample to 14, 20, and 26 months after first dose.
9.2.1.5, Bone Marrow 
Examination
Revised text and put it into table format.
Rationale: To clarify that the secondary objective and secondary endpoint is to assess the MRD negative rate
Synopsis, 
2.1, Objectives
To assess minimal residual disease (MRD) negative rate after treatment
Synopsis,
9.2.2, Endpoints
Assess MRD negative rate, as measured in subjects who achieve CR/sCR, at 14, 20, and 
26 months after first dose.
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JNJ-54767414 Daratumumab
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Applicable Section(s)
Description of Change(s)
Rationale: To clarify PRO and ECOG collection procedures
Time and Events 
Schedule
Clarified that both PRO questionnaires and ECOG performance status must be 
administered and completed prior to any other study procedures or assessments for that 
study visit
Time and Events 
Schedule;
9.6, PRO 
15, Study-specific 
Materials
All PRO measures will be collected via an electronic device (ePRO).
17.6, Data QA/QC
PRO data will be transmitted to the ePRO vendor database and then to the sponsor’s 
database.
Rationale: Removed 2-hr post infusion collection of vital signs on Cycle 1 Day 1, in absence of safety signal and in 
response to investigator request.  
Time and Events 
Schedule for Study 
Treatment, Cycle 1
On Cycle 1 Day 1: immediately before the start of dara infusion; at 0.5, 1, 1.5, 2, 3.5 hr 
after start of infusion; at end of infusion; 0.5,1, 2 hr after end of infusion.
Rationale: Align inclusion criteria with other daratumumab protocols.
4.1, Inclusion Criteria
#2: Added “without measurable disease in the serum or urine” to light chain myeloma
#5: Added cutoff for Gilbert syndrome “direct bilirubin ≤1.5xULN”
#5: Aligned creatinine clearance with new guidelines: “creatinine clearance ≥40 mL/min, 
may be calculated or measured according to local practice (if calculated, MDRD or 
CKD-EPI formulae preferred)”
#5: corrected serum calcium to “<=14” mg/dL (“<=3.5” mmol/L); or free ionized calcium 
“<=6.5” mg/dL (“<=1.6” mmol/L)
#7: changed screening pregnancy test to within 14 days prior to randomization
Rationale: Align exclusion criteria with other daratumumab protocols.
4.2, Exclusion 
Criteria
Attachment 4
#9: revised entire criterion for subjects with COPD or asthma, and added asthma guidelines 
as Attachment 4
#10: rewrote criteria for hepatitis B and hepatitis C
#12: specified only subjects with uncontrolled cardiac arrhythmia should be excluded
#17: specified vertebroplasty not considered to be major surgery
Rationale: Improve instructions for pre-infusion medications
6.1.3.1, Pre-infusion 
Medication
specified administration “approximately” 1 hour before daratumumab infusion, deleted 
infusion of antihistamine 12 hours before first daratumumab infusion on C1D1, clarified 
that dexamethasone PO is only if IV not available
Rationale: Provide examples of subjects at higher risk of respiratory complications for post-infusion medications.
6.1.3.2, Post-Infusion 
Medication
Specified subjects with higher risk of respiratory complications (eg, subjects with mild 
asthma, or subjects with COPD
NCT02195479


JNJ-54767414 Daratumumab
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Approved, Date: 14 February 2018
Applicable Section(s)
Description of Change(s)
Rationale: Improve guidelines for delay of daratumumab infusions
6.3.1.1, Daratumumab 
Toxicity Management
To emphasize the criteria when to stop daratumumab, bolded and underlined the following 
sentence: ONLY if any of the following criteria are met, and the event cannot be 
ascribed to components of the chemotherapy regimen, the daratumumab infusion 
must be held to allow for recovery from toxicity
The following changes were made to the criteria for dose delay to:

Added: Grade 4 hematologic toxicity 

Revised: Febrile neutropenia
Rationale: Clarify criteria for discontinuation of treatment after Cycle 9 due to dose delays.
6.3.1.1, Daratumumab 
Toxicity Management 
6.3.1.2, Daratumumab 
Interruption
10.2, Discontinuation 
of Treatment
Added wording that, after Cycle 9, if a subject misses 2 consecutive planned doses (rather 
than 4 weeks) then treatment should be discontinued.
Rationale: To allow prednisolone to substitute for prednisone in countries where prednisone is not available.
6.2.3, Melphalan and 
Prednisone Admin
Prednisolone may be substituted for prednisone in countries where prednisone is not 
available.
Rationale: Updated investigational product characteristics and handling according to new guidelines
14.1,Description of 
Study Drug
14.4, Preparation, 
Handling, Storage
Updated physical description of study drug, revised instructions for preparation and  
handling to refer to Investigational Product Preparation Instructions or SIPPM
Rationale: Revisions to improve  accuracy and consistency
Time and Events 
Schedule
Reorganized disease evaluations and specify window for SPEP, UPEP, IFE, and β-2 
microglobulin to within 14 days of C1D1.
3.1, Overview of 
Study Design
Revised definition of Treatment Phase
3.1, Overview of 
Study Design
5, Treatment 
Allocation
Changed International Scoring System to International Staging System
6.2.2, VELCADE 
Administration
Added sentence that VELCADE dose may be delayed up to 48 hours, as stated in Time and 
Events Schedule.
6.3.3, Dose 
Modification 
Guidelines
Removed hepatic criteria from guidelines for melphalan dose adjustment for renal 
impairment
8.3, Prohibited 
Therapies
Added interferon and clarithromycin as prohibited therapies
9.1.2, Screening 
Phase
Added provision that Sponsor will review eligibility, specified assessments that do not 
need to be repeated on Cycle 1 Day 1 if done within the prior 14 days, extended window 
for pregnancy test to 14 days, provided instruction for measurement or calculation of 
creatinine clearance
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Applicable Section(s)
Description of Change(s)
9.1.4, Follow-up 
Phase
Clarified reasons to stop disease evaluations and timing of visits after PD
9.2.1.2, Myeloma 
Protein Measurements
Revised testing of quantitative IgD and IgE to only subjects with IgD or IgE myeloma.
9.2.1.7, Assessment 
of Lytic Disease
Deleted text regarding use of radionucleotide scan as it is no longer relevant
11.11, Data 
Monitoring 
Committee
Corrected IDMC to consist of 2 clinicians and 1 statistician
11.4, PK Analyses
11.6, PK/PD Analyses
Removed redundancy between sections and consolidated into Section 11.6
Attachment 3
Deleted attachment for measuring creatinine clearance
Rationale: In response to PMDA comments, additional safety monitoring for Japanese subjects is added via an 
Attachment (and cross-references to the amendment in main text).
Synopsis (Safety 
Evaluations) 
During Cycle 1 at Japanese sites, an enhanced reporting, monitoring, and review of pre-
specified safety events that occur for Japanese subjects in Arm B will be performed until a 
minimum of 3 subjects in Arm B have completed Cycle 1.
12.4. Reporting, 
Monitoring, and 
Review of Safety 
Events in Japanese 
Subjects in Arm B; 
Attachment 7
Section and attachment added to describe the enhanced reporting, monitoring, and review 
of pre-specified safety events for Japanese subjects in Arm B (minimum of 3 subjects).
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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JNJ-54767414 Daratumumab
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SYNOPSIS
A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomib) Melphalan-
Prednisone (VMP) Compared to Daratumumab in Combination with VMP (D-VMP), in Subjects with 
Previously Untreated Multiple Myeloma who are Ineligible for High-dose Therapy
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor 
cells that express high levels of CD38, such as plasma cells from patients with multiple myeloma. This 
target is distinct from those of other approved agents for multiple myeloma therapy.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to determine if the addition of daratumumab to VMP will prolong PFS compared 
with VMP.
Secondary Objectives
The secondary objectives are:

To determine if the addition of daratumumab to VMP will improve clinical outcome as measured by:

Time to disease progression (TTP)

CR rate

Minimal residual disease (MRD) negativity rate

PFS2 (defined as time from randomization to progression on the next line of therapy or death, 
whichever comes first) 

Time to next treatment

Overall response rate (partial response [PR] or better)

Stringent CR (sCR) rate

Very good partial response (VGPR) or better rate

Time to response

Duration of response

Overall survival

To assess patient-reported outcomes and heath economic/resource utilization

To determine the pharmacokinetics and immunogenicity of daratumumab

To assess the safety and tolerability of daratumumab when administered in combination with VMP

To evaluate clinical efficacy of daratumumab when added to VMP in high risk molecular subgroups
Exploratory Objectives

To explore biomarkers predictive of response and resistance to therapy

To assess durability of MRD negativity
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JNJ-54767414 Daratumumab
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Hypothesis
The hypothesis of the study is that daratumumab continued until disease progression, in combination with 
9 cycles of VMP, will improve PFS compared with 9 cycles of VMP alone.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, parallel-group, controlled, multicenter study in subjects at least 18 years 
of age with previously untreated multiple myeloma who are ineligible for high dose therapy. A target of 
up to 700 subjects will be enrolled in this study with 350 subjects planned per treatment arm.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
Screening Phase will be up to 21 days before randomization. All subjects will receive up to 9 cycles of the 
VMP regimen (1 cycle = 6 weeks) with or without daratumumab.
The Treatment Phase will extend from Day 1 of Cycle 1 to discontinuation of all study treatment. Eligible 
subjects will be stratified by International Staging System (I vs II vs III based on central laboratory results 
at Screening), region (Europe vs Other), and age (<75 vs ≥75) and then randomized in a 1:1 ratio. 
Subjects in both treatment arms will receive 1.3 mg/m2 VELCADE by subcutaneous injection (SC) twice 
weekly (Weeks 1, 2, 4, and 5) in Cycle 1 followed by once weekly (Weeks 1, 2, 4, and 5) in Cycles 2 to 9. 
Melphalan PO at 9 mg/m2 and prednisone PO at 60 mg/m2 will be self-administered on Day 1-4 of each 
VELCADE cycle. For subjects randomized to the Treatment Arm B, 20 mg of dexamethasone will 
substitute for the planned dose of prednisone on Day 1 of each cycle. In this setting, dexamethasone will 
be utilized as the treatment dose of steroid for that particular day, as well as the required pre-medication 
prior to daratumumab infusion. Daratumumab 16 mg/kg will be administered to subjects in Treatment 
Arm B by IV infusion once every week for 6 weeks (Cycle 1; 1 VELCADE cycle); then once every 
3 weeks for 16 additional doses (Cycles 2-9). Measures to prevent infusion-related reactions (IRRs) will 
include pre-infusion medication with dexamethasone, paracetamol, and antihistamine before each 
daratumumab infusion.
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be 
conducted on bone marrow samples. Safety evaluations will include AE monitoring, physical 
examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology and 
chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance 
status. Blood samples will be drawn for assessment of pharmacokinetics and immunogenicity.
After completion of the VMP cycles, subjects in Arm A will enter the Follow-up Phase and should not be 
started on subsequent anti-myeloma therapy without confirmed disease progression. Subjects in Arm B 
will continue to receive daratumumab every 4 weeks until documented progression, unacceptable toxicity, 
or the study ends (see below for definition). Subjects who need to discontinue treatment with any one 
component of study treatment (VELCADE, melphalan, prednisone, or daratumumab) may continue to 
receive treatment with the other components of study treatment, as assigned. Upon discontinuation of 
daratumumab, subjects in Arm B will also enter the Follow-up Phase and should not be started on 
subsequent anti-myeloma therapy without confirmed disease progression.
In the Follow-up Phase, subjects who discontinue treatment before disease progression must continue to 
have disease evaluations according to the Time and Events Schedule until confirmed PD (see Section 8.4, 
Subsequent Therapies), subsequent anti-myeloma treatment, death, withdrawal of consent, lost to 
follow-up, or the end of the study. After disease progression is documented, follow-up will be obtained at 
least every 16 weeks. Subsequent anti-myeloma treatment, PFS2 (per investigator judgment), second 
primary malignancies, and survival will also be recorded.
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Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety, will be 
performed after a total of approximately 100 subjects have been treated for at least 2 cycles or 
discontinued the study treatment. The second interim analysis, with a purpose to evaluate cumulative 
interim safety and efficacy data, will be performed when approximately 216 PFS events have been 
accumulated. Investigators will be informed when each interim analysis is to occur. As the superiority of 
daratumumab combined with VMP over VMP alone with respect to PFS was established at the second 
interim analysis, the interim PFS analysis will serve as the primary PFS analysis, which otherwise was to 
occur when approximately 360 PFS events had been observed. As planned in the original protocol, two 
interim OS analyses will be performed at the time of the interim PFS (216 events) and the primary PFS 
(360 events) prior to the final OS analysis at 330 deaths. The second interim OS will occur when 200 
deaths (60% of all planned deaths) have been accumulated which about the same time of the primary PFS 
analysis as if it would have occurred. All available data prior to that time will be included in each of the 
respective analyses. An Independent Data Monitoring Committee (IDMC) will be commissioned for this 
study to review efficacy and safety results at the 2 planned interim analyses and to perform periodic 
reviews of safety data.
The end of the study will occur when 330 subjects have died, or 5 years after the last subject is 
randomized, whichever comes first. The sponsor will ensure that subjects benefiting from treatment with 
daratumumab will be able to continue treatment after the end of the study.
As a result of the positive second interim analysis, that established the superiority of daratumumab 
combined with VMP over VMP alone with respect to the primary endpoint (PFS), and consistent with the 
IDMC’s recommendation, the sponsor will ensure that access to daratumumab is provided for subjects 
randomized to Arm A (VMP) who have sponsor-confirmed disease progression (see Section 8.4, 
Subsequent Therapies).
SUBJECT POPULATION
Key eligibility criteria include the following: subjects who are 18 years of age (or legal age of consent), 
have a confirmed diagnosis of symptomatic multiple myeloma satisfying the calcium elevation, renal 
insufficiency, anemia, and bone abnormalities (CRAB) diagnostic criteria; monoclonal plasma cells (PCs)
in the bone marrow ≥10% or presence of a biopsy proven plasmacytomas; and measurable secretory 
disease, as assessed by the central laboratory; an Eastern Cooperative Oncology Group (ECOG) 
performance status score of 0, 1, or 2, must be newly diagnosed and not considered candidates for high-
dose chemotherapy with stem cell transplantation.
DOSAGE AND ADMINISTRATION
Daratumumab (16 mg/kg) will be administered to subjects in Arm B by IV infusion initially once every 
week for 6 weeks (Cycle 1; 1 VELCADE cycle); then once every 3 weeks for an additional 16 doses 
(Cycles 2-9); then once every 4 weeks thereafter (post-VMP Treatment Phase), until documented 
progression, unacceptable toxicity, or study end.
Subjects will receive 1.3 mg/m2 VELCADE as a SC injection twice weekly (Weeks 1, 2, 4, and 5) for one 
6-week cycle (Cycle 1; 8 doses per cycle) followed by once weekly (Weeks 1, 2, 4, and 5) administrations 
for eight 6-week cycles (Cycles 2 to 9; 4 doses per cycle).
Melphalan will be administered at 9 mg/m2 and prednisone will be administered at 60 mg/m2 on Day 1 to 
4 of each VELCADE cycle. Both melphalan and prednisone will be administered orally. For subjects 
randomized to the Treatment Arm B, 20 mg dexamethasone will substitute for the planned dose of 
prednisone on Day 1 of each cycle. In this setting, dexamethasone will be utilized as the treatment dose of 
steroid for that particular day, as well as the required pre-medication prior to daratumumab infusion.
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EFFICACY EVALUATIONS/ENDPOINTS
Disease evaluations must be performed every 3 weeks during the first year, every 4 weeks during the 
second year, and every 8 weeks thereafter until disease progression (or other reasons as per Section 10 of 
the protocol). A window of ±7 days is allowed. If treatment has been delayed for any reason, the disease 
evaluations must be performed according to the original schedule, regardless of any changes to the dosing 
regimen.
The primary endpoint is PFS, which is defined as the duration from the date of randomization to either 
progressive disease or death, whichever comes first. Disease progression will be determined according to 
the IMWG criteria (Durie 2006, Rajkumar 2011)8,37.
The secondary efficacy endpoints include:

Time to disease progression (TTP) is defined as the time from the date of randomization to the date 
of first documented evidence of PD, as defined in the IMWG criteria. For subjects who have not 
progressed, data will be censored at the date of the disease evaluation before the start of any 
subsequent anti-myeloma therapy.

CR rate, defined as the percentage of subjects achieving CR, as defined by:

Negative immunofixation of serum and urine, and

Disappearance of any soft tissue plasmacytomas, and

<5% PCs in bone marrow

For those subjects with negative or low SPEP (≤0.2 g/L) and suspected daratumumab 
interference on immunofixation, a reflex assay using anti-idiotype antibody will be utilized to
confirm daratumumab interference and rule out false positive immunofixation. Subjects who 
have confirmed daratumumab interference, but meet all other clinical criteria for CR or sCR, 
will be considered CR/sCR.

MRD negativity rate, defined as the proportion of subjects who have negative MRD at any time 
point after the date of randomization.

Progression-free Survival on Next line of Therapy (PFS2), defined as the time from randomization to 
progression on the next line of treatment or death, whichever comes first. Disease progression will be 
based on investigator judgment. Subjects who are still alive and not yet progressed on the next line 
of treatment will be censored on the last date of follow-up.

Time to next treatment, defined as the time from randomization to the start of the next-line treatment.

Overall response rate (ORR), defined as the proportion of subjects who achieve PR or better
according to the IMWG criteria, during or after the study treatment.

sCR rate, defined as the percentage of subjects achieving CR in addition to having a normal FLC 
ratio and an absence of clonal cells in bone marrow by immunohistochemistry, immunofluorescence, 
2-4 color flow cytometry.

Proportion of subjects who achieve VGPR or better, defined as the proportion of subjects achieving 
VGPR and CR (including sCR) according to the IMWG criteria during or after the study treatment at 
the time of data cutoff.

Time to response, defined as the time between randomization and the first efficacy evaluation that
the subject has met all criteria for PR or better. For subjects without response, data will be censored 
either at the date of progressive disease or, in the absence of progressive disease, at the last disease 
evaluation before the start of subsequent anti-myeloma therapy.
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
Duration of response, calculated from the date of initial documentation of a response (CR or PR) to 
the date of first documented evidence of progressive disease, as defined in the IMWG criteria. For 
subjects who have not progressed, data will be censored at the last disease evaluation before the start 
of any subsequent anti-myeloma therapy.

OS, measured from the date of randomization to the date of the subject’s death. If the subject is alive 
or the vital status is unknown, then the subject’s data will be censored at the date the subject was last 
known to be alive.

Impact of D-VMP compared to VMP on patient-reported perception of global health.

Clinical efficacy of D-VMP in high risk molecular subgroups compared to VMP alone.
Exploratory endpoints include:

Biomarkers predictive of response or resistance to daratumumab

Durability of MRD negativity
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the generation of 
antibodies to daratumumab (immunogenicity) will be obtained from all subjects in the D-VMP group 
according to the Time and Events Schedule. In the Follow-up Phase, for all subjects in Arm B (D-VMP), 
samples are to be collected 8 weeks after the last dose of daratumumab, regardless of whether there has 
been confirmed disease progression. At specified time points, venous blood samples (5 mL per sample) 
will be collected and the serum will be divided into 3 aliquots (1 aliquot for pharmacokinetic analysis, 
1 aliquot for immunogenicity assessment [when appropriate], and 1 aliquot as a back-up).
BIOMARKER EVALUATIONS
Bone marrow aspirates will be collected at screening and following treatment as outlined in the Time and 
Events Schedule. Baseline bone marrow aspirate samples will be subjected to DNA and RNA sequencing 
in order to classify subjects into high-risk molecular subgroups and to establish the myeloma clone for 
MRD monitoring.
In addition to planned bone marrow aspirate assessments, a whole blood sample will be collected from 
subjects as outlined in the Time and Events Schedule for processing to plasma and PBMCs.
SAFETY EVALUATIONS
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign measurements, 
physical examination findings, and assessment of ECOG performance status score.
During Cycle 1 at Japanese sites, an enhanced reporting, monitoring, and review of pre-specified safety 
events that occur for Japanese subjects in Arm B will be performed until a minimum of 3 subjects in Arm 
B have completed Cycle 1.
STATISTICAL METHODS
The sample size calculation is performed based on the assumption that the median PFS for the VMP 
group in this study is estimated to be 21 months. Assuming that the addition of daratumumab can reduce 
the risk of the disease progression or death by 27.6%, ie, assuming the hazard ratio (VMP vs. D-VMP) of 
0.724, which translates into a median PFS of 29 months for the D-VMP group, a total of 360 PFS events 
is needed to achieve a power of 85% to detect this hazard ratio with a log-rank test (two-sided 
alpha = 0.05). With a 20-month accrual period and an additional 21-month follow-up, the total sample 
size needed for the study is approximately 700 (350/treatment group) subjects. The sample size 
calculation has taken into consideration an annual dropout rate of 5%.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Long-term survival follow-up will continue until 330 deaths have been observed. Therefore, this study 
will achieve more than 80% power to detect a 27% reduction in the risk of death (hazard ratio=0.73) with 
a log-rank test (two-sided alpha=0.05).
Response to study treatment and progressive disease will be evaluated by a validated computer algorithm.
For the primary endpoint of PFS, the primary analysis will consist of a stratified log-rank test for the 
comparison of the PFS distribution between the 2 treatment groups. The Kaplan-Meier method will be 
used to estimate the distribution of overall PFS for each treatment. The treatment effect (hazard ratio) and 
its two-sided 95% confidence intervals are to be estimated using a stratified Cox regression model with 
treatment as the sole explanatory variable.
Details of the 2 planned interim analyses are provided in Synopsis, Overview of Study Design. After each 
interim review, the IDMC will make recommendations regarding the continuation of the study. In 
addition, the IDMC may also review cumulative safety data every 6 months besides the 2 interim 
analyses. The IDMC will no longer review study data after the database lock for the primary analysis has 
been completed.
As the superiority of daratumumab combined with VMP over VMP alone with respect to PFS was 
established at the second interim analysis, the interim PFS analysis will serve as the primary PFS 
analysis, which otherwise was to occur when approximately 360 PFS events had been observed. The date 
established for the primary PFS analysis (12 June 2017) will serve as the primary clinical cutoff date,
after which subject monitoring will be conducted according to Section 9.1.5 of the protocol. After the OS 
interim analysis (ie, when 200 deaths have occurred) subject monitoring will be conducted according to 
Section 9.1.6.
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JNJ-54767414 Daratumumab
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Approved, Date: 14 February 2018
TIME AND EVENTS SCHEDULE
Notes
Screening 
Phase
Treatment 
Phase
Follow-up 
Phase 
within 21 days 
before 
randomization
Cycle 1-9
VMP Treatment 
(6wk cycles), 
Arm A and
Arm B
Cycle 10+
Dara Treatment 
(4wk cycles),
Arm B ONLY
EOT
30 days 
after last 
dose
Prior to PD 
After PD 
(Q16wks
±2 weeks)
Study treatment should be initiated within 72 hours after randomization. The start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject. After 
EOT, subjects in both treatment arms prior to PD will continue to return for disease evaluations. After PD is documented, subjects will be followed for survival, PFS2, second primary malignancy, and 
subsequent anti-myeloma therapy. After the primary clinical cutoff date (12 June 2017), subject monitoring will be conducted as per Section 9.1.5. After the OS interim analysis, subject monitoring will be 
conducted according to Section 9.1.6.
Procedures
Informed consent
ICF must be signed before any study related procedures
Eligibility criteria
X
Demography/
Medical History
X
Height
X
Chest X-ray (or full 
chest CT scan)
Acceptable for screening if performed as part of SOC within 
42 days before randomization
X
Spirometry
FEV1 measured for subjects with COPD; acceptable for 
screening if performed as part of SOC within 42 days before 
randomization
X
ECOG
Prior to any other study procedures planned for the same day
X
Q3mo in year 1 (ie, every 12 weeks from C1D1), thereafter Q6mo (ie, every 24 weeks thereafter)
until PD, post PD Wk8, Wk16 (window ±14 days)
12-lead ECG
Acceptable for screening if performed as part of SOC within 
42 days before randomization
X
C3D1, C6D1
(±7 days)
X
Physical exam
including neurological exam
X
Symptom and disease directed exam as clinically indicated
Vital signs, weight
X
Please see following table for details
X
Blood type and 
Indirect 
AntiglobulinTest
ABO, Rh, and IAT to be assessed locally. Results will be 
included on wallet card for subjects in Arm B.
C1D1, Arm B only
Wallet Card
To be given to all subjects (in Arm A and in Arm B)
C1D1
Laboratory Assessments
Pregnancy test
For women of childbearing potential only, serum or urine 
pregnancy test within 14 days of randomization.
X
additional serum or urine pregnancy tests as clinically indicated
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
Notes
Screening 
Phase
Treatment 
Phase
Follow-up 
Phase 
within 21 days 
before 
randomization
Cycle 1-9
VMP Treatment 
(6wk cycles), 
Arm A and
Arm B
Cycle 10+
Dara Treatment 
(4wk cycles),
Arm B ONLY
EOT
30 days 
after last 
dose
Prior to PD 
After PD 
(Q16wks
±2 weeks)
Hematology
Acceptable for screening to meet CRAB criteria if performed 
as part of SOC within 42 days before randomization, but 
must also be performed within 21 days before randomization 
for other eligibility requirements.
X
Please see following table for details
X
Serum chemistry
Acceptable for screening to meet CRAB criteria if performed 
as part of SOC within 42 days before randomization, but 
must also be performed within 21 days before randomization 
for other eligibility requirements.
X
Please see following table for details
X
Daratumumab PK 
Arm B only. On dara infusion days, 1 sample is to be 
collected before the start of infusion (up to 2 hours before the 
start of the infusion) and 1 sample is to be collected after the 
end of infusion (up to 2 hours after the end of infusion). 
Samples to be sent to central laboratory. 
C1D1, C3D1, C6D1
Arm B ONLY
X
Arm B 
ONLY
8 wks after last dara dose
Arm B ONLY
Daratumumab 
immunogenicity 
Arm B only. No additional sample needed; will be taken from 
PK sample. If an infusion reaction occurs, obtain 
unscheduled blood sample as soon as possible. 
C1D1 predose 
Arm B ONLY
X
Arm B 
ONLY
8 wks after last dara dose
Arm B ONLY
Whole blood
Plasma and PBMC biomarker assessments
C1D1 predose
X
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule (window ±7 days, ePRO window ±14 days). Refer to Section 9.2 for details on efficacy evaluations
SPEP and IFE, 24-
hour UPEP and 
IFE
Sample to be sent to central laboratory. Randomization 
based on central laboratory values. After Cycle 1, IFE only 
when endogenous M-protein is 0 or nonquantifiable.
X
Q3wk in year 1, Q4wk in year 2, thereafter Q8wk until PD. Not required on C1D1 
if screening values were obtained from samples collected within the prior 14 days
Serum FLC
FLC to confirm CR and sCR. In addition, for subjects with 
light chain myeloma, perform according to schedule. Sample 
to be sent to central laboratory.
X
Q3wk in year 1, Q4wk in year 2, thereafter Q8wk until PD. Not required on C1D1 
if screening values were obtained from samples collected within the prior 14 days
Calcium, albumin
Sample to be sent to central laboratory. ISS staging based 
on central laboratory value.
X
Q3wk in year 1, Q4wk in year 2, thereafter Q8wk until PD. Not required on C1D1 
if screening values were obtained from samples collected within the prior 14 days
β2-microglobulin
Sample to be sent to central laboratory. ISS staging based 
on central laboratory value
X
Bone marrow 
aspirate/biopsy
For screening (up to 42 days before randomization) fresh 
aspirate or biopsy preferred. If not available, obtain non-
decalcified slides (bone marrow aspirate, touch preparation 
or clot selection) or FFPE block (clot section only, no bone 
marrow biopsy). Fresh biopsy or aspirate or both required to 
confirm CR/sCR. Samples for biomarker analysis to be sent 
to central laboratory.
X (Refer to 
Section 9.2.1.5
for required local 
bone marrow 
testing)
To confirm CR/sCR, assess MRD, and evaluate PD (if feasible). For subjects with 
CR/sCR, an additional bone marrow aspirate will be obtained 12, 18, 24 and 30 
months (+2 months) after first dose. A portion of all bone marrow aspirates may 
be used for other biomarker assessments (see Section 9.2.1.5 and Table 10)
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
Notes
Screening 
Phase
Treatment 
Phase
Follow-up 
Phase 
within 21 days 
before 
randomization
Cycle 1-9
VMP Treatment 
(6wk cycles), 
Arm A and
Arm B
Cycle 10+
Dara Treatment 
(4wk cycles),
Arm B ONLY
EOT
30 days 
after last 
dose
Prior to PD 
After PD 
(Q16wks
±2 weeks)
Quantitative Ig
See Section 9.2.1.2
X
C3D1, C5D1, 
C7D1, C9D1
Every 4 months until 
PD
Arm B ONLY
X
Every 3 months 
in Year 1, then 
every 4 months 
after Year 1 until 
PD
Lytic disease 
assessment
Acceptable for screening if performed as part of SOC within 
42 days before randomization
X
As clinically indicated, using the same methodology as used at screening
Extramedullary 
plasmacytomas
Subjects with history of plasmacytoma; acceptable for 
screening if performed as part of SOC within 42 days before 
randomization
X
If applicable, by physical exam Q6wks, by radiologic exam (if required) Q12wks, 
using the same methodology as used at screening. For subjects with history of 
plasmacytoma assessed by physical exam, repeat assessment on C1D1 if not 
done within 14 days prior to randomization.
PRO
EORTC-QLQ-30, EQ-5D-5L, collected using an electronic 
device (ePRO)
X
Q3mo in year 1 (ie, every 12 weeks from C1D1), thereafter Q6mo (ie, every 24 weeks thereafter)
until PD, post PD Wk8, Wk16 (window ±14 days); preferably to be completed prior to any other 
study procedures at that study visit
Follow-up
Survival, PFS2, second primary malignancy, subsequent anti-myeloma therapy
Q16wk
Ongoing Subject Review
Adverse Events
See Section 12 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Concomitant 
Medications
See Section 8 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Abbreviations to the Time and Events Schedules:
AE=adverse event; Arm A=VMP alone for nine 6-week cycles; Arm B=VMP + daratumumab for nine 6-week cycles, then daratumumab monotherapy until PD; C=cycle; COPD=chronic 
obstructive pulmonary disease; CR=complete response; CRAB=calcium elevation, renal insufficiency, anemia, and bone abnormalities; D=day; Dara=daratumumab; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End-of-Treatment; FEV1=Forced Expiratory Volume (in 1 second); FFPE=formalin-fixed paraffin embedded; 
FLC=free light chain; hr=hour; ICF=informed consent form; IFE=immunofixation; Ig=immunoglobulin; ISS=International Staging System; MRD=minimal residual disease; MRI=magnetic 
resonance imaging; OS=overall survival; PBMC=peripheral blood mononuclear cell ; PD=disease progression; PFS2=time from randomization to progression on the next line of therapy or 
death, whichever comes first; PK=pharmacokinetics; PRO=patient-reported outcomes; Q(3)(6)mo=every (3)(6) months; Q(3)(4)(8)(16)wk=every (3)(4)(8)(16) weeks; Q(2)(3)cycle=every 
(2)(3) cycles; SAE=serious adverse event; SC=subcutaneous; sCR=stringent complete response; SIPPM=Site Investigational Product Procedures Manual (or equivalent document); 
SOC=standard of care; SPEP=serum M-protein quantitation by electrophoresis; UPEP=urine M-protein quantitation by electrophoresis; VMP=VELCADE-melphalan-prednisone; 
Wk=week.
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TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 1 (VMP TREATMENT PHASE)
Notes
Week 
1
Week 
2
Week 3
Week 
4
Week 
5
Week 6
D1
D2
D3
D4
D8
D11
D15
D22
D25
D29
D32
D36
Study treatment should be administered in the following order: prednisone, daratumumab, VELCADE, and melphalan. Cycles are based on the administration of VELCADE. The start of each cycle may occur 
±3 days of the scheduled day in order to accommodate the schedule of the site or subject
Hematology
Local lab. Required for subjects in both treatment arms. For 
C1D1, no need to repeat tests if done within past 5 days. 
Testing may be performed up to 2 days before other 
treatment days. Results of hematology tests must be 
evaluated before administration of treatment. Perform at 
additional time points, as clinically indicated.
X
X
X
X
X
X
Clinical Chemistry
X
X
Weight
If weight changes by more than 10% from baseline, the dose 
of all study treatments will be re-calculated
X
Vital Signs
Vital signs (blood pressure, heart rate, temperature) 
measured in sitting position for subjects in both treatment 
arms. Additionally, for Arm B only, on Cycle 1 Day 1 before 
the start of dara infusion; at 0.5, 1, 1.5, 2, 3.5 hr after start of 
infusion; at end of infusion; 0.5,1 hr after end of infusion. For 
all other infusions, vital signs measured before start and at 
end of dara infusion.
X
X
X
X
X
X
Diary review
Accountability/exposure check
X
Pre-infusion Medications, Arm B only
Dexamethasone
Administer approximately 1 hour before dara infusion. PO 
pre-infusion medications may be administered within 3 hours 
before the infusion.
Dexamethasone 20 mg IV or PO. Substitutions for 
dexamethasone allowed, see Attachment 6. 
An antihistamine (diphenhydramine 25-50 mg IV or PO, or 
equivalent H1 blocker), see Attachment 5
Paracetamol (acetaminophen) 650-1000 mg IV or PO
Leukotriene inhibitor, montelukast 10 mg PO or equivalent, 
optional, C1D1
X
X
X
X
X
X
Antihistamine
X
X
X
X
X
X
Paracetamol
X
X
X
X
X
X
Leukotriene Inhibitor
(optional)
X
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
Notes
Week 
1
Week 
2
Week 3
Week 
4
Week 
5
Week 6
D1
D2
D3
D4
D8
D11
D15
D22
D25
D29
D32
D36
Study Treatment, Arm A and Arm B
Prednisone
Dispense on Day 1 for self-administration. Prednisone taken 
on Day 1 in Arm A only (dexamethasone will be given on 
Day 1 in Arm B), taken on Day 2-4 in both Arms.
X
X
X
X
VELCADE
Administer by SC injection. Dose may be delayed up to 
48 hrs, however subsequent doses must be adjusted to 
account for delay as all VELCADE doses should be at least 
72 hrs apart. Doses that need to be withheld are skipped and 
will not be made up later in the cycle. Individual doses within a 
cycle have a ±1 day window
X
X
X
X
X
X
X
X
Melphalan
Dispense on Day 1 for self-administration.
X
X
X
X
Study Treatment, Arm B only
Daratumumab
Refer to SIPPM for recommendations on daratumumab 
infusion rate. Skip if infusion cannot be given within 3 days.
Individual doses within a cycle have a ±1 day window.
X
X
X
X
X
X
TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 2 TO 9 (VMP TREATMENT PHASE)
Notes
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
D1
D2
D3
D4
D8
D11
D15
D22
D25
D29
D32
D36
Study treatment should be administered in the following order: prednisone, daratumumab, VELCADE, and melphalan. Cycles are based on the administration of VELCADE. The start of each cycle 
may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject
Hematology
Local lab. Required for subjects in both treatment arms. 
Testing may be performed up to 2 days before treatment 
day. Results of hematology tests must be evaluated before 
administration of treatment. Perform at additional time
points, as clinically indicated.
X
X
Clinical 
Chemistry
X
X
Weight
If weight changes by more than 10% from baseline, the 
dose of all study treatments will be re-calculated
X
Vital Signs
Vital signs (blood pressure, heart rate, temperature) 
measured in sitting position for subjects in both treatment 
arms. Additionally, for Arm B, vital signs before start and at 
end of dara infusion.
X
X
Diary review
Accountability/exposure check
X
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
Notes
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
D1
D2
D3
D4
D8
D11
D15
D22
D25
D29
D32
D36
Pre-infusion Medications, Arm B only
Dexamethasone
Administer approximately 1 hour before dara infusion. PO 
pre-infusion medications may be administered within 3 
hours before the infusion.

Dexamethasone 20 mg IV or PO. Substitutions for 
dexamethasone allowed, see Attachment 6. 

An antihistamine (diphenhydramine 25-50 mg IV or 
PO, or equivalent H1 blocker), see Attachment 5

Paracetamol (acetaminophen) 650-1000 mg IV or PO
X
X
Antihistamine
X
X
Paracetamol
X
X
Study Treatment, Arm A and Arm B
Prednisone
Dispense on Day 1 for self-administration. Prednisone taken 
on Day 1 in Arm A only (dexamethasone will be given on 
Day 1 in Arm B), taken on Day 2-4 in both Arms.
X
X
X
X
VELCADE
Administer by SC injection. Dose may be delayed up to 
48 hrs, however subsequent doses should be adjusted to 
account for delay as all VELCADE doses must be at least 
72 hrs apart. Doses that need to be withheld are skipped 
and will not be made up later in the cycle. Individual doses 
within a cycle have a ±1 day window.
X
X
X
X
Melphalan
Dispense on Day 1 for self-administration.
X
X
X
X
Study Treatment, Arm B only
Daratumumab
Refer to SIPPM for recommendations on daratumumab 
infusion rate. Skip if infusion cannot be given within 1 wk.
Individual doses within a cycle have a ± 1 day window.
X
X
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
TIME AND EVENTS SCHEDULE FOR STUDY TREATMENT, CYCLE 10+ (DARA TREATMENT PHASE, ARM B ONLY)
Notes
Day 1 every 4 weeks
The start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject.
Hematology
Local lab. Testing may be performed up to 2 days before treatment 
day. Results of hematology tests must be evaluated before each 
infusion. Perform at additional time points, as clinically indicated.
AST and ALT every 3 cycles.
X
Clinical Chemistry
X
Weight
If weight changes by more than 10% from baseline, the dose of all 
study treatments will be re-calculated
X
Vital Signs
Vital signs (blood pressure, heart rate, temperature) measured in 
sitting position before start and at end of daratumumab infusion.
X
Pre-infusion Medications, Arm B only
Dexamethasone
Administer approximately 1 hour before dara infusion. PO 
pre-infusion medications may be administered within 3 hours 
before the infusion

Dexamethasone 20 mg IV or PO. Substitutions for 
dexamethasone allowed, see Attachment 6. 

An antihistamine (diphenhydramine 25-50 mg IV or PO, or 
equivalent H1 blocker), see Attachment 5

Paracetamol (acetaminophen) 650-1000 mg IV or PO
X
Antihistamine
X
Paracetamol
X
Study Treatment, Arm B only
Daratumumab
Refer to SIPPM for recommendations on daratumumab infusion 
rate. Skip if infusion cannot be given within 2 wks.
X
NCT02195479


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
ABBREVIATIONS
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
AE
adverse event
ALT
alanine aminotransferase
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
BM-MNC
bone marrow mononuclear cell
BSA
body surface area
BUN
blood urea nitrogen
CDC
complement-dependent cytotoxicity
CKD-EPI
chronic kidney disease epidemiology collaboration
CL
total systemic clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration
COPD
chronic obstructive pulmonary disease
CR
complete response
CRAB
calcium elevation, renal insufficiency, anemia, and bone abnormalities
CrCl
creatinine clearance
CT
computed tomography
dara
daratumumab 
DLCO
diffusing capacity of the lung for carbon monoxide
DLT
dose limiting toxicity
DTT
dithiothreitol
D-VMP
daratumumab plus VELCADE-melphalan-prednisone
EBMT
European Group for Blood and Marrow Transplantation
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EU
European Union
FEV1
forced expiratory volume (in 1 second)
FFPE
formalin fixed paraffin embedded
FISH
fluorescence in situ hybridization
FLC
free light chain
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
HIV
human immunodeficiency virus
HR
hazard ratio
IAT
indirect antiglobulin test (also known as indirect Coombs test)
ICF
informed consent form
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFE
immunofixation
Ig
immunoglobulin
IHC
immunohistochemistry
IMiD
immunomodulatory agent
IMWG
International Myeloma Working Group
IRB
Institutional Review Board
IRR
infusion-related reaction
ISS
International Staging System
IV
intravenous
IWRS
interactive web response system
LDH
lactic acid dehydrogenase
LVEF
left ventricular ejection fraction
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3007 Amendment 5
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Approved, Date: 14 February 2018
mAb
monoclonal antibody
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MP
melphalan-prednisone
MPT
melphalan-prednisone-thalidomide
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRU
medical resource utilization
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next generation sequencing
NK
natural killer
OR
overall response
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PC
plasma cell
PD
disease progression
PFS
progression-free survival
PFS2
time from randomization to progression on the next line of therapy or death, whichever comes first
PI
proteasome inhibitor
PK
pharmacokinetics
PO
per oral
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome(s)
QD
once daily
QIg
quantitative immunoglobulins
RBC
red blood cell
Rd
lenalidomide plus low-dose dexamethasone
SAE
serious adverse event
SC
subcutaneous injection
sCR
stringent complete response
SCT
stem cell transplantation
SIPPM
Site Investigational Product Procedures Manual (or equivalent document)
SPEP
serum M-protein quantitation by electrophoresis
TTP
time to progression
ULN
upper limit of normal
UPEP
urine M-protein quantitation by electrophoresis
US
United States
V
volume of distribution
VD
VELCADE-dexamethasone
VGPR
very good partial response
VISTA
“VELCADE as Initial Standard Therapy in multiple myeloma” study
VMP
VELCADE-melphalan-prednisone
VMPT
VELCADE-melphalan-prednisone-thalidomide
VP
VELCADE-prednisone
VT
VELCADE-thalidomide
VTD
VELCADE-thalidomide-dexamethasone
VTP
VELCADE-thalidomide-prednisone
WHO
World Health Organization
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1.
INTRODUCTION
1.1.
Background
1.1.1.
Multiple Myeloma
Multiple myeloma is a malignant disorder of the plasma cells, characterized by uncontrolled and 
progressive proliferation of a plasma cell clone. The disease leads to progressive morbidity and 
eventual mortality by lowering resistance to infection and causing significant skeletal destruction 
(with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, neurological 
complications and hyperviscosity syndrome.
The majority of patients with multiple myeloma produce a monoclonal protein, also called 
paraprotein, M-protein or M-component, which is an immunoglobulin (Ig) or a fragment of one 
that has lost its function (Kyle 2009, Palumbo 2011).19,33 Normal immunoglobulin levels are 
compromised, leading to susceptibility of infections. The proliferating multiple myeloma cells 
displace the normal bone marrow leading to dysfunction in normal hematopoietic tissue and 
destruction of the normal bone marrow architecture, which is reflected by clinical findings such 
as anemia, neurologic symptoms, and bone resorption seen as diffuse osteoporosis or lytic 
lesions shown in radiographs (Kyle 2003).18 Furthermore, hypercalcemia, renal insufficiency or 
failure, and detectable monoclonal protein in the serum or urine are frequently seen (Palumbo 
2011).33 A small minority of patients with multiple myeloma are non-secretory.
At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that varies 
on the basis of both disease- and host-related factors (eg, age, renal function, stage, chromosomal 
abnormalities). Multiple myeloma causes significant morbidity and mortality. It accounts for 
approximately 1% of all malignancies and 13% of hematologic cancers. Approximately 
50,000 patients per year are diagnosed with multiple myeloma in the EU and US, and 
30,000 patients per year die due to multiple myeloma (ACS 2013, Ferlay 2010).1,11
1.1.2.
Treatment Options for Multiple Myeloma
Treatment choices for multiple myeloma vary with age, performance status, comorbidity, the 
aggressiveness of the disease, and related prognostic factors (Palumbo 2011).33 Newly diagnosed 
patients with multiple myeloma are typically categorized into 2 subpopulations usually defined 
by their age and suitability for the subsequent approach to treatment. Younger patients will 
typically receive an induction regimen followed by consolidation treatment with high-dose 
chemotherapy and autologous stem cell transplantation (ASCT). For those not considered 
suitable for high-dose chemotherapy and ASCT, longer-term treatment with multi-agent 
combinations including alkylators, high-dose steroids, and novel agents are currently considered 
as standards of care.
The availability of different efficacious multi-agent regimens has provided clinicians with the 
opportunity of tailoring treatment for each patient. Selection is based on patients' comorbidities 
and biologic age, while at the same time, taking into account the expected toxicity profiles of 
each treatment regimen (Gay 2011).12
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1.1.3.
Transplant-ineligible Population
In general, patients over the age of 65 or with significant comorbidities are usually not 
considered eligible for more intensive forms of first line therapy, and as a result the treatment 
approach often favors longer, less-intensive/toxic treatments (Gay 2011).12
Treatment 
traditionally consists of systemic chemotherapy, with adjunctive use of radiation or surgery in 
selected cases associated with extramedullary disease (NCCN 2013, Palumbo 2009, Smith 
2005).30,36,40 For many years, the oral combination melphalan-prednisone (MP) was considered 
the standard of care for patients with multiple myeloma who were not eligible for ASCT (Gay 
2011).12 The advent of immunomodulatory agents (IMiD) and proteasome inhibitors (PI) has led 
to a multiplicity of new treatment options for newly diagnosed patients not considered suitable 
for transplant based therapy. In Europe, the standard of care are combinations such as melphalan-
prednisone-thalidomide (MPT) (Fayers 2011)10, or VELCADE-melphalan-prednisone (VMP)
(San Miguel 2008).39 VELCADE in combination with melphalan and prednisone are approved in 
this setting within numerous countries worldwide including the European Union and the US.
1.1.4.
Treatment Until Progression in Transplant-ineligible Patients
There is growing evidence that continued treatment of multiple myeloma can prolong the period 
of remission; however, long-term treatment with current therapies is often compromised through 
unacceptable toxicity.
The VMP regimen is typically given for up to a year; the VISTA study (VELCADE as Initial 
Standard Therapy in multiple myeloma [VISTA]) demonstrated that complete responses 
continued to occur in the later cycles (Cycles 5-9) (Harousseau 2010).14 Furthermore, the study 
demonstrated that the longer patients were on treatment, the better the outcomes.
VELCADE, given to disease progression, has been investigated in combination with other agents 
in the transplant-ineligible population. In a study of 178 elderly untreated patients who were 
initially treated with an induction combination regimen comprising either VMP or 
VELCADE-thalidomide-prednisone (VTP), patients were treated until progression with either 
VELCADE-thalidomide (VT) or VELCADE-prednisone (VP). Progression-free survival or OS 
was not significantly different between the 2 treatment groups, but both resulted in median PFS 
of 32 (VP) to 39 (VT) months and a 5-year OS over 50% in both arms (Mateos 2012).27
In another randomized comparison of VELCADE- melphalan-prednisone- thalidomide (VMPT)
followed by continuous VT as maintenance, or VMP with no additional continuous therapy in 
511 previously untreated patients who were not eligible for transplant (aged 65 years or older), 
the arm with VMPT induction followed by the continuous VT therapy showed superiority over 
the VMP alone arm. The 3-year estimates of PFS were 56% in patients receiving VMPT-VT and 
41% in those receiving VMP (p=0.008) (Palumbo 2010).35
Further justification for continuous treatment until progression was demonstrated in a large, 
randomized Phase 3 study (MM-020/IFM 07-01) comparing 2 active-treatment arms consisting 
of different durations of lenalidomide plus low-dose dexamethasone (Rd) to a third active control 
arm of MPT in subjects newly diagnosed with multiple myeloma (Facon 2013).9 In this study, 
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1,623 subjects who were ineligible for ASCT were randomized to receive continuous Rd until 
disease progression (Arm A); Rd for eighteen 28-day cycles (72 weeks) (Arm B); or MPT for up 
to twelve 42-day cycles (72 weeks) (Arm C). The primary endpoint of the study is PFS
(Arm A vs Arm C). Secondary endpoints included OS, response rate, quality of life and safety. 
Continuous treatment with Rd significantly improved the primary endpoint of PFS compared 
with MPT. After a median follow-up of 37 months, the trial met the primary endpoint, 
demonstrating a 28% reduction in risk of progression or death (HR=0.72; p=0.00006). The 
preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of 
Arm A vs Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p<0.0096) was 
not crossed. All other secondary endpoints (ORR [PR or better], OR, and PFS2) consistently 
showed improvement in favor of Arm A vs. Arm C. The safety profile of Rd was manageable, 
with reduced hematologic second primary malignancies compared with MPT.
1.2.
Daratumumab
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed 
towards tumor cells that express high levels of CD38, such as plasma cells from patients with 
multiple myeloma. This target is distinct from those of other approved agents for multiple 
myeloma therapy.
For the most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the latest version of the Investigator's Brochure 
(IB Daratumumab 2013).16
1.2.1.
Nonclinical Studies
Based on preclinical data, daratumumab may utilize multiple effector cell functions, resulting in 
immune mediated killing of tumor cells. In ex vivo experiments utilizing human bone marrow 
stromal cells co-cultured with primary multiple myeloma cells, complement-dependent 
cytotoxicity (CDC) occurs rapidly and demonstrates maximal myeloma cell killing by 
daratumumab within 1 hour of antibody-mediated activation of the complement proteins (de 
Weers 2011).6 Daratumumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) is 
slower in its action, with maximal ADCC by daratumumab observed at 4 hours in vitro (de 
Weers 2011).6 Daratumumab has also been shown to induce antibody-dependent cellular 
phagocytosis (ADCP) in the presence of macrophages within 4 hours in vitro (Overdijk 2013).32
The precise role of some or all of these effector functions in reducing tumor burden in patients is 
unknown.
In toxicology studies in cynomolgus monkeys and chimpanzees, the major observed toxicities 
were cytokine release syndrome and thrombocytopenia along with a minor decrease in red blood 
parameters. Cytokine release was seen only following the first dose and was markedly reduced 
following implementation of a 10-mg predose of daratumumab. The effect on platelets and red 
cells was reversible.
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Preclinical evidence to support combining VMP with daratumumab is based on results of ex vivo 
flow cytometry-based assay platform, in which the addition of daratumumab to VMP 
significantly increased the treatment effect by almost doubling the bone marrow mononuclear 
cells lysis levels (van der Veer 2011a).42
In study GMB3003-070, the potential benefit of combining daratumumab with multi-drug 
chemotherapy regimens was evaluated in fresh tumor cells from subjects with multiple myeloma 
(data on file). Lysis of primary tumor cells was measured directly in bone marrow mononuclear 
cell (BM-MNC) isolates obtained from subjects with multiple myeloma. Synergistic tumor cell 
lysis was demonstrated when daratumumab was combined with lenalidomide and/or VELCADE, 
even in samples from subjects that were refractory to lenalidomide and VELCADE treatment. 
Treatment of BM-MNC with lenalidomide or VELCADE resulted in 10% and 18% lysis, 
respectively. A combination of lenalidomide and VELCADE resulted in 25% lysis of BM-MNC. 
When daratumumab was added to either lenalidomide or VELCADE, a 2-fold increase in lysis 
was observed compared with lenalidomide or VELCADE alone. When daratumumab was added 
to combinations of dexamethasone, lenalidomide and VELCADE or to VELCADE, prednisone, 
and melphalan, the cell lysis was significantly increased (p<0.001) compared with the triple 
combination alone (no daratumumab) (van der Veer 2011a).42 Refer to Figure 1 and Figure 2.
Figure 1:
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents
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Figure 2:
Dose-dependent Lysis of Multiple Myeloma cells in Triple Chemotherapy Treatments
1.2.2.
Clinical Studies
1.2.2.1.
Single-Agent Daratumumab Studies (GEN501 and MMY2002)
Two single-agent studies with daratumumab are ongoing (Studies GEN501 and MMY2002), as 
described in Table 1.
Among the 32 subjects treated in Part 1 of Study GEN501, the maximum tolerated dose (MTD) 
was not reached following intravenous (IV) infusions up to 24 mg/kg. Two subjects experienced 
dose-limiting toxicities (DLTs) in the lower dose cohorts (a subject in the 0.1-mg/kg group had 
Grade 3 anemia and Grade 4 thrombocytopenia, and a subject in the 1.0-mg/kg group had 
Grade 3 aspartate aminotransferase increased). 
Among the 51 subjects treated in Part 2 of Study GEN501, serious adverse events (SAEs) were 
reported in 37% of subjects (43% of subjects in the 8-mg/kg group and 29% of subjects in the 
16 mg/kg-group). The most frequently reported SAEs were pneumonia (6% subjects), and 
pyrexia (4% of subjects).
Among the 34 subjects treated in Stage 1 of Study MMY2002, SAEs were reported in 27% of 
subjects (33% of subjects in the 8 mg-kg group, and 19% of subjects in the 16 mg/kg-group). 
The most frequently reported SAE was renal failure acute (6% of subjects).
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Table 1:
Daratumumab Single-Agent Studies GEN501 and MMY2002
Study Number
Study Design
Number of subjects Treated/
Treatment Regimen
GEN501
Open-label, Phase 1/2, first-in-human, 
single-agent study in subjects with 
multiple myeloma whose disease is 
relapsed or refractory to at least 2 prior 
lines of therapies
Population was heavily treated with prior 
treatment, including ASCT, 
chemotherapy based regimens, IMiDs, 
and PIs
Part 1
n=32 total treated with daratumumab weekly
0.005-1 mg/kg (n=17)
2 mg/kg (n=3)
4 mg/kg (n=3)
8 mg/kg (n=3)
16 mg/kg (n=3)
24 mg/kg (n=3)
Part 2
n=51 total treated
8 mg/kg (n=30)
Weekly for 8 weeks, 
followed by q2w for an 
additional 16 weeks, and 
monthly thereafter
16 mg/kg (n=21)
First dose, followed by a 3-
week resting period, followed 
by weekly doses for 7 weeks, 
then q2w for an additional 14 
weeks, and monthly 
thereafter
MMY2002
Open-label, multicenter, 2-stage, Phase 2 
study of daratumumab for the treatment 
of subjects with multiple myeloma who 
have received at least 3 prior lines of 
therapy including a PI and an IMiD or 
whose disease is double refractory to 
both a PI and an IMiD
n=34 total treated in Stage 1
8 mg/kg (n=18)
q4w
16 mg/kg (n=16)
qw for 8 weeks, then q2w for 
another 16 weeks, and then 
q4w thereafter
ASCT=autologous stem cell transplantation; IMiD=immunomodulatory agent; PI=proteasome inhibitor; q2w=every 2 weeks; 
q4w=every 4 weeks
1.2.2.2.
Combination Daratumumab Studies
One study of daratumumab in combination with lenalidomide and dexamethasone 
(Study GEN503), and one study of daratumumab in combination with various backbone 
treatment regimens (Study MMY1001) are ongoing (Table 2).
Based on preliminary efficacy data, 15 of 20 subjects treated in Study GEN503 have achieved a 
PR or better following treatment with daratumumab in combination with lenalidomide and 
dexamethasone.
The safety profile observed in Study GEN503 is consistent with historical safety data for 
lenalidomide and dexamethasone. Doses ranged from 2 mg/kg to 16 mg/kg daratumumab, in 
combination with the approved doses of lenalidomide (25 mg daily Days 1-21 of 28 days) and 
dexamethasone (40 mg weekly). No dose-limiting toxicity (DLT) drug-related safety signals 
have been observed in this heavily pre-treated population of subjects with advanced multiple 
myeloma. The Part 2 daratumumab dose was determined to be 16 mg/kg. Across all dose cohorts
in Part 1 and in the 16 mg/kg expansion cohort for Part 2, the most frequently reported Grade 3 
or higher AE was neutropenia (6 subjects), which is a known toxicity of lenalidomide. Eight 
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serious adverse events (SAEs) have been reported. All SAEs were assessed by the investigator as 
not related to daratumumab. Four subjects experienced infusion-related reactions during the first 
infusion of daratumumab. These events were determined by the investigator to be related to 
daratumumab. In all instances, daratumumab was interrupted temporarily and restarted without 
complication or further incident.
In Study MMY1001, 5 subjects have been enrolled to the VMP plus daratumumab cohort as of 
21 May 2014. The same dose and schedule used in MMY1001 will be utilized in the present 
study. Emerging safety data will be communicated as appropriate.
Table 2:
Daratumumab Combination Studies GEN503 and MMY1001
Study Number
Study Design
Treatment Regimen
Status/Estimated 
Start Date
Number of 
subjects 
Treated/Planned
GEN503
Open-label, Phase 1/2 multicenter, dose-
escalating study investigating the safety of 
daratumumab in combination with 
lenalidomide and dexamethasone in subjects 
with relapsed or refractory multiple myeloma
Phase 1: 
2-16 mg/kg daratumumab, in 
combination with lenalidomide 
(25 mg daily Days 1-21 of 28 
days) and dexamethasone (40 mg 
weekly)
Phase 1: Ongoing 
(n=13 subjects 
treated)
2 mg/kg (n=3)
4 mg/kg (n=3)
8 mg/kg (n=4)
16 mg/kg (n=3)
Phase 2: 
16 mg/kg daratumumab, in 
combination with lenalidomide 
(25 mg daily Days 1-21 of 28 
days) and dexamethasone (40 mg 
weekly)
Phase 2:
n=18 subjects treated 
approximately 30 
subjects planned
MMY1001
Open-label, non-randomized, multicenter, 
Phase 1b study to evaluate the safety, 
tolerability, and dose regimen of 
daratumumab in combination with various 
backbone treatment regimens for multiple 
myeloma in either newly diagnosed or those 
who have received at least 2 prior therapies, 
depending on backbone treatment regimen
Daratumumab 16 mg/kg 
(initially, with possibility to de-
escalate, if necessary)
The backbone regimens to be 
combined with daratumumab 
include VELCADE-
dexamethasone (VD), VMP, 
VTD, and Pom-dex
n=18 subjects treated
VTD (n=6)
VMP (n=5)
Vd (n=1)
Pom-dex (n=6)
approximately 48 
subjects planned; 12 
per cohort
Pom-dex=pomalidomide-dexamethasone; VMP-VELCADE-melphalan-prednisone; VTD=VELCADE-thalidomide-
dexamethasone
Phase 3 combination studies include study MMY3003 comparing daratumumab, lenalidomide, 
and dexamethasone with Rd and study MMY3004 comparing daratumumab, VELCADE, and 
dexamethasone with Vd. Both ongoing studies are in patients with relapsed or refractory multiple 
myeloma.
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1.3.
Overall Rationale for the Study
Multiple myeloma remains incurable with standard chemotherapy, despite the availability of 
multi agent therapy. Strategies directed at improving and maintaining response for longer periods 
of time and new treatment options directed at alternative mechanisms are also urgently needed 
for patients with multiple myeloma.
The clinical utility of adding VELCADE to melphalan and prednisone (VMP) for the treatment 
of patients 65 years or older was investigated in the VISTA study (San Miguel 2008).39 The 
study demonstrated significant improvements in both time to progression and overall survival
compared to MP alone. In terms of response rate, 30% of patients in the VMP group had a 
complete response versus only 4% in the MP group (p<0.001). Median time to progression was 
24.0 months in the VMP group compared to 16.6 months in the MP group (HR=0.48, p<0.001). 
Median time to subsequent myeloma therapy was 20.8 months in the MP group and was not 
reached in the VMP group (p<0.001). After a median follow-up of 16.3 months, 45 patients 
(13%) in the VMP group and 76 patients (22%) in the MP group had died (hazard ratio in the 
VMP cohort=0.61, p=0.008); median survival was not reached in either group. As a result, VMP 
is now established as a standard of care in numerous countries worldwide.
Recent studies have indicated that multiple drug combinations are superior over single- or 
double-agent combinations in treating multiple myeloma (van der Veer 2011a).42 In particular, 
VELCADE-based treatment regimens have demonstrated significant improvements in response, 
progression-free survival (PFS), and overall survival (OS) compared with non-VELCADE-based 
therapy, both in newly diagnosed transplant ineligible patients and those suitable for induction 
and transplant (Sonneveld 2013, Dimopoulos 2009).41,7
Daratumumab’s immediate and effective cell mediated (and potentially direct) cytotoxic effects 
against multiple myeloma cells, combined with the observed remarkable synergy with 
VELCADE (even in samples from patients who are refractory to VELCADE), may potentially 
improve the clinical outcome for patients with multiple myeloma when combined with a 
VELCADE-based combination regimens (van der Veer 2011a).42 This study will explore the 
efficacy and safety of the combination of daratumumab and VMP in subjects who are not 
eligible for ASCT.
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2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to determine if the addition of daratumumab to VMP will prolong PFS 
compared with VMP. 
Secondary Objectives
The secondary objectives are:

To determine if the addition of daratumumab to VMP will improve clinical outcome as 
measured by:

Time to disease progression (TTP)

CR rate

Minimal residual disease (MRD) negativity rate

PFS2 (defined as time from randomization to progression on the next line of therapy or 
death, whichever comes first)

Time to next treatment

Overall response rate (partial response [PR] or better)

Stringent CR (sCR) rate

Very good partial response (VGPR) or better rate

Time to response

Duration of response

Overall survival

To assess patient-reported outcomes and heath economic/resource utilization

To determine the pharmacokinetics and immunogenicity of daratumumab

To assess the safety and tolerability of daratumumab when administered in combination with 
VMP

To evaluate clinical efficacy of daratumumab when added to VMP in high risk molecular 
subgroups.
Exploratory Objective

To explore biomarkers predictive of response and resistance to therapy.

To assess durability of MRD negativity
2.2.
Hypothesis
The hypothesis of the study is that daratumumab continued until disease progression, in 
combination with 9 cycles of VMP, will improve PFS compared with 9 cycles of VMP alone.
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3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, parallel-group, controlled, multicenter study in subjects at least 
18 years of age with previously untreated multiple myeloma who are ineligible for high dose 
therapy. A target of up to 700 subjects will be enrolled in this study with 350 subjects planned 
per treatment arm. A diagram of the study design is provided in Figure 3.
Figure 3:
Schematic Overview of the Study
Dara=daratumumab; PD=disease progression; Q4wks=every 4 weeks; Q16wks=every 16 weeks; 
VMP=VELCADE-melphalan-prednisone
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 21 days before randomization.  All subjects will receive up to 
9 cycles of the VMP regimen (1 cycle = 6 weeks) with or without daratumumab.
The Treatment Phase will extend from Day 1 of Cycle 1 to discontinuation of all study treatment. 
Eligible subjects will be stratified by International Staging System (I vs II vs III), region (Europe 
vs Other), and age (<75 vs ≥75) and then randomized in a 1:1 ratio. Subjects in both treatment 
arms will receive 1.3 mg/m2 VELCADE by subcutaneous injection (SC) twice weekly (Weeks 1, 
2, 4, and 5) in Cycle 1 followed by once weekly (Weeks 1, 2, 4, and 5) in Cycles 2 to 9. 
Melphalan PO at 9 mg/m2 and prednisone PO at 60 mg/m2 will be self-administered on Day 1-4 
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of each VELCADE cycle. For subjects randomized to the Treatment Arm B, 20 mg of 
dexamethasone will substitute for the planned dose of prednisone on Day 1 of each cycle. In this 
setting, dexamethasone will be utilized as the treatment dose of steroid for that particular day, as 
well as the required pre-medication prior to daratumumab infusion. Daratumumab 16 mg/kg will 
be administered to subjects in Treatment Arm B by IV infusion once every week for 6 weeks
(Cycle 1; 1 VELCADE cycle); then once every 3 weeks for 16 additional doses (Cycles 2-9). 
Measures to prevent infusion related reactions (IRRs) will include pre-infusion medication with 
dexamethasone, paracetamol, and antihistamine before each daratumumab infusion.
After completion of the VMP cycles, subjects in Arm A will enter the Follow-up Phase and 
should not be started on subsequent anti-myeloma therapy without confirmed disease 
progression. Subjects in Arm B will continue to receive daratumumab every 4 weeks until 
documented progression, unacceptable toxicity, or the study ends (see below for definition). 
Subjects who need to discontinue treatment with any one component of study treatment 
(VELCADE, melphalan, prednisone, or daratumumab) may continue to receive treatment with 
the other components of study treatment, as assigned. Upon discontinuation of daratumumab, 
subjects in Arm B will also enter the Follow-up Phase and should not be started on subsequent 
anti-myeloma therapy without confirmed disease progression.
In the Follow-up Phase, subjects who discontinue treatment before disease progression must 
continue to have disease evaluations according to the Time and Events Schedule until confirmed 
PD (see Section 8.4, Subsequent Therapies), subsequent anti-myeloma treatment, death, 
withdrawal of consent, lost to follow-up, or the end of the study. After disease progression is 
documented, follow-up will be obtained at least every 16 weeks. Subsequent anti-myeloma
treatment, PFS2 (per investigator judgment), second primary malignancies, and survival will also 
be recorded.
Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety, 
will be performed after a total of approximately 100 subjects have been treated for at least 
2 cycles or discontinued the study treatment. The second interim analysis, with a purpose to 
evaluate cumulative interim safety and efficacy data, will be performed when approximately 
216 PFS events have been accumulated. As the superiority of daratumumab combined with VMP 
over VMP alone with respect to PFS was established at the second interim analysis, the interim 
PFS analysis will serve as the primary PFS analysis, which otherwise was to occur when 
approximately 360 PFS events had been observed. The date established for the primary PFS 
analysis (12 June 2017) will serve as the primary clinical cutoff date, after which subject 
monitoring will be conducted according to Section 9.1.5 of the protocol. As planned in the 
original protocol, two interim OS analyses will be performed at the time of the interim PFS (216 
events) and the primary PFS (360 events) prior to the final OS analysis at 330 deaths. The second 
interim OS will occur when 200 deaths (60% of all planned deaths) have been accumulated 
which is about the same time of the primary PFS analysis as if it would have occurred. After the 
OS interim analysis, subject monitoring will be conducted according to Section 9.1.6.
Investigators will be informed when each interim analysis is to occur. All available data prior to 
that time will be included in each of the respective analyses.
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The end of the study will occur when 330 subjects have died, or 5 years after the last subject is 
randomized, whichever comes first. The sponsor will ensure that subjects benefiting from 
treatment with daratumumab will be able to continue treatment after the end of the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to 
review efficacy and safety results at the 2 planned interim analyses. After the interim review, 
they will make recommendations regarding the continuation of the study. In addition, the IDMC 
may also review cumulative safety data every 6 months besides the two interim analyses. The 
IDMC will no longer review study data after the database lock for the primary analysis has been 
completed.
As a result of the positive second interim analysis, that established the superiority of 
daratumumab combined with VMP over VMP alone with respect to the primary endpoint (PFS), 
and consistent with the IDMC’s recommendation, the sponsor will ensure that access to 
daratumumab is provided for subjects randomized to Arm A (VMP) who have sponsor-confirmed 
disease progression (see Section 8.4, Subsequent Therapies).
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will 
be conducted on bone marrow samples. Safety evaluations will include AE monitoring, physical 
examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology 
and chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) 
performance status. Blood samples will be drawn for assessment of pharmacokinetics and 
immunogenicity.
3.2.
Study Design Rationale
Choice of VELCADE Schedule
The most common side effect of VELCADE therapy is peripheral neuropathy. In an effort to 
manage this toxicity, a number of clinical investigators have made minor adaptations to the 
VELCADE schedule in order to reduce the incidence and severity of this AE, with the intention 
of keeping patients on therapy longer; thus ensuring that patients receive appropriate intensity 
and duration of treatment with corresponding positive effects on the length of remission. A study 
comparing 2 regimens, VMP versus VMPT, as up-front therapy for patients >65 years, showed 
that the weekly infusion of VELCADE significantly reduced the incidence of Grade 3-4 
peripheral neuropathy (18% in the biweekly vs 9% in the weekly schedule for the VMPT arm, 
and 12% in the biweekly vs 3% in the weekly schedule for the VMP arm) (Table 3) without 
adversely influencing outcome (Palumbo 2008).34 The once-weekly schedule of VELCADE 
resulted in a reduced discontinuation rate and prolonged the time on therapy: in both groups, 
patients received a median of 9 cycles, and the median cumulative delivered dose of VELCADE 
was similar, 40.1 mg/m2 for twice-weekly and 39.4 mg/m2 for once-weekly regimens-
corresponding to a dose intensity of 59% for twice-weekly and 84% for once-weekly regimens 
(Bringhen 2010).2
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Table 3:
Complete responses, progression-free survival and peripheral neuropathy in all patients and in 
those who received weekly infusion of VELCADE 
VMPT (n=152)
VMP group (n=152)
All Patients
(n=152)
Subgroup with 
VELCADE weekly 
infusion (n=90)
All Patients
(n=152)
Subgroup with 
VELCADE weekly 
infusion (n=90)
CR rate (%)
31
28
16
10
2 year PFS (%)
84
87
76
78
Grade 3-4 peripheral 
neuropathy (%)
18
9
12
3
Source: (Palumbo 2008)34
Similarly, the beneficial impact of a weekly administration schedule of VELCADE was also 
shown in a Spanish multicenter study comparing VMP with VELCADE-thalidomide-prednisone 
(VTP). This study showed that VELCADE-based regimens that use an intensive dosing of 
VELCADE twice-per-week in the first cycle followed by less intensive weekly dosing, are not 
only well-tolerated, but are also an active approach for elderly populations, with similar efficacy 
for VMP and VTP (Mateos 2010).26
In a recent paper, Mateos et al evaluated the safety and efficacy of 4 different VMP regimens
(Mateos 2014).25 The VISTA study was compared to the GIMEMA MM-03-05 study (both 
once- and twice-weekly Velcade groups) and the GEM2005MAS65 study (once-weekly 
Velcade, 6 cycles). The median cumulative dose of VELCADE was notably higher in patients 
receiving twice-weekly VELCADE. Overall response rate for VMP treatment was similar 
between all the regimens and averaged between 74% to 87%. Overall survival was similar across 
all studies, however PFS was slightly longer in the GEM2005MAS65 study likely secondary to 
extended VELCADE usage for up to 3 years (38 months vs 21-25 months). Although the 
efficacy was similar, Mateos and colleagues reported that the risk of peripheral neuropathy and 
discontinuation due to AEs was much higher in the studies that utilized twice-weekly 
VELCADE vs once-weekly VELCADE. For example, the rate of Grade 3/Grade 4 peripheral 
neuropathy was 13% in VISTA and 14% in the twice-weekly GIMEMA study, but was 2% to 
7% in the once-weekly VELCADE studies. The authors concluded that regimens that 
predominantly use once-weekly VELCADE result in high efficacy, comparable to response rates 
seen in VISTA, with improved safety and tolerability.
This study will incorporate twice-weekly dosing of VELCADE in the first cycle, to obtain rapid 
reduction in plasma cell tumor burden, followed by once-weekly dosing in subsequent cycles for 
improved tolerability. The 54-week treatment duration is based on the accepted duration of 
treatment with melphalan-prednisone. Note that for ease of reading, the VMP “lite” regimen is 
referred to as “VMP” throughout the protocol.
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Rationale for VELCADE Subcutaneous Administration
VELCADE is approved in the US and the EU for both IV and SC routes of administration for all 
labeled indications. In this study, VELCADE will be administered subcutaneously. In clinical 
studies, SC administration has been shown to be non-inferior to the standard IV route of delivery 
and appears to have an improved systemic safety profile, notably resulting in significantly lower 
rates of peripheral neuropathy, an important side effect of VELCADE (Moreau 2011).29
Furthermore, SC administration is a useful alternative to IV administration, particularly for 
patients with poor venous access or with an increased risk of side effects and also affords greater 
flexibility for the site and convenience for the patient.
Therefore, in this study, subjects will receive 1.3 mg/m2 VELCADE as a SC injection twice 
weekly (Weeks 1, 2, 4, and 5) for one 6-week cycle (Cycle 1; 8 doses per cycle) followed by 
once weekly (Weeks 1, 2, 4, and 5) administrations for eight 6 week cycles (Cycles 2 to 9; 
4 doses per cycle).
Rationale for Daratumumab Dose
CD38, the target for daratumumab, is expressed on NK cells and clinical data has shown NK cell 
suppression to be a marker of on target drug activity. Clinical pharmacokinetic data have shown 
the 16 mg/kg dose to be the lowest dose that results in nearly complete target suppression at all 
time points. This dose and schedule continuously suppressed NK cells throughout dosing. 
Daratumumab maximal target suppression is presented in Figure 4.
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Figure 4:
Daratumumab Maximal Target Suppression 
8 mg/kg: Observed trough concentration 
values below predicted 90% suppression 
throughout dosing
16 mg/kg: Observed trough concentration 
values at 90% suppression throughout 
dosing
The ORR appeared higher for the 16 mg/kg dose compared with the 8 mg/kg dose, based on 
early preliminary data from Part 2 of Study GEN501 and from Study MMY2002 (both ongoing 
studies) as of a cutoff date of 24 January 2014. In Study GEN501, the ORRs (ie, PR or greater) 
were 11% and 40% for the 8 mg/kg (n=28) and 16 mg/kg (n=15) dose regimens, respectively. 
For Study MMY2002, the unconfirmed ORRs for the 8 mg/kg and 16 mg/kg dose regimens were 
similar to those observed in GEN501. In addition, VGPRs were observed for 7 of 30 subjects 
treated with the 16 mg/kg dose in the 2 studies. VGPR had not been observed at lower dose 
levels. These preliminary data support that full target saturation at the 16 mg/kg dose is needed 
to achieve higher and deeper response rates. 
Rationale for DNA and Biomarker Collection
Biomarker samples will be collected to evaluate the depth of clinical response to daratumumab 
through evaluation of MRD, using DNA sequencing of immunoglobulin genes, and to determine 
response rates in specific molecular subgroups of multiple myeloma, using DNA/RNA 
sequencing of MM cells to allow for assessment of high–risk genomics such as deletion 17p, 
t(4;14), t(14;20), t(14;16), deletion13, GEP signatures such as UAMS-70, and mutations in p53, 
BRAF, FGFR, IGH, PI3K, or other molecular subtypes associated with disease progression.
Other biomarker goals include evaluation of potential mechanisms of resistance, inter-individual 
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variability in clinical outcomes or identification of population subgroups that respond differently 
to treatment.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 21 days before randomization.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be at least 18 years of age (or the legal age of consent in the jurisdiction in 
which the study is taking place).
2.
Criterion modified per Amendment 1
2.1. Criterion modified per Amendment 2
2.2 Subject must have documented multiple myeloma satisfying the calcium elevation, 
renal insufficiency, anemia, and bone abnormalities (CRAB) diagnostic criteria 
(see Attachment 1), monoclonal plasma cells in the bone marrow ≥10% or presence of a 
biopsy proven plasmacytomas, and measurable secretory disease, as assessed by the 
central laboratory, and defined by any of the following:

IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine 
M-protein level ≥200 mg/24 hours; or

IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL or urine 
M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in the serum or urine: 
Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum 
immunoglobulin kappa lambda free light chain ratio.
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3.
Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT 
due to:

Being age ≥65 years, Or

In subjects <65 years: presence of important comorbid condition(s) likely to have a 
negative impact on tolerability of high dose chemotherapy with stem cell 
transplantation. Sponsor review of these comorbid conditions and approval is 
required before randomization.
4.
Subject must have an ECOG performance status score of 0, 1, or 2 (Attachment 2)
5.
Criterion modified per Amendment 1
5.1 Subject must have pretreatment clinical laboratory values meeting the following 
criteria during the Screening Phase:
a)
hemoglobin 7.5 g/dL (mmol/L; prior red blood cell [RBC] transfusion or 
recombinant human erythropoietin use is permitted);
b)
absolute neutrophil count (ANC) 1.0 x 109/L (G-CSF use is permitted);
c)
AST ≤2.5 x upper limit of normal (ULN);
d)
ALT ≤2.5 x ULN;
e) total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia, 
such as Gilbert syndrome, then direct bilirubin ≤1.5 x ULN;
f)
creatinine clearance 40 mL/min, may be calculated or measured according to 
local practice (if calculated, MDRD or CKD-EPI formulae preferred, see 
Section 9.1.2)
g)
corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L); or free ionized calcium 
≤6.5 mg/dL (≤1.6 mmol/L) (Attachment 3);
h)
platelet count 70 x 109/L for subjects in whom <50% of bone marrow 
nucleated cells are plasma cells; otherwise platelet count >50 × 109/L
(transfusions are not permitted to achieve this minimum platelet count).
6.
Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control 
simultaneously. This includes one highly effective form of contraception (tubal
ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, 
vaginal rings or implants] or partner’s vasectomy) and one additional effective 
contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). 
Contraception must begin prior to dosing. Reliable contraception is indicated even 
where there has been a history of infertility, unless due to hysterectomy or bilateral 
oophorectomy
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7.
Criterion modified per Amendment 1
7.1 A woman of childbearing potential must have a negative serum or urine pregnancy 
test at screening within 14 days prior to randomization.
8.
Each subject (or their legally acceptable representative) must sign an informed consent 
form (ICF) indicating that he or she understands the purpose of and procedures required 
for the study and are willing to participate in the study. Subject must be willing and able 
to adhere to the prohibitions and restrictions specified in this protocol, as referenced in 
the ICF.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of 
undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy
of undetermined significance is defined by presence of serum M-protein <3 g/dL; 
absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to 
the M-protein; and (if determined) proportion of plasma cells in the bone marrow of 
10% or less (Kyle 2003).18 Smoldering multiple myeloma is defined as asymptomatic 
multiple myeloma with absence of related organ or tissue impairment or end-organ 
damage (Kyle 2003, Kyle 2007).18,20
2.
Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM 
M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone 
lesions.
3.
Subject has prior or current systemic therapy or SCT for multiple myeloma, with the 
exception of an emergency use of a short course (equivalent of dexamethasone 
40 mg/day for a maximum 4 days) of corticosteroids before treatment.
4.
Subject has peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 4.
5.
Subject has a history of malignancy (other than multiple myeloma) within 3 years 
before the date of randomization (exceptions are squamous and basal cell carcinomas of 
the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the 
investigator, with concurrence with the sponsor's medical monitor, is considered cured 
with minimal risk of recurrence within 3 years).
6.
Subject has had radiation therapy within 14 days of randomization.
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7.
Subject has had plasmapheresis within 28 days of randomization.
8.
Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
9.
Criterion modified per Amendment 1
9.1a)
Subject has known chronic obstructive pulmonary disease (COPD) with a Forced 
Expiratory Volume in 1 second (FEV1) < 50% of predicted normal. Note that 
FEV1 testing is required for subjects suspected of having COPD and subjects 
must be excluded if FEV1 <50% of predicted normal
9.1b)
Subject has had known moderate or severe persistent asthma within the last 
2 years (see Attachment 4), or currently has uncontrolled asthma of any 
classification. (Note that subjects who currently have controlled intermittent 
asthma or controlled mild persistent asthma are allowed in the study).
10.
Criterion modified per Amendment 1
10.1 Subject is known to be seropositive for human immunodeficiency virus (HIV), 
known to have hepatitis B surface antigen positivity, or known to have a history of 
hepatitis C.
11.
Subject has any concurrent medical or psychiatric condition or disease (eg, active 
systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) 
that is likely to interfere with the study procedures or results, or that in the opinion of 
the investigator, would constitute a hazard for participating in this study.
12.
Criterion modified per Amendment 1
12.1 Criterion modified per Amendment 2
12.2 Subject has clinically significant cardiac disease, including:

myocardial infarction within 1 year before randomization, or an unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart Association Class III-IV)

uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities

screening 12-lead ECG showing a baseline corrected QT interval (QTc) >470 msec
13.
Subject has known allergies, hypersensitivity, or intolerance to boron or mannitol, 
corticosteroids, monoclonal antibodies or human proteins, or their excipients (refer to 
respective package inserts or Investigator's Brochure), or known sensitivity to 
mammalian-derived products.
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14.
Subject has plasma cell leukemia (according to WHO criterion: ≥20% of cells in the 
peripheral blood with an absolute plasma cell count of ≥2×109/L) or POEMS syndrome 
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin 
changes).
15.
Subject is known or suspected of not being able to comply with the study protocol 
(eg, because of alcoholism, drug dependency, or psychological disorder). Subject has 
any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the subject (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. Subject is taking any prohibited 
medications as per Section 8.3.
16.
Criterion Modified per Amendment 2
16.1 Subject is a woman who is pregnant, or breast-feeding, or planning to become 
pregnant while enrolled in this study or within 3 months after the last dose of any 
component of the treatment regimen. Or, subject is a man who plans to father a child 
while enrolled in this study or within 3 months after the last dose of any component of 
the treatment regimen.
17.
Criterion modified per Amendment 1
17.1 Subject has had major surgery within 2 weeks before randomization or has not
fully recovered from surgery, or has surgery planned during the time the subject is 
expected to participate in the study. Kyphoplasty or vertebroplasty are not considered 
major surgery. Note: subjects with planned surgical procedures to be conducted under 
local anesthesia may participate.
18.
Subject has received an investigational drug (including investigational vaccines) or used 
an invasive investigational medical device within 4 weeks before randomization or is 
currently enrolled in an interventional investigational study.
19.
Incidence of gastrointestinal disease that may significantly alter the absorption of oral 
drugs.
NOTE: Investigators should ensure that all study enrollment criteria have been met at 
screening. If a subject's status changes (including laboratory results or receipt of additional 
medical records) after screening but before the first dose of study treatment is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded 
from participation in the study. Section 17.4 describes the required documentation to support 
meeting the enrollment criteria. Subjects who fail to meet the inclusion and exclusion criteria 
(ie, screen failures) may be rescreened once if their condition changes. Rescreening must be 
discussed with and approved by the sponsor on a case-by-case basis. Subjects who are 
determined to be eligible for rescreening must sign a new ICF and will then be assigned a new 
screening number.
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4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation. For restrictions related 
to concomitant medications, please refer to Section 8.3.
1.
For women of childbearing potential, adequate contraception as specified in Section 4.1
must continue during the Treatment Phase, during any dose interruptions, and for 
3 months after the last dose of daratumumab. In addition, women must not donate ova 
during the study and for 3 months after the last dose of daratumumab.
2.
A man who is sexually active with a woman of childbearing potential must always use a 
latex or synthetic condom during the study and for 3 months after discontinuing 
daratumumab. All men must not donate sperm during the study and for 3 months after 
the last dose of daratumumab.
3.
Typically, IV contrast is NOT used in computed tomography (CT) scanning of subjects 
with secretory multiple myeloma because of the risk to the kidney. If administration of 
IV contrast is necessary, then adequate precautions including hydration are indicated.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Eligible subjects will be stratified by International Staging System (I vs II vs III based on central 
laboratory results at Screening, see Attachment 9), region (Europe vs Other), and age (<75 vs 
≥75) and then randomized to treatment in a 1:1 ratio to either Treatment Arm A (VMP alone) or 
Treatment Arm B (daratumumab+VMP [D-VMP]). The method of randomization is randomly 
permuted blocks. An interactive web based randomization system (IWRS) will be used. Each 
subject will be assigned a unique subject number.
Blinding
As this is an open study, blinding procedures are not applicable.
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6.
DOSAGE AND ADMINISTRATION
In this protocol, the term “study drug” refers to daratumumab only, and “study treatment” refers 
to daratumumab, VELCADE, melphalan, and prednisone. Daratumumab is to be administered as 
described in the Time and Events Schedule. On dosing days where the combination products are 
given with daratumumab (ie, Arm B only), the study drug and chemotherapy should be 
administered in the following order:

prednisone, daratumumab, VELCADE, and melphalan
Detailed information on the composition of the study treatments can be found in the Site 
Investigational Product Procedures Manual (SIPPM) or equivalent document. The administration 
schedule is provided in the Time and Events schedule. Cycles are based on the administration of 
VELCADE and will be approximately 42 days (6 weeks) in duration. 
In Cycles 2-9, before initiating a new cycle of therapy, subjects should meet the following 
criteria:

Platelet count ≥70 x 109/L

ANC ≥1.0 x 109/L

Non-hematological toxicities resolved to Grade 1 or baseline
The start of each cycle may occur within ±3 days of the scheduled day in order to accommodate 
the schedule of the site or subject. If the start of a cycle is delayed, Day 1 of subsequent cycles 
should be adjusted accordingly to maintain the 42-day cycle duration. In Cycles 1 through 9, 
weekly or every-three-week daratumumab infusions may be given within ±1 day of the 
scheduled day in order to accommodate the schedule of the site or subject. Additionally, weekly 
or twice weekly VELCADE doses may be given within ±1 day of the scheduled day in order to 
accommodate the schedule of the site or subject. Changes to within-cycle dosing should not 
impact Day 1 of the next cycle.
Subjects are to receive VMP for a maximum of 9 cycles. For subjects randomized into Treatment 
Arm B, daratumumab will be given according to the Time and Events Schedule until disease 
progression, unacceptable toxicity, or other reasons as listed in the Section 10.2.
A schematic of study treatment administration is provided in Figure 5.
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Figure 5:
Study Treatment Administration
6.1.
Daratumumab (Arm B Only)
6.1.1.
Daratumumab Preparation
The infusion solution will be prepared on the day of the planned infusion. Detailed instructions
for preparation and administration of daratumumab will be supplied in the Site Investigational 
Product Procedures Manual (SIPPM) or equivalent document.
6.1.2.
Daratumumab Administration
Daratumumab (16 mg/kg) will be administered to subjects in Arm B by IV infusion initially once 
every week for 6 weeks (Cycle 1; 1 VELCADE cycle); then once every 3 weeks for an 
additional 16 doses (Cycles 2-9); then once every 4 weeks thereafter (post-VMP Treatment 
Phase), until documented progression, unacceptable toxicity, or study end. After the end of the 
study, the sponsor will ensure that subjects benefiting from treatment with daratumumab will be 
able to continue treatment.
A daratumumab infusion will be skipped if it cannot be administered within the prescribed time 
window as outlined in Table 4. Each subject’s dose will be calculated based on the subject’s 
weight rounded to the nearest kilogram. There is no cap on the absolute dose allowed, as long as 
the dose does not exceed 16 mg/kg. If a subject’s weight changes by more than 10% from 
baseline, the dose of daratumumab will be re-calculated. For recommendations on daratumumab 
infusion rate, please refer to the SIPPM or equivalent document. 
D1
D32
D11
VELCADE
1.3 mg/m2 SC
(ALL SUBJECTS)
D8
D29
Follow-up
D1
D22
DARATUMUMAB
16 mg/kg IV
(ARM B ONLY)
Cycle 10+ 
(4 week cycles)
D15
D1
D1
D22
Follow-up
D22
D8
D1
Cycle 1 
(6 week cycle)
Cycles 2-9 
(6 week cycles)
D29
D36
MELPHALAN 9 mg/m2 PO 
PREDNISONE 60 mg/m2 PO 
(ALL SUBJECTS) 
D1-D4
Follow-up
D1-D4
D4 D8
D25
D29
D22
Cycle 1 
(6 week cycle)
Cycles 2-9 
(6 week cycles)
Cycle 1 
(6 week cycle)
Cycles 2-9 
(6 week cycles)
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As noted in the Time and Events Schedule, vital signs should be monitored extensively on 
Cycle 1 Day 1 before, during, and after the first infusion of daratumumab. For all other infusions, 
vital signs should be measured before the start of infusion and at the end of the infusion. If a 
subject experiences any significant medical event, then the investigator should assess whether 
the subject should stay overnight for observation.
6.1.3.
Guidelines for Prevention of Infusion Reactions
6.1.3.1.
Pre-infusion Medication 
Pre-infusion medications for subjects receiving daratumumab will be administered as described 
in the Time and Events Schedules. On daratumumab infusion days, subjects will receive the 
following medications prior to infusion:

Paracetamol (acetaminophen) 650-1000 mg IV or PO approximately 1 hour or less prior to 
daratumumab infusion

An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent H1 blocker; see 
Attachment 5) approximately 1 hour prior to daratumumab infusion.

Dexamethasone 20 mg IV or PO, approximately 1 hour or less prior to daratumumab 
infusion. Substitutions for dexamethasone are allowed, please refer to Attachment 6. On 
days when subjects receive this dose of dexamethasone in the clinic, prednisone will not be 
self-administered at home.

Leukotriene Inhibitor (optional) on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent, 
approximately 1 hour or less before the daratumumab infusion
If necessary, all PO pre-infusion medications may be administered outside of the clinic on the 
day of the infusion, provided they are taken within 3 hours before the infusion.
6.1.3.2.
Post-Infusion Medication
For subjects with higher risk of respiratory complications (eg, subjects with mild asthma, or 
subjects with COPD who have a FEV1 <80%), the following post-infusion medications should 
be considered:

Antihistamine (diphenhydramine or equivalent) 

Leukotriene inhibitor (montelukast or equivalent)

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 

Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol ± inhaled corticosteroids for subjects with COPD)
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In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their FEV1 should be measured before discharge. If 
these subjects are not hospitalized, then a follow up telephone call should be made to monitor 
their condition within 48 hours after all infusions. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
not be reported as a serious adverse event. Investigators may prescribe bronchodilators, 
antihistamines, and corticosteroids that are deemed necessary to provide adequate supportive 
care in the event a bronchospasm occurs after subjects are released from the hospital/clinic. If an 
at-risk subject experiences no major infusion-related reactions, then these post-infusion 
medications may be discontinued after 4 full doses at the investigator’s discretion.
6.1.4.
Management of Infusion-related Reactions
Subjects in Arm B should be carefully observed during daratumumab infusions. Trained study 
staff at the clinic should be prepared to intervene in case of any infusion-related reactions 
occurring, and resources necessary for resuscitation (eg, agents such as epinephrine and 
aerosolized bronchodilator, also medical equipment such as oxygen tanks, and a defibrillator) 
must be available. Attention to staffing should be considered when multiple subjects will be 
dosed at the same time.
If an infusion-related reaction develops, then the infusion should be temporarily interrupted. 
Subjects who experience adverse events during the infusion must be treated according to the 
investigator’s judgment and best clinical practice. The following guidelines may apply:

Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, 
subjects may require vasopressors.

In the event of a life-threatening infusion-related reaction (which may include pulmonary or 
cardiac events), or anaphylactic reaction, daratumumab should be discontinued and no 
additional daratumumab should be administered to the subject. Aggressive symptomatic 
treatment should be applied.
If an infusion is paused, then a longer-than-anticipated infusion time may occur. Overnight stays 
at the hospital because of slow infusion times should not be reported as a serious adverse event.
However, if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such.
6.1.4.1.
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses an adverse event to be related to the daratumumab infusion, then the 
infusion should be paused. When the subject’s condition is stable, the infusion may be restarted 
at the investigator’s discretion. Upon restart, the infusion rate should be half of that used before 
the interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion. 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from the onset, then the subject must be withdrawn from treatment.
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6.1.4.2.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related adverse events that are Grade 4, the infusion should be stopped and 
treatment with daratumumab will be discontinued for that subject.
For infusion-related adverse events that are Grade 3, the daratumumab infusion must be stopped, 
and the subject must be observed carefully until the resolution of the adverse event or until the 
intensity of the event decreases to Grade 1, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the 
procedure described in this section may be repeated at the investigator’s discretion. Should the 
intensity of the adverse event increase to Grade 3 for a third time, then treatment with 
daratumumab will be discontinued for that subject.
6.2.
VELCADE, Melphalan, and Prednisone (Arm A and Arm B)
The sponsor will provide VELCADE to the sites, if required. Sites will use commercially 
available melphalan and prednisone for administration in this study unless otherwise 
communicated to the site. Before administering, refer to the currently approved package inserts 
for complete prescribing information. 
6.2.1.
Dose Calculation of VELCADE, Melphalan, and Prednisone
The amount (in mg) of VELCADE, melphalan, and prednisone to be administered will be 
determined by body surface area (BSA), which will be calculated according to a standard 
nomogram (Attachment 7). The total calculated dose may be rounded to the nearest decimal 
point (eg, a calculated dose of 2.47 mg can be rounded to 2.5 mg). There is no cap on the 
absolute dose allowed, as long as the dose is based on the subject’s BSA. If a subject’s weight 
changes by more than 10% from baseline, the dose of VELCADE, melphalan, and prednisone 
will be re-calculated.
6.2.2.
VELCADE Administration
Subjects will receive 1.3 mg/m2 VELCADE as a SC injection twice weekly (Weeks 1, 2, 4, and 
5) for one 6-week cycle (Cycle 1; 8 doses per cycle) followed by once weekly (Weeks 1, 2, 4, 
and 5) administrations for eight 6-week cycles (Cycles 2 to 9; 4 doses per cycle). 
On treatment days when both VELCADE and daratumumab are administered, VELCADE must 
be administered after the daratumumab infusion. VELCADE will be supplied in sterile, single-
use vials containing 3.5 mg of VELCADE. Each vial is for single-use administration. 
VELCADE dosing may be delayed up to 48 hours, however subsequent doses must be adjusted 
to account for the delay. Note that there should be at least 72 hours between doses of 
VELCADE. Skipped doses of VELCADE will not be made up later in the cycle. Individual 
doses within a cycle have a ±1 day window.
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For subjects with unacceptable toxicity at the local injection site despite dose modifications or 
change in injection concentration, VELCADE can be administered intravenously as a 3 to 5 sec 
bolus injection. Please refer to local prescribing information for further details on either SC or 
IV administration.
6.2.3.
Melphalan and Prednisone Administration
Melphalan will be administered at 9 mg/m2 and prednisone will be administered at 60 mg/m2 on 
Day 1 to 4 of each VELCADE cycle. Both melphalan and prednisone will be administered 
orally. For subjects randomized to the Treatment Arm B, 20 mg dexamethasone will substitute 
for the planned dose of prednisone on Day 1 of each cycle. In this setting, dexamethasone will be 
utilized as the treatment dose of steroid for that particular day, as well as the required pre-
medication prior to daratumumab infusion. Prednisolone may be substituted for prednisone in 
countries where prednisone is not available. Melphalan and prednisone doses may be reduced, or 
the treatment schedule may be modified for the management of the study treatment-related 
toxicities.
In exceptional circumstances, a subject may not tolerate sudden corticosteroid withdrawal at the 
end of 4 days of prednisone treatment. In such an instance, a tapering regimen of prednisone 
(30 mg/m2 on Day 5, 20 mg/m2 on Day 6, 10 mg/m2 on Day 7, then stop) can be prescribed to 
the subject after sponsor review. Under no circumstances will melphalan administration be 
prolonged beyond 4 days.
Breaking or dividing melphalan or prednisone tablets is strongly discouraged; the total calculated 
dose should be rounded to the closest dose that can be administered using the tablets available. 
Prednisone tablets are to be taken with or immediately after a meal or snack, preferably in the 
morning.
If subjects develop renal and/or hepatic impairment, please follow recommendations given in 
Table 8.
6.3.
Dose Delays and Dose Modification
Subjects who need to discontinue treatment with any one component of study treatment 
(VELCADE, melphalan, prednisone, or daratumumab) may continue to receive treatment with 
the other components of study treatment, as assigned.
6.3.1.
Daratumumab Dose Modification
Dose modification of daratumumab is not permitted; dose delay is the primary method for 
managing daratumumab-related toxicities. 
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6.3.1.1.
Daratumumab-Related Toxicity Management
Refer to Section 6.1.3 for details on management of infusion-related reactions. Only if any of 
the following criteria are met and the event cannot be ascribed to other components of the 
chemotherapy regimen, the daratumumab infusion must be held to allow for recovery from 
toxicity. The criteria for a dose delay are:

Grade 4 hematologic toxicity

Grade 3 thrombocytopenia with bleeding

Febrile neutropenia 

Neutropenia with infection, of any grade

Grade 3 or higher non-hematologic toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days

Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab

Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Other than on Day 1 of a cycle, if a daratumumab infusion does not commence within the 
pre-specified window (Table 4) of the scheduled administration date, then the dose will be 
considered a missed dose. Administration may resume at the next planned dosing date. A missed 
dose will not be made up.
Table 4:
Daratumumab-Related Toxicity Management
Frequency
Dose Miss
Dosing Re-start
Cycle 1
Weekly 
(q1wk)
>3 days
next planned weekly dosing date
Cycle 2-9
Every 3 weeks
(q3wks)
>1 week
next planned every-third-week dosing date
Post VMP
Every 4 weeks 
(q4wks)
>2 weeks
next planned every-fourth-week dosing date
If the daratumumab infusion cannot be given on Day 1 of a cycle, the start of the cycle should be 
delayed. Day 1 of a cycle should not be skipped. If a dose is delayed, then subsequent 
pharmacokinetic and pharmacodynamic assessments should be performed based on the actual 
administration days of daratumumab, not on the original scheduled administration day. A 
maximum delay of 4 weeks is allowed in Cycle 1 to Cycle 9. Any adverse event deemed to be 
related to daratumumab that requires a dose hold of more than 4 weeks will result in permanent 
discontinuation of daratumumab. After Cycle 9, any adverse event deemed to be related to 
daratumumab that requires a dose hold of 2 consecutive planned doses will result in permanent 
discontinuation of daratumumab.
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6.3.1.2.
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 4) from the per-
protocol administration date for any reason other than toxicities suspected to be related to 
daratumumab should be brought to the attention of the Sponsor at the earliest possible time. 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 9) or 2 consecutive 
planned doses (after Cycle 9) should have study drug discontinued, unless, upon consultation 
with the sponsor and the review of safety and efficacy, continuation is agreed upon.
6.3.2.
Dose Reductions (VELCADE, Melphalan, and Prednisone)
VELCADE will be reduced or discontinued according to the guidelines presented in Table 5. In 
addition to the VELCADE dose modification guidelines presented in Section 6.3.3, Table 8, if 
several VELCADE doses in a cycle are withheld due to VELCADE-related toxicity (≥3 doses 
during twice weekly administration or ≥2 doses during weekly administration), VELCADE dose 
should be reduced by 1 dose level. Once reduced due to toxicity, doses of VELCADE, 
melphalan, or prednisone should not be re-escalated, with the exception of melphalan 
re-escalation following recovery of renal function (Table 8).
Table 5:
Dose Reduction for VELCADE
Starting Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
VELCADE 1.3 mg/m2
VELCADE 1.0 mg/m2
VELCADE 0.7 mg/m2
Discontinue VELCADE
Melphalan will be reduced or discontinued according to the guidelines presented in Table 6.
Table 6:
Dose Reduction for Melphalan
Starting Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
9 mg/m2 QD on Days 1-4 
6.75 mg/m2 QD on Days 1-4 4.5 mg/m2 QD on Days 1-4 Discontinue melphalan
QD=every day
Prednisone will be reduced or discontinued according to the guidelines presented in Table 7.
Table 7:
Dose Reduction for Prednisone
Starting Dose
First Dose Reduction
Second Dose Reduction
Third Dose Reduction
60 mg/m2 QD on Days 1-4 45 mg/m2 QD on Days 1-4
30 mg/m2 QD on Days 1-4
Discontinue prednisone
QD=every day
6.3.3.
Dose Modification Guidelines for VELCADE, Melphalan, and 
Prednisone Related Toxicities
Dose modification guidelines for VELCADE, melphalan, and prednisone are provided in
Table 8.
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Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone 
Body System
NCI-CTC Adverse Event and or 
Symptom and Category
VELCADE
Melphalan
Prednisone
Allergic reactions
Allergic reaction or hypersensitivity
Grade 2 OR 3
Hold all therapy.
If the toxicity resolves to Grade 1, restart VMP. Reduce by 1 dose-level the suspected medication(s) AND implement 
appropriate anti-allergic prophylaxis therapy.
If the reaction was anaphylactic in nature, do not resume VMP.
NOTE: If the reaction was cutaneous in nature, refer to the cutaneous category below.
Allergic reaction or hypersensitivity
Grade 4
Discontinue VMP.
Constitutional
Fluid Retention (ie, edema) >Grade 3 
(limiting function and unresponsive to 
therapy or anasarca)
Administer diuretics as 
needed, and decrease 
dexamethasone or prednisone 
dose by 1 dose-level; if 
edema persists despite above 
measures, decrease dose 
another dose-level.
Discontinue prednisone and 
do not resume if symptoms 
persist despite second 
reduction.
Fatiguea
Grade 3 (ie, severe fatigue 
interfering with activities of daily 
living)
Reduce VELCADE by 1 dose-level.
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Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone 
Body System
NCI-CTC Adverse Event and or 
Symptom and Category
VELCADE
Melphalan
Prednisone
Cutaneous
Non-blistering rash
Grade 2
Hold VELCADE therapies. Begin treatment with 
antihistamines and/or low-dose steroids as per 
institutional practice.
If the toxicity resolves to Grade 1, restart at 1 dose 
reduced level of VELCADE
Non-blistering rash
Grade 3 or 4 
Hold VELCADE therapies. Begin treatment with 
antihistamines and/or low-dose steroids as per 
institutional practice.
If the toxicity resolves to Grade 1, restart 
VELCADE (only) at 1 dose reduced level and 
continue antihistamines and/or low-dose steroids as 
per institutional practice. 
If toxicity recurs despite above measure, discontinue 
VELCADE permanently, as appropriate. 
Desquamating (blistering) rash-
any grade or erythema multiform 
Grade 3
Discontinue VELCADE permanently.
Hold other therapies. Begin treatment with antihistamines and/or low-dose steroids as per institutional practice.
If the toxicity resolves to Grade 1, restart other medications. 
Gastrointestinal
Constipationb
Grade 3
Hold.
Upon recovery to Grade 1, restart VELCADE at 1 
dose-reduced level.
Diarrheac
Grade 3
Hold VELCADE and consider loperamide therapy.
Upon recovery to Grade 1, restart VELCADE at 
1 dose-reduced level.
Dyspepsia, gastric or duodenal ulcer, 
gastritis Grade 1-2 (requiring medical 
management)
Treat with histamine-2 
blockers, sucralfate, or 
omeprazole. 
If symptoms persist despite 
above measures, decrease 
prednisone dose by 1 
dose-level.
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Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone 
Body System
NCI-CTC Adverse Event and or 
Symptom and Category
VELCADE
Melphalan
Prednisone
Dyspepsia, gastric or duodenal ulcer, 
gastritis Grade 3 (requiring 
hospitalization or surgery)
Hold prednisone and consider 
treatment with histamine-2 
blockers, sucralfate, or 
omeprazole.
Restart prednisone 1 dose 
reduction level if symptoms 
are adequately controlled. 
If symptoms persist despite 
above measures, discontinue 
prednisone and do not 
resume.
Hematological
Neutropenia
Grade 3 (without complications)
No dose reduction required of VELCADE. Consider 
treatment with G-CSF.
Continue melphalan dosing and 
add G-CSF support.
Grade 3 neutropenia associated with 
fever (≥38.5°C) or any Grade 4 
neutropenia
Hold therapy with all drugs until recovery to baseline OR Grade 2.
Upon recovery, restart melphalan at 1 dose reduced level. Maintain VELCADE at current 
dose and consider G-CSF support.
If recurrence is seen, reduce VELCADE by 1 dose-level.
Thrombocytopenia
Grade 3 (without complications)
No dose reduction required for VELCADE.
Reduce melphalan by 
1 dose-level
Platelet count ≤ 30 x 109/L or ANC 
≤0.75 x 109/L on a VELCADE dosing 
day (See Section 6 for minimum 
criteria for dosing on Day 1 of a cycle)
Withhold VELCADE therapy.
Platelet count <25,000/L (ie, Grade 
4) or Grade 3 thrombocytopenia with 
bleeding
Hold therapy with all drugs until recovery to baseline OR Grade 2.
Upon recovery, restart melphalan and VELCADE at 1 dose reduced level. If recurrence is 
seen, reduce melphalan by 1 further dose-level.
Infection
Herpes Zosterd activation or 
reactivation
ANY grade
Hold ALL therapies until lesions are dry. If not already underway, begin antiviral treatment
Once the infection is resolved all medications can be restarted without a dose reduction; however, continued antiviral 
prophylaxis is required.
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Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone 
Body System
NCI-CTC Adverse Event and or 
Symptom and Category
VELCADE
Melphalan
Prednisone
Musculoskeletal
Muscle weakness >Grade 2 
(symptomatic and interfering with 
function +/- interfering with activities 
of daily living)
Decrease prednisone dose by 
1 dose-level. If weakness 
persists despite above 
measures, decrease dose by 
1 further dose-level. If 
symptoms still persist, 
discontinue and do not 
resume if symptoms persist.
Metabolic
Hyperglycemia
Grade 3
Treatment with insulin or oral 
hypoglycemics. If 
uncontrolled despite above 
measures, decrease dose by 1 
dose-level until levels are 
satisfactory.
Neurologicale
Peripheral Neuropathy (Sensory or Motor) and/or Neuropathic 
Pain
Grade 1 
(paresthesias and/or 
loss of reflexes) 
without pain or loss 
of function
No action required.
Grade 1 with pain 
or Grade 2 
(interfering with 
function but not 
with activities of 
daily living)
Reduce VELCADE by 1 dose-level or change 
schedule to once weekly
Grade 2 with pain 
or Grade 3 
(interfering with 
activities of daily 
living)
Hold VELCADE until toxicity resolves to <Grade 2. 
When toxicity resolves, reinitiate with a reduction 
by 1 dose-level and change VELCADE treatment 
schedule to once per weekf
Grade 4 (permanent 
sensory loss that 
interferes with 
function) and/or 
severe autonomic 
neuropathy
Discontinue VELCADE permanently.
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Table 8: 
Dose modification Guidelines for VELCADE, Melphalan, and Prednisone 
Body System
NCI-CTC Adverse Event and or 
Symptom and Category
VELCADE
Melphalan
Prednisone
Neuro-
psychological 
Confusion or mood alteration >Grade 
2 (interfering with function 
+/- interfering with activities of daily 
living)
Hold prednisone until 
symptoms resolve. 
Restart with 1 dose-level 
reduction. 
If symptoms persist despite 
above measures, discontinue 
prednisone and do not 
resume.
Thromboembolic
Venous and /or pulmonary thrombo-
embolism Grade 3 [Deep vein 
thrombosis or cardiac thrombosis 
intervention indicate; eg: 
anticoagulation, lysis, filter, invasive 
procedure.]
Stop until toxicity resolves 
and, if not already given, start 
anticoagulation therapy.
Restart prednisone at full 
dose after adequate 
anticoagulation,
Renal 
Impairment
If a subject develops renal 
function impairment with a serum 
creatinine >2 mg/dL 
(>176.8 mcmol/L) but less than 
Grade 3, the melphalan dose must 
be reduced to 4.5 mg/m2, while 
VELCADE and prednisone can 
be continued at the current dose. 
On recovery of renal function, 
melphalan can be re escalated to 
the previous dose.
Other toxicities
Any reported 
Grade 3
Determine drug attribution of the toxicity and hold the therapy(ies) as appropriate.
If toxicity resolves to Grade 1, resume therapy with 1 level of dose reduction for suspect drug.
a Determine if fatigue is possibly not medication-related but due to an underlying cause (eg, infection, progression of disease, diarrhea, anemia, depression) and treat these 
symptoms/causes as appropriate.
b  Prior to dose reduction of medications, consider/eliminate other possible causes of constipation. 
c Prior to dose reduction of medications, consider/eliminate other possible causes (ie, bacterial or viral infections) of diarrhea.
d  In the event that a subject is already receiving antiviral treatment at the time of the Herpes Zoster activation, consider switching to or adding another antiviral agent.
e The neurotoxicity-directed questionnaire is a useful tool for determining the presence and intensity of neuropathic pain and/or peripheral neuropathy from the subject’s perspective. 
Neuropathic symptoms are more prominent than abnormalities on the clinical examination. After the subject completes the neurotoxicity directed questionnaire, the questionnaire should 
be reviewed to assist with the evaluation of the onset and intensity of peripheral neuropathy and other neurotoxicities that may require intervention or dose modification.
f  If therapy is continued as twice weekly, VELCADE treatment should be continued at once weekly dosing.
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7.
TREATMENT COMPLIANCE
Study drug (daratumumab) and VELCADE will be administered by qualified site staff, and the 
details of each administration will be recorded in the electronic case report form (eCRF). 
Subjects will be provided with a treatment diary which will be used to assess compliance with 
melphalan and prednisone treatment. Additional details are provided in the SIPPM or equivalent 
document.
8.
CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The 
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
Routine systemic use of the following concomitant medications will be collected in the eCRF 
and recorded in the source documents beginning with signing of the ICF to 30 days after the last 
dose of the last study treatment or until the start of subsequent anti-myeloma treatment, if earlier: 
growth factors, transfusions, anti-infectives (antibacterials, antivirals, and antimycotics), steroids, 
anti-arrhythmics and other cardiac supportive therapy, anti-epileptics, centrally acting psychiatric 
medication, anti-histamines and other medications targeting post-infusion systemic reactions,
bisphosphonates, and any anti-myeloma therapy (including radiation). Concomitant medications 
to manage AEs and SAEs will be recorded as per Section 12.3.1. 
8.1.
Recommended Therapies
8.1.1.
Bisphosphonate Therapy
Bisphosphonate therapy is recommended to be continued per treatment guidelines (NCCN 
2013).30 Commercially available IV bisphosphonates (pamidronate and zoledronic acid) are 
preferred when available, and should be used according to the manufacturer’s recommendations, 
as described in the prescribing information, for subjects with osteolytic or osteopenic 
myelomatous bone disease. Oral bisphosphonates may be used as alternatives if IV 
bisphosphonates are not available at the study site.
Subjects who are currently using bisphosphonate therapy when they enter the study should 
continue the same treatment. If clinically indicated, subjects may initiate bisphosphonate therapy 
as soon as possible during Screening and no later than the end of Cycle 1. After Cycle 1, 
investigators should not prescribe bisphosphonates to subjects who have not received them 
before, unless approved by the sponsor after confirming that the subject does not have disease 
progression at the time of bisphosphonate initiation.
8.1.2.
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor 
lysis syndrome, including dehydration and abnormal laboratory test results such as 
hyperkalemia, hyperuricemia, and hypocalcemia, are
highly recommended. It is also 
recommended that high-risk subjects, ie, those with a high tumor burden, be treated 
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prophylactically in accordance with local standards (eg, rehydration; diuretics; allopurinol 
300 mg daily and medication to increase urate excretion).
8.1.3.
Prophylaxis for Pneumocystis carinii
Pneumocystis carinii pneumonia prophylaxis should be considered, as per institutional 
guidelines.
8.1.4.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase, as per 
institutional guidelines.
8.1.5.
Prevention of Hemorrhagic Cystitis
Melphalan may cause hemorrhagic cystitis, especially in patients who have marginal renal 
function and/or dehydration. Measures to prevent hemorrhagic cystitis include IV hydration and 
the administration of Mesna. These measures are permitted therapies during the course of the 
study and may be used per institutional policy. Urine alkalinization is not recommended.
8.2.
Permitted Therapies
Subjects are to receive full supportive care during the study. The following medications and 
supportive therapies are examples of support therapies that may be used during the study:

Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells

Loperamide is recommended for the treatment of diarrhea, starting at the time of the first 
watery stool. The loperamide dose and regimen is according to institutional guidelines. 
Prophylactic loperamide is not recommended.

It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool 
softeners if needed)

Adequate hydration is recommended for prevention of myeloma-related kidney disease

Prophylactic antiemetics, with the exception of corticosteroids
8.3.
Prohibited Therapies
Concomitant administration of any other antineoplastic therapy for the intention of treating 
multiple myeloma is prohibited prior to confirmation of disease progression, including 
medications that target CD38, as well as medications used for other indications that have 
anti-myeloma properties (for example, interferon and clarithromycin [Ghosh 2013]13).
Continuation of the study drug and components of the VMP regimen during or after emergency 
orthopedic surgery or radiotherapy for conditions related to multiple myeloma may occur only in 
the absence of disease progression and after review by the sponsor. Such emergency 
radiotherapy may consist of localized radiotherapy for pain control or for stabilization of an 
extensive bone lesion at high risk of pathologic fracture or damage to surrounding tissues in a 
subject in whom delay of systemic therapy is not appropriate. Such radiotherapy is to occur 
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within the first 2 cycles of treatment and the absence of evidence of disease progression is to be 
reviewed by the sponsor.
Concomitant administration of investigational agents is prohibited. Administration of 
commercially available agents with activity against or under investigation for multiple myeloma, 
including systemic corticosteroids (>10 mg prednisone per day or equivalent) (other than those 
given for infusion-related reactions as described in Section 6.1.3.2) should be avoided. 
Nonsteroidal anti-inflammatory agents should be used with caution in order to prevent 
myeloma-related kidney disease. Typically, IV contrast is NOT used in computed tomography 
(CT) scanning of the subjects with secretory multiple myeloma because of the risk to the kidney. 
If administration of IV contrast is necessary, then adequate precautions including hydration are 
indicated. The sponsor must be notified in advance (or as soon as possible thereafter) of any 
instances in which prohibited therapies are administered.
Concomitant administration of strong CYP3A4 inducers is prohibited with the use of 
VELCADE. Administration of strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir) should be 
avoided and is not recommended in patients receiving VELCADE. If a strong CYP3A4 inhibitor 
must be given in combination with VELCADE, monitor patients for signs of VELCADE toxicity 
and consider a VELCADE dose reduction. For an ongoing list of CYP3A inhibitors and 
inducers, see http://medicine.iupui.edu/flockhart/.
8.4.
Subsequent Therapies
After completion or discontinuation of study therapy subjects should continue efficacy 
evaluations per the Time and Events Schedule until PD. Subsequent anti-myeloma therapy
cannot be started before disease progression is established per the IMWG criteria 
(Section 9.2.1.1, Response Categories) or prior to sponsor confirmation of PD.
After sponsor confirmation of PD, choice of subsequent therapy is at the discretion of the 
investigator. Subjects randomized to Arm A (VMP) may have the option to receive daratumumab 
provided by the sponsor (in any subsequent line of therapy) if recommended by the investigator. 
Eligibility for and administration of daratumumab must be in accordance with local prescribing 
information and local regulations. Subjects in Arm A (VMP) who receive daratumumab post 
progressive disease through the sponsor will remain in the Follow-up phase of study. SAEs 
(including second primary malignancies) must be reported for these subjects until 30 days after 
daratumumab is discontinued. The option for sponsor provision of daratumumab will not be 
implemented in Japan or in countries where daratumumab is not approved.
All subsequent therapy for multiple myeloma (including start and end date, best response, and 
date of progression to the subsequent therapy) should be documented in the appropriate section 
of the eCRF.
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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, 
pharmacokinetic, 
immunogenicity, 
biomarker, 
patient-reported 
outcomes,
and 
safety 
measurements applicable to this study.
All visit-specific PRO assessments should preferably be conducted/completed before any tests, 
procedures, or other consultations for that visit to prevent influencing subject perceptions. Refer 
to Section 9.6 for details.
Blood collections for pharmacokinetic assessments should be kept as close to the specified time 
as possible. Other measurements may be done earlier than specified time points if needed. Actual 
dates and times of assessments will be recorded in the source documentation.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The total blood volume for the study is estimated at approximately 45 mL during screening and 
480 mL during VMP treatment in the first year. In the post-VMP treatment phase, blood 
sampling for subjects in Arm B will be approximately 305 mL per year on treatment. In the 
Follow-up Phase, subjects prior to PD will have approximately 120 mL blood drawn per year for 
serum disease evaluations. This includes laboratory assessments associated with safety, efficacy, 
and pharmacokinetic evaluations, as well as scientific research samples. Repeat or unscheduled 
samples may be taken for safety reasons or for technical issues with the samples.
9.1.2.
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. The 
Screening Phase begins when the first screening assessment is conducted (that was not 
performed as part of the subject’s standard of care). During the Screening Phase, eligibility 
criteria will be reviewed and a complete clinical evaluation will be performed as specified in 
Time and Events Schedule. Screening procedures will be performed within 21 days before 
randomization; however, results of tests such as skeletal survey, radiologic tests (eg, magnetic 
resonance imaging [MRI]) to document baseline size of known or suspected extramedullary 
plasmacytomas; ECG; chest X-rays (or full chest CT scan); or bone marrow aspirate/biopsy) 
performed up to 6 weeks (42 days) before randomization as routine standard of care for the 
subject’s disease can be used. If collection of blood and urine specimens for disease evaluation
(SPEP, UPEP, calcium, and albumin) is performed within 14 days of Cycle 1 Day 1, it does not 
need to be repeated on Cycle 1 Day 1.
Prior to randomization, the Sponsor will review key eligibility criteria for all subjects. Relevant 
eCRF forms will be completed by site staff for review prior to approval for randomization being 
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granted by the Sponsor (further details provided as a separate document). Subjects <65 years
must have known presence of important comorbid condition(s) likely to have a negative effect on 
the tolerability of high dose chemotherapy with SCT. Documentation of the condition, for 
example diagnosis of concomitant infectious disease, should be provided.
At screening, creatinine clearance may be measured or calculated according to local practice. If 
calculated, formulae according to the modification of diet in renal disease [MDRD, 
Levey 2006]22 or chronic kidney disease epidemiology collaboration [CKD-EPI, Levey 2009]23
are preferred. For online calculators, please go to https://www.kidney.org/professionals/KDOQI/ 
gfr_calculator. Creatinine clearance will be analyzed locally. 
A negative pregnancy test for women of childbearing potential must be documented within 
14 days before the first dose of any component of the treatment regimen.
All attempts should be made to determine eligibility of the subject based on the central 
laboratory results of Screening blood and urine M-protein measurements. In exceptional 
circumstances, the local laboratory results of blood and urine M-protein measurements may be 
used to determine eligibility, but only if the results are clearly (eg, 25% or more) above the 
thresholds for measurability.
9.1.3.
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and 
Events Schedule. Subjects should start study treatment within 72 hours after randomization. The 
start of each cycle may occur within ±3 days of the scheduled day in order to accommodate the 
schedule of the site or subject. If the start of a cycle is delayed, Day 1 of subsequent cycles 
should be adjusted accordingly to maintain the 42-day cycle duration. In Cycles 1 through 9, 
weekly or every-three-week daratumumab infusions may be given within ±1 day of the 
scheduled day in order to accommodate the schedule of the site or subject. Additionally, weekly 
or twice weekly VELCADE doses may be given within ±1 day of the scheduled day in order to 
accommodate the schedule of the site or subject. Changes to within-cycle dosing should not 
impact Day 1 of the next cycle.
Subjects will be closely monitored for adverse events, laboratory abnormalities, and clinical 
response. Clinical evaluations and laboratory studies may be repeated more frequently, if 
clinically indicated. If disease progression is diagnosed, then the subject will discontinue study 
treatment, complete the End-of-Treatment Visit, and enter the Follow-up Phase.
End of Treatment Visits
Unless a subject withdraws consent for study participation or is lost to follow up, an End-of-
Treatment Visit is to occur within 30 days after the last dose all study treatments. Every effort 
should be made to conduct the End-of-Treatment Visit before the subject starts subsequent 
treatment. If a subject is unable to return to the site for the End-of-Treatment Visit, then the 
subject should be contacted to collect information on adverse events that occur up to 30 days 
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after the last dose of study treatment. Additional information on reporting of adverse events is 
presented in Section 12.
9.1.4.
Follow-up Phase
The Follow-up Phase will begin once a subject completes the VMP regimen (Treatment Arm A) 
or completes the daratumumab-VMP regimen (Treatment Arm B), or discontinues treatment in 
either arm for any reason. Subjects who discontinue treatment before disease progression must 
continue to have disease evaluations according to the Time and Events Schedule (ie, every 3 
weeks in Year 1, every 4 weeks in Year 2, and every 8 weeks thereafter) until confirmed PD
(see Section 8.4, Subsequent Therapies), subsequent anti-myeloma treatment, death, withdrawal 
of consent, lost to follow-up, or the end of the study. After disease progression is documented, 
follow-up information will be obtained every 16 weeks (±2 weeks). Every 16-week follow-up 
contacts, as well as Week 8 post-PD and Week 16 post-PD ECOG and ePRO assessments,
should be scheduled from the date of confirmed progression (ie, the date of the confirmatory 
laboratory assessment, not the date of confirmation by the sponsor). In subjects for whom disease 
progression cannot be documented (eg, received subsequent anti-myeloma treatment or refused 
disease evaluations, but agreed to follow-up contacts), the every-16-week follow-up should be 
scheduled from the date of the End of Treatment Visit. Subsequent anti-myeloma treatment, 
PFS2 (per investigator judgment), second primary malignancies, and survival will also be 
recorded.
If the information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the subject has died, the 
date and cause of death will be collected and documented in the eCRF.
The end of the study occurs after 330 subjects have died, or for a maximum of 5 years after the 
last subject is randomized, whichever occurs first. The sponsor will ensure that subjects 
benefiting from treatment with daratumumab will be able to continue treatment after the end of 
the study.
9.1.5.
Assessments Following the Positive Second Interim Analysis of PFS
Following the positive second interim analysis of PFS, subjects remaining in the study will 
continue to be monitored as follows until the next interim analysis of OS (ie, when 200 deaths 
have occurred):
Subjects who have had disease progression
For subjects whose disease has already progressed, every-16-week follow-up contacts should be 
performed to capture:

Survival

Subsequent anti-myeloma therapy

New second primary malignancies
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These data may be collected by telephone. Beyond the end of the serious adverse event reporting 
period (30 days after the last dose of study drug or the start of any subsequent anti-myeloma
treatment, whichever comes first), only those serious adverse events that are considered to be 
possibly, probably, or definitely related to the study drug need to be reported.
Subjects who have not had disease progression
For subjects in the randomized portion of the study who have not experienced disease 
progression, disease assessments will continue to occur every 3 weeks in Year 1, every 4 weeks 
in Year 2, and every 8 weeks thereafter until disease progression is confirmed by central 
laboratory examination per the Time and Event Schedules.
9.1.6.
Assessments Following the OS Interim Analysis
Following the OS interim analysis (ie, when 200 deaths have occurred), subjects remaining in the 
study will continue to be monitored as follows until the study end (ie, when 330 deaths have 
occurred, or 5 years after the last subject is randomized, whichever comes first):

For subjects whose disease has already progressed at the time of the OS interim analysis, 
only survival, subsequent anti-myeloma therapy, and all new second primary malignancy 
information will be collected, which may be obtained by telephone contact.

For subjects without disease progression at the time of the OS interim analysis, disease 
assessments will continue but will be performed locally per the standard of care. Sponsor 
confirmation of disease progression will no longer be required prior to initiation of 
subsequent anti-myeloma therapy.

For subjects in Arm B who are continuing to receive study medication at the time of the OS 
interim analysis, dosing data and safety information will be collected. Safety information 
will include adverse events during treatment and within 30 days after last dose, concomitant 
medications associated with a serious adverse event, and information on all second primary 
malignancies.
9.2.
Efficacy
9.2.1.
Evaluations
9.2.1.1.
Response Categories
Disease evaluations must be performed every 3 weeks during the first year, every 4 weeks during 
the second year, and every 8 weeks thereafter until disease progression (or other reasons as per 
Section 10). A window of ±7 days is allowed. If treatment has been delayed for any reason, the 
disease evaluations must be performed according to the original schedule, regardless of any 
changes to the dosing regimen.
Disease evaluations will be performed by a central laboratory (unless otherwise specified). This 
study will use the IMWG consensus recommendations for multiple myeloma treatment response 
criteria (Durie 2006, Kumar 2016, Rajkumar 2011).8,17,37 For quantitative immunoglobulin, 
M-protein, and immunofixation measurements in serum and 24-hour urine, the investigator will 
use results provided by the central laboratory. Disease progression must be consistently 
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documented across clinical study sites using the criteria in Table 9. Per Table 9, for patients with 
measurable disease by SPEP and/or UPEP at baseline, increases in serum free light chains or the 
FLC ratio alone do not meet criteria for progressive disease.
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Table 9:
International Uniform Response Criteria Consensus Recommendations
Response 
Response Criteria
Stringent 
complete
Response (sCR)

CR as defined below, plus

Normal FLC ratio, and

Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2- to 4-color 
flow cytometry
Complete 
response (CR)*

Negative immunofixation on the serum and urine, and

Disappearance of any soft tissue plasmacytomas, and

<5% PCs in bone marrow
Very good 
partial
Response 
(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
Partial response 
(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

If serum and urine M-protein are not measurable, and serum free light assay is also not 
measurable, ≥50% reduction in bone marrow PCs is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was ≥30%

In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft 
tissue plasmacytomas is also required.
Stable disease 
(SD)

Not meeting criteria for CR, VGPR, PR, or progressive disease
Progressive 
disease (PD)†

Increase of 25% from lowest response value in any one of the following:

Serum M-component (absolute increase must be ≥0.5 g/dL), 

Urine M-component (absolute increase must be ≥200 mg/24 hours), 

Only in subjects without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)

Only in subjects without measurable serum and urine M-protein levels and without 
measurable disease by FLC levels, bone marrow PC percentage (absolute percentage must 
be ≥10%)

Bone marrow plasma cell percentage: the absolute percentage must be >10%

Definite development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be 
attributed solely to the PC proliferative disorder
EBMT = European Group for Blood and Marrow Transplantation; FLC = free light chain; PC = plasma cell
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution 
of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone 
lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of 
whether disease at baseline was measurable on serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. 
For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M-component 
is ≥5 g/dL.
*Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC 
levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such 
subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.
†Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in subjects without measurable 
disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results, and does not refer 
to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not need to be a confirmed 
value. 
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
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Table 9:
International Uniform Response Criteria Consensus Recommendations
Clinical Relapse
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria (Durie 2006, Rajkumar 2011).8,37 In the 
IMWG criteria, clinical relapse is defined as requiring one or more of the following direct indicators of increasing disease or 
end-organ dysfunction that are considered related to the underlying plasma cell proliferative disorder:
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other 
imaging
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least 
1 cm) increase as measured serially by the sum of the products of the cross-diameters of the measurable lesion
3. Hypercalcemia (>11.5 mg/dL; >2.875mM/L)
4. Decrease in hemoglobin of more than 2 g/dL (1.25 mM) or to less than 10 g/dL
5. Rise in serum creatinine by more than or equal to 2 mg/dL (≥177 mM/L)
6. Hyperviscosity
In some subjects, bone pain may be the initial symptom of relapse in the absence of any of the above features. However, bone 
pain without imaging confirmation is not adequate to meet these criteria in studies.
For continuation of treatment, the IMWG response will be determined on an ongoing basis by 
the investigator. For data analysis and reporting, however, the sponsor will use a validated 
computer algorithm that has been shown to provide consistent review of the data necessary to 
determine disease progression and response according to the IMWG criteria.
Serum free light chain assay test results will be analyzed by the central laboratory for the 
assessment of sCR, according to the most recently published IMWG criteria (Durie 2006).8 For 
subjects who discontinue study treatment before disease progression, disease evaluations should 
continue to be performed per the Time and Events Schedule until confirmed disease progression
(see Section 8.4, Subsequent Therapies), death, the start of a new treatment for multiple 
myeloma, withdrawal of consent for study participation, lost to follow-up, or the end of study, 
whichever occurs first. Disease evaluations scheduled for treatment days should be collected 
before study treatment is administered.
9.2.1.2.
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a 
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the 
central laboratory to perform the following tests.

All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD at Screening. During the 
study, subjects with IgD or IgE disease will be evaluated for IgG, IgA, IgM, IgE, and IgD 
and subjects with IgG, IgA, or IgM disease will be evaluated for IgG, IgA, and IgM.

Serum M-protein quantitation by electrophoresis (SPEP)

Serum immunofixation at Screening and thereafter when a CR is suspected. If daratumumab 
interference is suspected based on SPEP and immunofixation (IFE) results, additional reflex 
IFE testing may be performed.

Serum free light chain assay will be done at screening, and to confirm CR. In addition, FLC 
will be used to monitor subjects who have light chain only disease

24-hour urine M-protein quantitation by electrophoresis (UPEP)

Urine immunofixation at Screening and thereafter when a CR is suspected
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Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule
until the development of confirmed disease progression. Disease progression based on 1 of the 
laboratory tests alone must be confirmed by a repeat investigation performed at least 1 day later. 
Disease evaluations will continue beyond relapse from CR until disease progression is 
confirmed. Serum and urine IFE and serum free light chain assay will be performed at Screening 
and thereafter when a CR is suspected (when SPEP or UPEP are 0 or nonquantifiable). For 
subjects with light chain multiple myeloma, serum FLC assay will be performed routinely per
the Time and Events Schedule. Previous studies have demonstrated potential interference of 
therapeutic monoclonal antibodies with detection of endogenous myeloma M-protein on serum 
IFE (McCudden 2010).28 For subjects with suspected daratumumab interference on SPEP and/or 
serum IFE, a follow-up test will be run utilizing anti-idiotype antibodies against daratumumab to 
remove antibody interference. Subjects who meet all other IMWG criteria for CR or sCR, and 
whose positive IFE is confirmed to be daratumumab, will be considered complete responders or 
stringent complete responders.
9.2.1.3.
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected and 
analyzed centrally (as specified in the Time and Events Schedules) until the development of
confirmed disease progression. During the Treatment Phase, development of hypercalcemia 
(corrected serum calcium >11.5 mg/dL or 2.8 mmol/L) can indicate disease progression or 
relapse if it is not attributable to any other cause (see disease response criteria). Calcium binds to 
albumin and only the unbound (free) calcium is biologically active; therefore, the serum calcium 
level must be adjusted for abnormal albumin levels (“corrected serum calcium”). Measurement 
of free ionized calcium is an acceptable alternative to corrected serum calcium for determining 
hypercalcemia. Free ionized calcium levels greater than the ULN (local laboratory reference 
ranges) are considered to be hypercalcemic for this study.
9.2.1.4.
β2-microglobulin and Albumin
Blood samples for β2 microglobulin and albumin are to be collected at Screening, and will be
analyzed by the central laboratory. The central laboratory values will be used to calculate 
International Staging System (ISS) stage.
9.2.1.5.
Bone Marrow Examination
Bone marrow assessments to be performed locally and centrally are summarized in Table 10.
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Table 10:
Bone Marrow Testing
Local Testing
Central Testing
Screening
Disease characterization 
(morphology and either 
immunohistochemistry or 
immunofluorescence or flow 
cytometry). Cytogenetics by 
conventional karyotype or FISH.
MRD and molecular subtyping: a portion 
of bone marrow aspirates collected at 
screening will be sent to a central 
laboratory.
If a fresh bone marrow aspirate will not be 
performed at screening because a sample is 
available within 42 days prior to 
randomization, obtain non-decalcified 
slides (bone marrow aspirate, touch 
preparation or clot selection) or FFPE 
block (clot section only, no bone marrow 
biopsy).
CR, sCR
For response confirmation, 
additional bone marrow aspirates 
or biopsies (or both) will be 
performed locally to confirm 
sCR or CR. Response 
characterization (morphology by 
immunohistochemistry or 
immunofluorescence or flow 
cytometry).
For sCR: Detection of 
kappa/lambda ratio by 2-4 color 
flow cytometry is strongly 
preferred. If flow cytometry is 
not available at site, either 
immunohistochemistry or 
immunofluorescence can be 
done, however, kappa/lambda 
ratio from analysis of ≥100 
plasma cells is required to 
confirm sCR.
If sCR is not met, repeat local 
testing for sCR with subsequent 
bone marrow examinations will 
be done at the time of the next 
protocol-required bone marrow 
examination.
MRD Assessment: 
A portion of bone marrow aspirate 
collected for confirmation of CR/sCR will 
be sent to the central laboratory for MRD 
assessment.
For subjects with CR/sCR, an additional 
bone marrow aspirate will be obtained at 
12, 18, 24, and 30 months after first dose 
and sent to the central laboratory to 
monitor for MRD. For the 12, 18, 24, and 
30-month bone marrow aspirate, subjects 
can have a window of 2 months after each 
time point to complete the bone marrow 
aspiration (ie, range of 12-14, 18-20, 24-26 
and 30-32 months after C1D1).
Disease 
Progression
Not applicable.
If feasible, a bone marrow aspirate is 
requested to be collected from subjects in 
both treatment arms at disease progression 
to evaluate mechanisms of resistance.
CR=complete response; FFPE=formalin-fixed paraffin embedded; FISH=fluorescence in situ 
hybridization; MRD=minimal residual disease; sCR=stringent complete response
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9.2.1.6.
Minimal Residual Disease Assessment
Minimal Residual Disease (MRD) assessment by next-generation sequencing (NGS) is a 
relatively new and effective tool in the assessment of patients with multiple myeloma 
(Ladetto, 2014).21 Several studies have demonstrated that MRD status is correlated with PFS and 
OS (Martinez-Lopez, 2014).24 In the present study, bone marrow aspirate will be collected for 
MRD analysis when bone marrow samples are obtained at Screening, confirmation of CR/sCR, 
and subsequent time points after the first dose (see Table 10).
9.2.1.7.
Assessment of Lytic Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, 
femora, and any other bones for which the investigator suspects involvement by disease) is to be 
performed and evaluated by the local laboratory by roentgenography (or the local standard of 
care imaging, eg, low-dose CT) during the Screening Phase. Please note that the same 
methodology used at Screening should be used throughout the study for comparison purposes. 
During the Treatment Phase and before disease progression is confirmed, imaging should be 
performed whenever clinically indicated based on symptoms, to document response or 
progression. Magnetic resonance imaging (MRI) is an acceptable method for evaluation of bone 
disease, and may be included as an additional assessment at the discretion of the investigator (see 
the disease response criteria in Table 9).
Sometimes subjects present with disease progression manifested by symptoms of pain due to 
bone changes. Therefore, disease progression may be documented, in these cases, by skeletal 
survey or other radiographs, depending on the symptoms that the subject experiences. If the 
diagnosis of disease progression is obvious by radiographic investigations, then no repeat 
confirmatory imaging is necessary. In instances where changes may be subtler, repeat imaging
may be performed in 1 to 3 weeks per investigator discretion.
9.2.1.8.
Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary plasmacytomas must be documented during the Screening Phase. 
Clinical examination or MRI may be used to document extramedullary sites of disease. 
Computed tomography scan evaluations are an acceptable alternative if there is no 
contraindication to the use of intravenous contrast. Positron emission tomography scan or 
ultrasound tests are not acceptable to document the size of extramedullary plasmacytomas.
Extramedullary plasmacytomas should be assessed for all subjects with a history of 
plasmacytomas or if clinically indicated at Screening, by clinical examination or radiologic 
imaging. For subjects with a history of plasmacytomas assessed by physical examination, 
physical examination should be repeated on Cycle 1 Day 1 if not done within 14 days prior to 
randomization. Assessment of measurable sites of extramedullary disease will be performed and 
evaluated locally every 6 weeks (by physical examination) or every 12 weeks by imaging 
(if required) for subjects with a history of plasmacytomas or as clinically indicated during 
treatment for other subjects, until confirmed disease progression. For every subject, the 
methodology used for evaluation of each disease site should be consistent across all visits. 
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Irradiated or excised lesions will be considered not measurable, and will be monitored only for 
disease progression.
To qualify for PR, the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have decreased by at least 50%, and new plasmacytomas 
must not have developed (see the disease response criteria in Table 9). To qualify for disease 
progression, either the sum of products of the perpendicular diameters of the existing 
extramedullary plasmacytomas must have increased by at least 50% or a new plasmacytoma 
must have developed. In the cases where not all existing extramedullary plasmacytomas are 
reported, but the sum of products of the perpendicular diameters of the reported plasmacytomas 
have increased by at least 50%, this will also qualify as disease progression.
9.2.2.
Endpoints
Primary Endpoints
The primary endpoint is PFS, which is defined as the duration from the date of randomization to 
either progressive disease or death, whichever comes first. Disease progression will be 
determined according to the IMWG criteria (Durie 2006, Rajkumar 2011).8,37 For subjects who 
have not progressed and are alive, data will be censored at the last disease evaluation before the 
start of any subsequent anti-myeloma therapy. Relapse from CR by positive immunofixation or 
trace amount of M-protein is not considered to be progressive disease and is not included in the 
PFS calculation.
As the superiority of daratumumab combined with VMP over VMP alone with respect to PFS 
was established at the second interim analysis, the interim PFS analysis will serve as the primary 
PFS analysis, which otherwise was to occur when approximately 360 PFS events had been 
observed.
Secondary Endpoints
The secondary efficacy endpoints include:

Time to disease progression (TTP) is defined as the time from the date of randomization to 
the date of first documented evidence of PD, as defined in the IMWG criteria. For subjects 
who have not progressed, data will be censored at the date of the disease evaluation before 
the start of any subsequent anti-myeloma therapy.

CR rate, defined as the percentage of subjects achieving CR, as defined by:

Negative immunofixation of serum and urine, and

Disappearance of any soft tissue plasmacytomas, and

<5% PCs in bone marrow

For those subjects with negative or low SPEP (≤0.2 g/L) and suspected daratumumab 
interference on immunofixation, a reflex assay using anti-idiotype antibody will be 
utilized to confirm daratumumab interference and rule out false positive 
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immunofixation. Subjects who have confirmed daratumumab interference, but meet all 
other clinical criteria for CR or sCR, will be considered CR/sCR.

MRD negativity rate, defined as the proportion of subjects who have negative MRD at any 
time point after the date of randomization.

Progression-free Survival on Next line of Therapy (PFS2), defined as the time from 
randomization to progression on the next line of treatment or death, whichever comes first. 
Disease progression will be based on investigator judgment. Subjects who are still alive and 
not yet progressed on the next line of treatment will be censored on the last date of 
follow-up.

Time to next treatment, defined as the time from randomization to the start of the next-line 
treatment.

Overall response rate (ORR), defined as the proportion of subjects who achieve PR or better, 
according to the IMWG criteria, during or after the study treatment.

sCR rate, defined as the percentage of subjects achieving CR in addition to having a normal 
FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry, 
immunofluorescence, 2-4 color flow cytometry.

Proportion of subjects who achieve VGPR or better, defined as the proportion of subjects 
achieving VGPR and CR (including sCR) according to the IMWG criteria during or after the 
study treatment at the time of data cutoff.

Time to response, defined as the time between randomization and the first efficacy 
evaluation that the subject has met all criteria for PR or better. For subjects without 
response, data will be censored either at the date of progressive disease or, in the absence of 
progressive disease, at the last disease evaluation before the start of subsequent anti-
myeloma therapy.

Duration of response, calculated from the date of initial documentation of a response (PR or 
better) to the date of first documented evidence of progressive disease, as defined in the 
IMWG criteria. For subjects who have not progressed, data will be censored at the last 
disease evaluation before the start of any subsequent anti-myeloma therapy.

OS, measured from the date of randomization to the date of the subject’s death. If the 
subject is alive or the vital status is unknown, then the subject’s data will be censored at the 
date the subject was last known to be alive.

Impact of D-VMP compared to VMP on patient-reported perception of global health.

Clinical efficacy of D-VMP in high risk molecular subgroups compared to VMP alone.
Exploratory Endpoints

Biomarkers predictive of response or resistance to daratumumab.

Durability of MRD negativity.
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9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the 
generation of antibodies to daratumumab (immunogenicity) will be obtained from all subjects in 
the D-VMP group according to the Time and Events Schedule. In the Follow-up Phase, for all 
subjects in Arm B (D-VMP), samples are to be collected 8 weeks after the last dose of 
daratumumab, regardless of whether there has been confirmed disease progression. At specified 
time points, venous blood samples (5 mL per sample) will be collected and the serum will be 
divided into 3 aliquots (1 aliquot for pharmacokinetic analysis, 1 aliquot for immunogenicity 
assessment [when appropriate], and 1 aliquot as a back-up).
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
or equivalent document for sample collection requirements. Collected samples must be stored 
under the specified and controlled conditions for the temperatures indicated in the laboratory 
manual. 
Samples collected for determining serum concentrations of daratumumab in this study may be 
retained to address questions about drug characteristics that may arise at a later time point.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab using validated immunoassay methods by or under the supervision of 
the sponsor’s bioanalytical facility. 
For the immunogenicity assessments, serum samples will be screened for antibodies binding to 
daratumumab and serum titer will also be determined from confirmed positive samples. Other 
immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to 
further characterize the immune responses that are generated.
9.3.3.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
For daratumumab, the pharmacokinetic evaluations include Cmin and Cmax. If sufficient data 
are available, then other pharmacokinetic parameters may be calculated. If sufficient data are 
available, population pharmacokinetic analysis of serum concentration-time data of 
daratumumab may be performed and may include data from other clinical studies; details will be 
provided in a population pharmacokinetic analysis plan and results will be presented in a 
separate report.
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9.3.4.
Immunogenicity Assessments (Antibodies to daratumumab)
Serum from venous blood samples collected from D-VMP subjects will be assessed for the 
generation of antibodies to daratumumab (immunogenicity) according to the Time and Events 
Schedule. In the Follow-up Phase, for all subjects in Arm B (D-VMP), samples are to be 
collected for immunogenicity assessments 8 weeks after the last dose of daratumumab, 
regardless of whether there has been confirmed disease progression. Daratumumab concentration 
is also evaluated at all immunogenicity time points to ensure appropriate interpretation of 
immunogenicity data. When both serum concentration and immunogenicity analyses are 
specified, they are performed on aliquots from the same blood draw and no additional sampling 
is required. Procedures for sample collection, preparation, identification, storage, and shipment 
will be provided in the Laboratory Manual or equivalent document. 
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab 
any time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety 
or efficacy aspects that address concerns arising during or after the study period or for the 
evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy. If these analyses are performed, then the details and results 
will be presented in a separate report.
9.5.
Biomarkers
Biomarker assessments will focus on two main objectives including evaluating the ability of 
daratumumab + VMP to reduce minimal residual disease (MRD) in subjects that achieve a 
complete response (compared to VMP alone), and to determine the clinical benefit (ORR, PFS, 
and OS) of daratumumab + VMP in high-risk molecular subtypes (del17p, t(4;14), t(14;16), 
specific gene signatures, specific mutations). Bone marrow aspirates will be collected at 
screening and following treatment as outlined in the Time and Events Schedule.  Baseline bone 
marrow aspirate samples will be subjected to DNA and RNA sequencing in order to classify 
subjects into high-risk molecular subgroups and to establish the myeloma clone for MRD 
monitoring. A fresh bone marrow aspirate or biopsy at Screening is required if at all possible; by 
exception non-decalcified diagnostic tissue (bone marrow aspirate slides or FFPE tissue) may be 
supplied for MRD assessment instead. For subjects who achieve a CR or sCR, bone marrow 
aspirates will be utilized for assessment of MRD by next-generation sequencing (NGS) of 
immunoglobulin heavy and light chains (Vij 2013).43 If this methodology is unavailable, or 
determined to be scientifically inferior, then alternative methods for MRD assessment may be 
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utilized. In cases where daratumumab is suspected of interfering with serum IFE and preventing 
clinical CR response calls, subjects with VGPR will also be evaluated for MRD by NGS.  
In addition to planned bone marrow aspirate assessments, a whole blood sample will be collected 
from subjects as outlined in the Time and Events Schedule for processing to plasma and PBMCs. 
These samples may be used to evaluate specific subsets of immune cells such as cytotoxic 
T cells, regulatory T cells, MDSCs, and activated NK cells. Cells may also be used for additional 
phenotypic and functional profiling. Proteomic analysis may also be used to evaluate changes in 
cytokines, complement proteins, soluble CD38, soluble CD59, IFNγ, granzyme, perforin, and 
other proteins associated with ADCC/CDC/ADCP to evaluate potential biomarkers of response 
and resistance.
Potential mechanisms of tumor resistance, such as changes in antigen (CD38) expression or 
increased expression in complement inhibitory proteins (CD46, CD55, and CD59) in multiple 
myeloma cells, may be monitored in subjects if a bone marrow aspirate sample is deemed 
feasible for collection at progressive disease. In addition, changes in expression patterns of genes 
associated with ADCC, CDC, or other mechanisms of action of daratumumab may be evaluated. 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if, during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or if there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation. In the event the study is terminated early 
or shows poor clinical efficacy, completion of biomarker assessments is based on justification 
and intended utility of the data. Samples for biomarker evaluations will be collected as specified 
in the Time and Events Schedule.
9.6.
Patient-reported Outcomes
It is anticipated that the addition of daratumumab will provide benefits in terms of symptom 
reduction, improved functioning, and improved utilities. To measure functional status, well-
being, and symptoms, the EORTC QLQ-C30 and the EQ-5D-5L instruments will be used. Both 
questionnaires will be completed at the time points outlined in the Time and Events Schedule
before any other study procedures scheduled for the same day. All PRO measures will be 
completed using an electronic device (ePRO). For more details, refer to the ePRO user manual.
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning, 
role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global 
Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single 
items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The 
recall period is 1 week (the past week). The EORTC QLQ-C30 has been widely used among 
cancer patients. Scores are transformed to a 0 to 100 scale. Administration time is approximately 
11 minutes. Reliability, validity, and clinically meaningful change have been demonstrated in 
patients with multiple myeloma (Wisloff 1996, Wisloff 1997).44,45 The focus of the 
PRO assessment will be the global health scale which is designated as a secondary endpoint. The 
remaining domains are included as exploratory endpoints.
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The EQ-5D-5L is a generic measure of health status. For purposes of this study, the EQ-5D-5L 
will be used to generate utility scores for use in cost effective analyses. The EQ-5D-5L is a 
5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression plus a visual analog scale rating “health today” with 
anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state)
(Herdman 2011).15 The scores for the 5 separate questions are categorical and cannot be 
analyzed as cardinal numbers. However, the scores for the 5 dimensions are used to compute a 
single utility score ranging from zero (0.0) to 1 (1.0) representing the general health status of the 
individual.
9.7.
Medical Resource Utilization
Medical resource utilization (MRU) data, principally number of hospitalizations, will be derived 
from data collected in the eCRF for all subjects throughout the study.
9.8.
Safety Evaluations
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign 
measurements, physical examination findings, and assessment of ECOG performance status 
score. Any clinically relevant changes occurring during the study must be recorded on the 
Adverse Event section of the eCRF. Any clinically significant abnormalities persisting at the end 
of the study/early withdrawal will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached.
Based on the previous human experience with daratumumab, in vitro studies, and animal 
toxicological 
findings, 
infusion-related 
reactions/allergic 
reactions, 
hemolysis, 
and 
thrombocytopenia will be closely monitored. As a biologic agent, immunogenicity also will be 
monitored. Any of the safety monitoring assessments may be performed more frequently, and 
adverse events should be evaluated by the investigator according to the standard practice, if 
clinically indicated.
Details regarding the Independent Data Monitoring Committee are provided in Section 11.11.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule:
Adverse Events
Adverse events (with the exception of progression of multiple myeloma) will be reported by the 
subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable 
representative) from the time a signed and dated informed consent is obtained until 30 days 
following the last dose of study treatment. Adverse events will be followed by the investigator as 
specified in Section 12, Adverse Event Reporting.
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Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the eCRF. The laboratory reports must 
be filed with the source documents.
The following tests will be performed by the local laboratory:

Hematology Panel
-hemoglobin
-absolute neutrophil count
-white blood cell (WBC) count 
-platelet count
-absolute lymphocyte count

Serum Chemistry Panel
Screening, Cycles 1-9 and End-of-Treatment:
-blood urea nitrogen (BUN) or urea
-alkaline phosphatase
-creatinine
-lactic acid dehydrogenase (LDH)
-glucose
-uric acid
-aspartate aminotransferase (AST)
-total protein
-alanine aminotransferase (ALT)
-sodium*
-total bilirubin (direct bilirubin if total 
bilirubin >1.5xULN)
-potassium*
*Sodium and potassium assessments were added in Protocol Amendment 2, however, entry 
of sodium and potassium results in the eCRF will be done retrospectively from the date of 
subject consent for the duration of the study, if collected as part of routine care.
Cycle 10+:
-creatinine
-blood urea nitrogen (BUN) or urea
-sodium
-potassium
Cycle 10+, every third cycle:
-aspartate aminotransferase (AST)
-alanine aminotransferase (ALT)

Pregnancy testing: Serum or urine pregnancy test for women of childbearing potential only

Calcium and albumin adjusted calcium: These parameters will be part of the efficacy 
evaluations as specified in Section 9.2.1.3, and will be analyzed by the central laboratory. 
Measurement of calcium and albumin should follow the schedule for disease assessments. 
Measurement of free ionized calcium is an acceptable alternative to corrected serum calcium 
for determining hypercalcemia.
Daratumumab Interference with Indirect Antiglobulin Test (IAT) Results
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine 
pre-transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/RhD 
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typing. CD38 is expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 
on erythrocytes, which results in a positive IAT (Indirect Coombs Test). This positive result 
masks the detection of antibodies to minor antigens and may prevent or delay blood banks from 
issuing donor blood for transfusion. This effect occurs during daratumumab treatment and for up 
to 6 months after treatment ends. Subjects will receive a patient identification wallet card for the 
study that includes the blood profile (ABO, Rh, and IAT) determined before the first infusion of 
daratumumab along with information on the IAT interference for healthcare providers/blood 
banks. Subjects are to carry this card throughout the treatment period and for at least 6 months 
after treatment ends. Blood banks can eliminate the daratumumab IAT interference by treating 
reagent RBCs with dithiothreitol (DTT) (Chapuy 2015, Chapuy 2016).5,4
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically or genotypically matched units
b)
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
daratumumab IB.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during screening. Refer to 
Section 6.1.3.2 for details on subjects with higher risk of respiratory complications.
Electrocardiogram (ECG)
During the collection of ECGs, subjects should be in a quiet setting without distractions 
(eg, television, cell phones). Subjects should rest in a supine position for at least 5 minutes 
before ECG collection and should refrain from talking or moving arms or legs. If blood sampling 
or vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
Vital Signs (heart rate, temperature, blood pressure) will be performed as specified in the Time 
and Events Schedule. It is recommended that blood pressure (sitting) and heart rate
measurements be preceded by at least 5 minutes of rest in a quiet setting without distractions 
(eg, television, cell phones). Only vital signs at Screening or associated with an AE will be 
entered in the eCRF; all measurements will be recorded in the source documents.
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Physical Examination
A complete physical examination (including neurological examination) should be performed 
during the Screening Phase. Height will be measured at screening only; weight will be measured 
regularly as specified in the Time and Events Schedule. Thereafter, only a symptom and disease 
directed physical examination is required. Abnormalities will be recorded in the appropriate
sections of the eCRF.
Eastern Cooperative Oncology Group (ECOG) Performance Status
When scheduled, ECOG assessments along with PRO questionnaires should be obtained prior to 
any other study procedures planned for the same day.
9.9.
Sample Collection and Handling
If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of 
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. After blood sample 
collection, the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia
(or equivalent)/sodium heparin of 10 U/mL and charged with a volume equal to the dead space 
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has finished all protocol-
specified procedures before the end of the study, has not been lost to follow up, or has not 
withdrawn consent for study participation before the end of the study. The study end is defined 
as when 330 deaths have occurred, or 5 years after the last subject is randomized, whichever 
comes first.
Completion of Study Treatment
Subjects in Arm A (VMP) will be considered to have completed the study treatment if they have 
received at least 1 dose of study treatment in Cycle 9 and have not discontinued study treatment 
in Cycle 9 due to any of the reasons in Section 10.2 (Discontinuation of Study Treatment).
Subjects in Arm B (D-VMP) will continue daratumumab monotherapy until PD or until 
discontinuation due to an AE. As there is no protocol-defined study treatment period for this
arm, no subjects in Arm B will be considered to complete study treatment at any time.
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10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this 
will not result in automatic withdrawal of the subject from the study. After treatment 
discontinuation, the subject will move into the Follow-up Phase. The End-of-Treatment Visit and 
Follow-up visit assessments should continue as specified in the Time and Events Schedule. If 
study treatment is discontinued for a reason other than disease progression, then disease 
evaluations will continue to be performed as specified in the Time and Events Schedule.
Subjects who need to discontinue treatment with any one component of study treatment 
(VELCADE, melphalan, prednisone, or daratumumab) may continue to receive treatment with 
the other components of study treatment, as assigned.
A subject's study treatment should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant 

The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study treatment

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for multiple myeloma

The subject experiences unacceptable toxicity, including infusion-related reactions as 
described in Section 6.1.4

The subject’s dose of daratumumab is held for more than 4 weeks (Cycle 1 to Cycle 9), after 
Cycle 9 if the subject misses 2 consecutive planned doses (unless Sponsor approves 
continuation)

The subject experiences disease progression (please see below). Relapse from CR is not 
considered as disease progression
A subject who experiences a second primary malignancy that can be treated by surgery alone, 
may continue to receive the assigned study treatment and should continue to be followed for 
subsequent progression of multiple myeloma.
If any component of VMP requires dose reduction for a third time, only the component requiring 
dose reduction for a third time should be discontinued (ie, other components of the VMP 
regimen may continue to be administered).
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Before subjects discontinue study treatment due to disease progression, sites will document 
disease progression (for example by completing a disease progression form or by contacting the 
IWRS) as soon as possible and within 48 hours. The medical monitor will confirm that treatment 
should be discontinued. After confirmation from the sponsor, study treatment may be 
discontinued and the subject entered into Follow-up.
The primary reason for discontinuation of study treatment is to be recorded in the eCRF.
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent for study participation

Death

The study investigator or Sponsor, for any reason, stops the study or stops the subject’s 
participation in the study
Before a subject is considered lost to follow-up, every reasonable effort must be made by the 
study 
site 
personnel 
to 
contact 
the 
subject 
and 
determine 
the 
reason 
for 
discontinuation/withdrawal. The measures taken to follow up must be documented.
When a subject withdraws from the study, the reason for withdrawal is to be documented in the 
eCRF and in the source document. Study treatment assigned to the withdrawn subject may not be 
assigned to another subject. If a subject withdraws from the study before the end of treatment, 
assessments outlined in the End-of-Treatment Visit should be completed. If the reason for 
withdrawal from the study is withdrawal of consent then no additional assessments are allowed.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to 
Section 16.2.5). In such a case, samples will be destroyed after they are no longer needed for the 
clinical study. Details of the sample retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan.
11.1.
Subject Information
The primary analysis population will be the intent-to-treat (ITT) population, which will include 
all randomized subjects. Safety will be evaluated for the population of all treated subjects. The 
pharmacokinetic analyses will be performed on the pharmacokinetic evaluable population. 
Continuous variables will be summarized using descriptive statistics such as mean, standard 
deviation, and range. Categorical variables will be summarized using frequency tables. For 
time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
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11.2.
Sample Size Determination
In the VISTA study, the median PFS (as calculated by algorithm), was 18.3 months. The sample 
size calculation is performed based on the assumption that the median PFS for the VMP group in 
this study is estimated to be 21 months. Assuming that the addition of daratumumab can reduce 
the risk of the disease progression or death by 27.6%, ie, assuming the hazard ratio (VMP vs. 
D-VMP) of 0.724, which translates into a median PFS of 29 months for the D-VMP group, a 
total of 360 PFS events is needed to achieve a power of 85% to detect this hazard ratio with a 
log-rank test (two-sided alpha = 0.05). With a 20-month accrual period and an additional 
21-month follow-up, the total sample size needed for the study is approximately 700 
(350/treatment group) subjects. The sample size calculation has taken into consideration an 
annual dropout rate of 5%.
Long-term survival follow-up will continue until 330 deaths have been observed. Therefore, this 
study will achieve more than 80% power to detect a 27% reduction in the risk of death (hazard 
ratio=0.73) with a log-rank test (two-sided alpha=0.05).
11.3.
Efficacy Analyses
Response to study treatment and progressive disease will be evaluated by a validated computer 
algorithm. 
Primary Endpoint
For the primary endpoint of PFS, the primary analysis will consist of a stratified log-rank test for 
the comparison of the PFS distribution between the 2 treatment groups. The Kaplan-Meier 
method will be used to estimate the distribution of overall PFS for each treatment. The treatment 
effect (hazard ratio) and its two-sided 95% confidence intervals are to be estimated using a 
stratified Cox regression model with treatment as the sole explanatory variable. 
Secondary Endpoints
Other time-to-event efficacy endpoints, including TTP, PFS2, OS, and time to next treatment, 
will be analyzed using the same method as for PFS. For overall survival, the final analysis will 
occur after 330 deaths have been observed. Earlier analyses, in which overall survival is 
analyzed, will be considered as interim analyses. Even though the significance of PFS has 
already been established at the second interim analysis, testing of OS will continue as planned 
until a definitive conclusion on OS is reached. The details about testing of OS over time are 
specified in Section 11.10. The analysis of OS may be confounded by subjects from Arm A 
receiving daratumumab after their study treatment was stopped. Exploratory analysis may be 
performed to adjust for the effect daratumumab exposure may have on OS for the subjects who 
were randomized to Arm A (VMP).
Comparison between the 2 treatment groups of overall response rates, rate of VGPR or better,
rate of CR or better, and other binary endpoints will be conducted using the stratified Cochran 
Mantel Haenszel test. The Mantel-Haenszel odds ratio will be provided along with its two-sided 
95% confidence interval, and will be provided as the measure of treatment effect. Duration of 
response will be provided descriptively without formal statistical comparison.
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Strong control of familywise Type I error rate will be controlled at a two-sided significance level 
of 0.05 for the major secondary endpoints, including ORR, rate of VGPR or better, rate of CR or 
better, MRD negativity rate, and OS. A sequential hierarchical testing procedure will be used. 
The details of the testing procedure will be pre-specified in a statistical analysis plan that will be 
finalized prior to any unblinded efficacy analysis.
11.4.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population, 
defined as subjects who have received one dose of daratumumab and at least one post-infusion 
sample. All serum concentrations below the lowest quantifiable concentration or missing data 
will be labeled as such in the concentration data presentation. Concentrations below the lowest 
quantifiable concentration will be treated as zero in the summary statistics. All subjects and 
samples excluded from the analysis will be clearly documented in the study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling time point and pharmacokinetic parameters of daratumumab such as Cmin and Cmax. 
If sufficient data are available, then other pharmacokinetic parameters may be calculated, 
including but not limited to CL and V.
11.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab will be summarized for all subjects who receive a 
dose of daratumumab and have appropriate samples for detection of antibodies to daratumumab.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then population pharmacokinetic analysis of serum 
concentration-time data of daratumumab may be performed using nonlinear mixed-effects 
modeling. The potential population PK analysis may also include PK data from other clinical 
studies. If the population pharmacokinetic analysis is conducted, then details will be given in a 
population pharmacokinetic analysis plan, and the results of the analysis will be presented in a 
separate report.
11.7.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. Analyses will be performed and stratified by clinical covariates or molecular 
subgroups using the appropriate statistical methods (eg, parametric or non-parametric, univariate 
or multivariate, analysis of variance, or survival analysis, depending on the endpoint). 
Correlation of baseline expression levels or changes in expression levels with response or 
time-to-event endpoints will identify responsive (or resistant) subgroups in addition to genes and 
pathways attenuated following treatment with daratumumab. In order to remove any 
confounding influence of prognostic factors, any predictive biomarker identified in this study 
could be verified in a prospective clinical study with a control treatment arm.
Any biomarker measures will be listed, tabulated, and where appropriate, plotted. Subjects will 
be grouped by prescribed dose. Complete responders will be utilized to investigate the prognostic 
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effect of MRD on PFS. MRD analysis will include evaluation of data from other studies to 
determine if decreased MRD is seen with daratumumab + VELCADE based chemotherapy 
regimen compared with the VELCADE based chemotherapy alone. 
Results of biomarker and pharmacodynamic analyses may be presented in a separate report. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging study data show no likelihood of providing useful scientific information.
In addition, due to the small sample sizes of high-risk subgroups within the multiple myeloma
patient population, a meta-analysis may be performed across daratumumab Phase 3 studies to 
evaluate clinical efficacy of daratumumab with standard of care agents in pre-specified 
subgroups of multiple myeloma patients. The meta-analysis protocol will pre-specify the 
objective of the meta-analysis, the criteria for inclusion and exclusion of studies, the hypotheses 
and endpoints, and statistical methods including a method for investigation of heterogeneity. 
This meta-analytic approach, supported by high-quality data from the individual trials, should be 
able to provide definitive evidence on the effectiveness of daratumumab in the subpopulation of 
multiple myeloma subjects with high-risk molecular abnormalities. In a similar fashion, a meta-
analysis examining MRD negativity in daratumumab treated patients in frontline, newly 
diagnosed multiple myeloma (MMY3006, MMY3007, MMY3008) may also be performed.
11.8.
Patient-reported Outcomes
EORTC-QLQ-C30 scores will be evaluated for all domains except “financial problems” among 
patients with at least one post-baseline assessment and 50% completion of the relevant items for 
a domain.  Descriptive analyses followed by mixed model repeated measures will be used to 
analyze each domain score.  No adjustment for multiple comparisons will be made.
EQ-5D-5L scores will be summarized at each time point.
11.9.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). The severity assessment for 
an adverse event or serious adverse event should be completed using the NCI CTCAE Version 4.
All reported adverse events with onset during the treatment phase (ie, treatment-emergent 
adverse events, and adverse events that have worsened since baseline) will be included in the 
analysis. For each adverse event, the percentage of subjects who experience at least 1 occurrence 
of the given event will be summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe 
or a serious adverse event.
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Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline 
and for observed values and changes from baseline at each scheduled time point. Changes from 
baseline results will be presented in pre- versus post-treatment cross-tabulations (with classes for 
below, within, and above normal ranges). Frequency tabulations of the abnormalities will be 
made. A listing of subjects with any laboratory results outside the reference ranges will be 
provided. A listing of subjects with any markedly abnormal laboratory results will also be 
provided.
Parameters with predefined NCI CTCAE toxicity grades will be summarized. Change from 
baseline to the worst toxicity grade experienced by the subject during the study will be provided 
as shift tables. Worst toxicity grade during treatment will be presented, according to NCI
CTCAE (version 4). Clinically relevant changes (i.e. causing a treatment intervention and/or 
need for concomitant therapy) will be also recorded on the adverse event eCRF. All other lab 
abnormalities need not be recorded as adverse events.
Electrocardiogram (ECG)
Electrocardiogram data will be summarized by ECG parameter and listed.
Vital Signs
Descriptive statistics of baseline temperature, pulse/heart rate, and blood pressure (systolic and 
diastolic) values will be summarized.
11.10. Interim Analysis
Two interim analyses are planned for this study. The first interim analysis will be performed 
after a total of approximately 100 subjects have been treated for at least 2 cycles or discontinued 
the study treatment. Its purpose is to evaluate safety. The second interim analysis will be 
performed when approximately 216 PFS events, which is 60% of the total planned PFS events, 
have been accumulated. The purpose of this interim analysis is to evaluate cumulative interim 
safety and efficacy data. The significance level at this interim analysis to establish the superiority 
of D-VMP over VMP with regard to PFS will be determined based on the observed number of 
PFS events at the interim analysis, using the O’Brien-Fleming boundaries as implemented by the 
Lan-DeMets alpha spending method. Assuming 216 PFS events are observed, the alpha to be 
spent in this interim analysis will be 0.00762 (2-sided). If the experimental group (D-VMP) is 
numerically worse than the control group in terms of PFS (observed hazard ratio >1 favoring the 
control group), then the study may be terminated for futility.
As planned in the original protocol, two interim OS analyses will be performed at the time of the 
interim PFS (216 events) and the primary PFS (360 events) prior to the final OS analysis at 
330 deaths. As the superiority of daratumumab combined with VMP over VMP alone with 
respect to PFS was established at the interim PFS analysis, the second interim OS will occur 
when 200 deaths (60% of all planned deaths) have been accumulated which is about the same 
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time of the primary PFS analysis as if it would have occurred. The stopping boundary for OS 
will be determined using an alpha-spending approach. At the interim PFS analysis, an alpha of 
0.0001 will be spent. For the second OS interim and final analyses, the alpha to be spent will be 
determined by a linear alpha spending function based on the observed number of deaths at that 
time, ie, the cumulative alpha to be spent will be the total alpha (0.05) multiplied by the 
proportion of the observed number of deaths out of the total planned number of deaths (330).
11.11. Data Monitoring Committee
An IDMC, consisting of 2 clinicians and 1 statistician who are independent experts not otherwise 
participating in the study, will be established to review efficacy and safety results at the 2 
planned interim analyses. After the interim review, they will make recommendations regarding 
the continuation of the study. In addition, the IDMC may also review cumulative safety data 
every 6 months besides the two interim analyses. The IDMC will no longer review study data 
after the database lock for the primary analysis has been completed. The details will be provided 
in a separate IDMC charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
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Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study treatment and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For daratumumab, the expectedness of an 
adverse event will be determined by whether or not it is listed within the Reference Safety 
Information included in the Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
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Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4. Any adverse event or serious adverse event not listed in the 
NCI CTCAE Version 4 will be graded according to investigator clinical judgment by using the 
standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening of disabling adverse event
Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:
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
Overdose of a sponsor study drug. No MTD has been reached for daratumumab. However, if 
the dose exceeds the maximum tested dose of 24 mg/kg, then it will be considered as 
overdose in this study.

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the adverse event page of the 
eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the time a signed and dated ICF is obtained until 30 days after the last dose of 
study treatment unless the subject withdraws consent for study participation or starts subsequent 
anti-myeloma therapy. For subjects who have received subsequent treatment with therapeutic 
intent for multiple myeloma during the adverse event reporting period, only adverse events that 
are considered to be possibly, probably, or definitely related to daratumumab need to be 
reported. Serious adverse events, including those spontaneously reported to the investigator 
within 30 days after the last dose of study treatment, must be reported using the Adverse Event 
Form. The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to 
Section 12.1.1). Death should not be recorded as an adverse event or serious adverse event, but 
as the outcome of an adverse event. The adverse event that resulted in the death should be 
reported as a serious adverse event.
Only clinically relevant laboratory abnormalities (ie, those causing a treatment intervention or 
need for concomitant therapy) should be recorded on the adverse event eCRF. All other 
laboratory abnormalities need not be recorded as adverse events.
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. Anticipated events will be 
recorded and reported as described in Attachment 10.
All adverse events, regardless of seriousness, severity, or presumed relationship to study 
treatment, must be recorded using medical terminology in the source document and the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
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"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning 
the relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator’s assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the investigational institute where required). The sponsor assumes responsibility for 
appropriate reporting of anticipated events to the regulatory authorities per requirements of the 
countries in which the studies are conducted. The investigator (or sponsor where required) must 
report these events to the appropriate Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) that approved the protocol unless otherwise required and documented by the 
IEC/IRB.
For all studies with an outpatient phase, including open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study treatment phase (Arm A) and for at least 6 months after the study treatment is 
discontinued (Arm B) indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Blood type and indirect antiglobulin test results (as described in Section 9.8 for subjects in 
Treatment Arm B)
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
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All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

If the subject is hospitalized overnight due to slow daratumumab infusion, or for observation 
after daratumumab infusion, and in the absence of a significant medical event

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must promptly discontinue further study treatment.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Reporting, Monitoring, and Review of Safety Events in Japanese Subjects
in Arm B (Japanese Sites Only)
There will be enhanced reporting, monitoring, and review of pre-specified safety events that 
occur during Cycle 1 at Japanese sites, for Japanese subjects in Arm B until a minimum of 
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3 Japanese subjects in Arm B have completed Cycle 1. A list of these pre-specified safety events 
and details regarding the reporting requirements are available in Attachment 8.
12.5.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The daratumumab supplied for this study is a colorless to yellow liquid and sterile concentrate of 
20 mg/mL in a vial. It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL.
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14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage
All study drug vials must be stored in the original carton at controlled temperatures in a 
refrigerator ranging from 2°C to 8°C and must not be utilized after the expiry date printed on the 
label. The product must be protected from light and must not be frozen. Daratumumab does not 
contain preservatives; therefore, any unused portion remaining in the vial must be discarded.
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl) 
prior to IV administration. Refer to the Investigational Product Preparation Instructions or Site 
Investigational Product Procedures Manual for details regarding dose preparation, storage, and 
handling of diluted solutions.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug, or used returned study drug for destruction, will be documented on the drug return form. 
When the study site is an authorized destruction unit and study drug supplies are destroyed on-
site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for daratumumab
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
Site Investigational Product Procedures Manual

Laboratory manual

PRO questionnaires on a TrialSlate and user guidelines

eCRF completion guidelines

Sample ICF

Subject diaries

Subject wallet card indicating blood type and indirect antiglobulin test results

Other manuals and guidance documents as needed
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with infusion-related reactions; see 
Section 6.1.3 for prevention details. Based on the mode of action of daratumumab, a potential risk 
could be infection; therefore, the protocol requires the review of hematological laboratory results 
prior to daratumumab infusion. CD38 is distributed in erythrocytes and platelets. A significant 
reduction of platelets was reported in an animal study. In a human clinical study (Study GEN501), 
thrombocytopenia was also reported. However, safety laboratory monitoring did not show a 
clinically meaningful reduction of platelets. Anemia was also reported in Study GEN501. Free 
hemoglobin was mildly elevated, but other parameters did not support hemolysis. No bleeding 
events were observed. Routine safety laboratory measurement of RBCs and platelets will be 
closely monitored in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume for the study is estimated at approximately 45 mL during screening and 
480 mL during VMP treatment in the first year. In the post-VMP treatment phase, blood 
sampling for subjects in Arm B will be approximately 305 mL per year on treatment. In the 
Follow-up Phase, subjects prior to PD will have approximately 120 mL blood drawn per year for 
serum disease evaluations. This is considered to be within the normal range of a single blood 
donation.
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16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects
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
If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
Furthermore, where required, progress reports/written summaries of the trial status will be 
submitted to the IRB/IEC annually, or more frequently if requested.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
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that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent disease-
related treatments, or to obtain information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or legally acceptable representative must be informed about the study as soon as possible 
and give consent to continue.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
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related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker/PK/immunogenicity research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand daratumumab, to 
understand multiple myeloma, to understand differential drug responders, and to develop 
tests/assays related to daratumumab and multiple myeloma.  The research may begin at any time 
during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
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During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page(s) provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Pre-Study Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
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The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all sub-investigators

Documentation of sub-investigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of signed informed consent; dates of visits; results of safety and efficacy 
parameters as required by the protocol; record of all adverse events and follow-up of adverse 
events; concomitant medication; drug receipt/dispensing/return records; study treatment
administration information; and date of study completion and reason for early discontinuation of 
study treatment or withdrawal from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
Subject- and investigator-completed scales and assessments designated by the sponsor (EORTC 
QLQ-C30 and EQ-5D-5L) will be recorded directly into an electronic device or other tool and 
will be considered source data.
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The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. Data must be entered 
into eCRFs in English. Study site personnel must complete the eCRF as soon as possible after a 
subject visit, and the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 3 
different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
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17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's data base, and 
direct transmission of PRO data to the ePRO vendor database and then to the sponsor’s database. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the sponsor and 
study-site personnel and are accessible for verification by the sponsor study-site contact. If 
electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed after 330 deaths have occurred or 5 years after the last subject 
is randomized, whichever is first. The final data from the study site will be sent to the sponsor
(or designee) after completion of the final subject at that study site, in the time frame specified in 
the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
biomarker analyses performed after the Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
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Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary 
(multicenter) data and information without approval from the investigator. The investigator has 
the right to publish study site-specific data after the primary data are published. 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. Expedited 
reviews will be arranged for abstracts, poster presentations, or other materials. If requested by 
the sponsor in writing, the investigator will withhold such publication for up to an additional 
60 days to allow for filing of a patent application. In the event that issues arise regarding 
scientific integrity or regulatory compliance, the sponsor will review these issues with the 
investigator. The sponsor will not mandate modifications to scientific content and does not have 
the right to suppress information. For multicenter study designs and substudy approaches, 
secondary results generally should not be published before the primary endpoints of a study have 
been published. Similarly, investigators will recognize the integrity of a multicenter study by not 
submitting for publication data derived from the individual study site until the combined results 
from the completed study have been submitted for publication, within 18 months after study end 
date, or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as 
those described in the ICMJE Recommendations for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical Journals, which state that the named authors must 
have made a significant contribution to the conception or design of the work; or the acquisition, 
analysis, or interpretation of the data for the work; and drafted the work or revised it critically for 
important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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Martinez-Lopez J, Lahuerta JJ, Pepin F, et al.  Prognostic value of deep sequencing method for minimal 
residual disease detection in multiple myeloma.  Blood, prepublished online March 19, 2014: 10.1182/blood-
2014-01-55020.
25.
Mateos MV, Bringhen S, Richardson PG, et al. Bortezomib cumulative dose, efficacy, and tolerability with 
three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible 
for high-dose therapy. Haematologica. 2014:Apr 24 [Epub ahead of print].
26.
Mateos MV, Oriol A, Martinez-Lopez J, et al. Bortezomib, melphalan, and prednisone versus bortezomib, 
thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and 
thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a 
randomised trial. Lancet Oncol. 2010;11:934-941.
27.
Mateos MV, Oriol A, Martínez-López J, et al. Maintenance therapy with bortezomib plus thalidomide or 
bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. 
Blood. 2012;120:2581-2588.
28.
McCudden, CR, Voorhees PM, Hainsworth SA, et al. Interference of monoclonal antibody therapies with serm 
protein electrophoresis tests. Clin Chem. 2010;56:1897-1904.
29.
Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in 
patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 
2011;12:431-440.
30.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Multiple Myeloma, version 2.2013.
31.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655.
32.
Overdijk MB, Verploegen S, Bogels M, et al. Phagocytosis is a potent mechanism of action for the therapeutic 
human monoclonal antibody daratumumab in lymphoma and multiple myeloma. Submitted to Blood. 
13 May 2013. 
33.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-1060.
34.
Palumbo A, Brighen S, Rossi D, et al. A Prospective, Randomized, Phase III Study of Bortezomib, Melphalan, 
Prednisone and Thalidomide (VMPT) Versus Bortezomib, Melphalan and Prednisone (VMP) in Elderly Newly 
Diagnosed Myeloma Patients. Blood. 2008;112:652. ASH Annual Meeting Abstract.
35.
Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by  
Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial 
Treatment of Multiple Myeloma: A Randomized Controlled Trial. J Clin Oncol. 2010;28:5101-5109.
36.
Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of 
multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell 
transplantation. Leukemia. 2009;23:1716-1730.
37.
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695.
38.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for 
the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548.
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39.
San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment 
of multiple myeloma. N Engl J Med. 2008;359:906-917.
40.
Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of multiple myeloma. Br J 
Haematol. 2005;132:410-451.
41.
Sonneveld P, Goldschmidt H, Rosinol L, et al. Bortezomib-Based Versus Nonbortezomib-Based Induction 
Treatment Before Autologous Stem-Cell Transplantation in Patients With Previously Untreated Multiple 
Myeloma: A Meta-Analysis of Phase III Randomized, Controlled Trials. J Clin Oncol. 2013:31;3279-3287.
42.
van der Veer M, de Weers M, van Kessel B. The therapeutic human CD38 antibody daratumumab improves 
the anti-myeloma effect of newly emerging multi-drug therapies. Blood Cancer Journal. 2011a; 1 e41. 
Doi:10.1038/bcj.2011.42.
43.
Vij R, Mazumder A, Klinger M, et al. Deep sequencing reveals myeloma cells in peripheral blood in majority 
of multiple myeloma patients, Clinical Lymphoma, Myeloma and Leukemia (2013), doi: 
10.1016/j.clml.2013.09.013.
44.
Wisloff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Nordic 
Myeloma Study Group. Br J Haematol. 1996;92:604-613.
45.
Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemotherapy predicts for 
survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol. 1997;97:29-37.
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Attachment 1:
Modified IMWG Diagnostic Criteria for Multiple Myeloma
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytomaa AND any one or more of the following myeloma defining events: 
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative 
disorder, specifically:

Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or
>2.75 mmol/L (>11 mg/dL)

Renal insufficiency: creatinine clearanceb
<40mL/min or serum creatinine 
>177 µmol/L (>2 mg/dL)

Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin 
<10 g/dL

Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-
CTc
Footnotes:
a)
Clonality should be established by showing /light-chain restriction on flow cytometry, 
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage 
should preferably be estimated from a core biopsy specimen; in case of a disparity between 
the aspirate and the core biopsy, the highest value should be used. 
b)
Measured or estimated by validated equations.
c)
If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required 
to distinguish from solitary plasmacytoma with minimal marrow involvement.
Reference: Rajkumar 201438
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Attachment 2:
ECOG Performance Status Scale
Grade ECOG Performance Status 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
Reference:  Oken 198231
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Attachment 3:
Serum Calcium Corrected for Albumin
If calcium is expressed in mg/dL and albumin is expressed in g/dL:
Corrected calcium (mg/dL) = 
serum calcium (mg/dL) + 0.8•(4 - serum albumin [g/dL])
If calcium is expressed in mmol/L and albumin is expressed in g/L:
Corrected calcium (mmol/L) = 
serum calcium (mmol/L) + 0.02•(40 - serum albumin [g/L])
Source: Burtis 19993
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Attachment 4:
Guideline for Asthma Eligibility Criteria
Components of Severity
ClassificationofAsthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4
yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Impairment
Normal 
FEV1/FVC :
8-19 yr 85%
20-39 yr
80%
40-59 yr
75%
60-80 yr
70%
Symptoms
≤2 days/week
≤2 days/week but not daily
Daily
Throughout the day
Nighttime 
awakenings
0
≤2x/month
1-2x/
month
3-4x/month
3-4x/
month
> 1x/week but not 
nightly
> 1x/
month
Often 7x/week
SABA use for 
symptom control 
(not prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/ 
week but
not daily,
and
not more 
than 1x
on
any day
Daily
Several time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced
5%
N/A
< 60%
< 75%
< 60% 
Reduced
5%
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 exacerbations in
6 months requiring
oral steroids or >4 
wheezing 
episodes/1 year
lasting >1 day and
risk factors for 
persistent asthma
≥ 2/year
Relative 
annual
risk may
be related
to FEV1.
≥ 2/year
Relative 
annual
risk may
be related
to FEV1.
≥ 2 exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year
lasting >1 day and
risk factors for 
persistent asthma
≥ 2/year
Relative 
annual
risk may
be related
to FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations
in
6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day 
and risk factors 
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual
risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
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Recommended Step for
Initiating Treatment
Step 1
Step 2
Step 3 and 
consider short 
course of oral 
steroids
Step 3: 
medium
dose ICS
and 
consider
short 
course of
oral 
steroids
Step 3 and 
consider 
short 
course of
oral 
steroids
Step 3 and 
consider short 
course of oral 
steroids
Step 3: 
medium
dose ICS
OR Step 4 
and
consider 
short course
of oral
steroids
Step 4 or
5 and
consider 
short 
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved. 0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or
adjusting therapy. 5-11 and 12+ years: adjust therapy accordingly.
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Components of 
Control
Classification of Asthma Control
Well Controlled
Not Well Controlled
Very Poorly Controlled
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Symptoms
≤ 2 days/week but not more
than once on each day
≤ 2 days/
week
> 2 days/week or 
multiple times on ≤2 
days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime 
awakenings
≤ 1x/month
≤ 2x/month
> 1x/month
≥ 2x/month
1-3x/week
> 1x/week
≥ 2x/week
≥ 4x/week
Interference with 
normal activity
None
Some limitation
Extremely limited
SABA use for symptom control 
(not prevention of EIB)
≤2 days/week
> 2 days/week
Several times per day
Lung function
FEV1 or peak flow
FEV1/FVC
N/A
> 80%
> 80%
> 80%
N/A
60-80%
75-80%
60-80%
N/A
< 60%
< 75%
< 60%
Validated questionnaires
ATAQ
ACQ
ACT
0
≤ 0.75
≥ 20
1-2
≥ 1.5
16-19
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral 
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung 
function
Evaluation requires long-term follow-up
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Recommended Action for
Treatment
• Maintain current step
• Regular follow-up every 1-6 
months
• Consider step down if well 
controlled for at least 3 months
Step up 1 
step
Step up at 
least 1 step
• Step up 1 
step
• Reevaluate
in 2-6 
weeks
• For side 
effects, 
consider 
alternative 
treatment 
options
• Consider short
course of oral steroids
• Step up 1-2 steps
• Consider 
short course 
of oral 
steroids
• Step up 1-
2 steps
• 
Reevaluate 
in 2 weeks
• For side
effects, 
consider 
alternative 
treatment 
options
• Before step up:
Review adherence to
medication, inhaler 
technique, and 
environmental control. If 
alternative treatment was 
used, discontinue it and use 
preferred treatment for that 
step.
• Reevaluate the level of 
asthma control in 2-6
weeks to achieve 
control.
0-4 years: If no clear benefit
is observed in
4-6 weeks, consider
alternative diagnoses or 
adjusting therapy.
5-11 years: Adjust therapy
accordingly.
• For side effects, 
consider alternative 
treatment options.
• Before step up:
Review adherence to
medication, inhaler 
technique, and 
environmental control. If 
alternative treatment was 
used, discontinue it and 
use preferred treatment for 
that step.
• Reevaluate the level
of asthma control in 
2-6 weeks to achieve 
control.
0-4 years: If no clear 
benefit is observed in
4-6 weeks, consider
alternative diagnoses or 
adjusting therapy.
5-11 years: Adjust therapy
accordingly.
• For side effects, 
consider alternative 
treatment options.
American Lung Association of Minnesota
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Attachment 5:
Antihistamine Medications
The following antihistamines may be used for daratumumab pre-infusion medication (including, 
but not limited to):

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine

Promethazine*
* The IV use of promethazine should be avoided. 
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Attachment 6:
Conversion Table for Glucocorticosteroid Dose
Generic Name
Oral or Intravenous
Dose (mg)
Dexamethasone
0.75
Methylprednisolone
4
Prednisolone
5
Prednisone
5
Betamethasone
0.6
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Attachment 7:
Body Surface Area Nomogram
Body surface area should be calculated according to the following formula:
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Attachment 8: Reporting, Monitoring, and Evaluating Safety Events in Japanese 
Subjects in Arm B (Japanese Sites Only)
Enhanced reporting of specific events (as described below) will be required until a minimum of 
3 Japanese subjects in Arm B have completed Cycle 1 of treatment.  If these specific events (as described 
below) occur in Cycle 1 in ≥2 subjects from the first 3 treated subjects in Arm B, an additional 3 subjects 
in Arm B will be monitored (for a total of 6 subjects).  The events (as described below) that occur during 
Cycle 1 of treatment in Japanese subjects in Arm B will be reported to the sponsor by the investigator or 
study personnel within 24 hours of awareness.
Definitions of Adverse Events in Japanese Subjects in Arm B that are Subject to Evaluation 
by External Safety Monitor (ESM)
Any of the following events considered by the investigator to be related to study treatment
(VELCADE, melphalan, prednisone, or daratumumab):
Infusion-related reactions

Any Grade 4 infusion-related reactions occurring within 48 hours of the infusion of daratumumab

Any Grade 3 infusion-related reactions occurring within 48 hours of the infusion of daratumumab 
that do not resolve with a reduced infusion rate or temporarily stopping (maximum 2 hours) the 
infusion, supportive care, and symptomatic therapy such as administration of steroid and 
antihistamine
Non-hematologic toxicity of Grade 3 or higher with the exception of:

Grade 3 nausea or Grade 3 vomiting that responds to antiemetic treatment

Grade 3 diarrhea that responds to antidiarrheal treatment

Grade 3 fatigue or asthenia present at baseline or lasting for less than 7 days after the last 
administration of daratumumab
Hematologic toxicity, defined as:

Grade 4 thrombocytopenia (platelet count <25,000/mm3) lasting for more than 7 days, or Grade 3 or
4 thrombocytopenia with bleeding

Grade 4 neutropenia (ANC <500 cells/mm3) lasting for more than 7 days

Grade 3 febrile neutropenia (ANC <1000 cells/mm3 and a single temperature >38.3°C or a sustained 
temperature >38°C for >1 hour), or sepsis

Grade 4 anemia
These events should follow the same reporting process as serious adverse events (see Section 12.3.2). 
Receipt of a report of a serious adverse event or any of the events listed above during Cycle 1 of treatment 
will, in turn, trigger enhanced reporting and review as described below.
An External Safety Monitor (ESM) who is a hematologist will evaluate these events in Japan and will 
review the reported safety data and may request additional information from the sites. If the ESM 
identifies a critical safety signal, he/she may, at his/her discretion, suspend enrollment in Japan until 
Independent Data Monitoring Committee (IDMC) review is completed. The IDMC chair will be notified 
of the signal and will review the data. After the review is complete, the IDMC chair will communicate the 
final recommendation to the sponsor.
Japanese sites will be notified when the first 3 subjects in Arm B have completed Cycle 1 of treatment. 
However, if the above events occur in Cycle 1 in ≥2 subjects from the first 3 treated subjects in Arm B, an 
additional 3 subjects in Arm B will be monitored (for a total of 6 subjects) as described above.  After 
enrollment of a minimum of 3 subjects (and up to 6 subjects, as described above) is complete, enhanced 
reporting, monitoring, and evaluation of the above safety events in Japanese subjects will no longer be 
required.  However, serious adverse events and adverse events of special interest must continue to be 
reported to the sites within 24 hours of awareness, as described in Section
12.3.2.
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Attachment 9:
International Staging System (ISS) Staging
International Staging System
Stage
Criteria
Median Survival (months)
I
Serum ß2 microglobulin <3.5 mg/L, serum 
albumin ≥3.5 g/dL
62
II
Not I or IIIa
44
III
Serum ß2 microglobulin ≥5.5 mg/L
29
a There are 2 possibilities for Stage II: 
  1) Serum ß2 microglobulin <3.5 mg/L but serum albumin <3.5 g/dL, or 
  2) Serum ß2 microglobulin 3.5 to <5.5 mg/L irrespective of the serum albumin
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Attachment 10:
Anticipated Adverse Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease related) or 
background regimen.
For the purposes of this study the following events will be considered anticipated events: 

Anemia

Bleeding

Bone diseases

Hypercalcemia 

Hyperuricemia

Hyperviscosity syndrome

Infection

Neutropenia

Renal failure or insufficiency

Thrombocytopenia
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be 
anticipated events and will be reported to the sponsor as described in Section 12.3.1, All Adverse 
Events. Any anticipated event that meets serious adverse event criteria will be reported to the 
sponsor as described in Section 12.3.2 Serious Adverse Events. These anticipated events are 
exempt from expedited reporting as individual single cases to Health Authorities. However, if 
based on an aggregate review, it is determined that an anticipated event is possibly related to 
study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of 
pre-specified anticipated events at an aggregate level. The ARC is a safety committee within the 
sponsor’s organization that is independent of the sponsor’s study team. The ARC will meet to aid 
in the recommendation to the sponsor’s study team as to whether there is a reasonable possibility 
that an anticipated event is related to the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and 
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Ming Qi, MD, PhD
Institution:
Janssen Research & Development
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
NCT02195479


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ming Qi
15Feb2018, 05:12:59 AM, UTC
Document Approval
NCT02195479

SAP_001.pdf: 
1
Approved, Date: 19 July 2017
Janssen Research & Development 
Statistical Analysis Plan
A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomib) 
Melphalan-Prednisone (VMP) Compared to Daratumumab in Combination with VMP (D-
VMP), in Subjects with Previously Untreated Multiple Myeloma who are Ineligible for 
High-dose Therapy
Protocol 54767414MMY3007; Phase 3
JNJ-54767414  (daratumumab)
Authors: 
Status:
Approved
Date:
19 July 2017
Prepared by:
Janssen Research & Development, LLC; 
Document No.:
EDMS-ERI-142546005, 3.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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JNJ-54767414  (daratumumab)
Statistical Analysis Plan 54767414MMY3007
2
Approved, Date: 19 July 2017
TABLE OF CONTENTS
TABLE OF CONTENTS................................................................................................................................2
ABBREVIATIONS.........................................................................................................................................5
1.
INTRODUCTION..................................................................................................................................6
1.1.
Overview of Trial Design ..................................................................................................................6
1.2.
Statistical Hypotheses for Trial Objectives.......................................................................................8
1.3.
Sample Size Determination..............................................................................................................8
1.4.
Interim Analyses...............................................................................................................................9
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................9
2.1.
Visit Windows ...................................................................................................................................9
2.2.
Pooling Algorithm for Analysis Centers............................................................................................9
2.3.
Study Treatment and Study Drug.....................................................................................................9
2.4.
Study Treatment Dosing Date..........................................................................................................9
2.5.
Baseline Measurement...................................................................................................................10
2.6.
Unique Lab Value...........................................................................................................................10
2.7.
Imputation of Partial Dates .............................................................................................................10
2.7.1.
Missing/Partial Adverse Event Onset Date.................................................................................10
2.7.2.
Missing/Partial Adverse Event End Date ....................................................................................11
2.7.3.
Partial Concomitant Medication Start/End Date .........................................................................11
2.7.4.
Partial Multiple Myeloma Diagnosis Date ...................................................................................11
2.7.5.
Partial Subsequent Antimyeloma Therapy Start Date.................................................................12
2.8.
General Analysis Method ...............................................................................................................12
2.9.
Analysis Sets..................................................................................................................................12
2.10.
Definition of Subgroups..................................................................................................................13
3.
SUBJECT INFORMATION................................................................................................................14
3.1.
Demographics and Baseline Characteristics .................................................................................14
3.2.
Disposition Information...................................................................................................................15
3.3.
Extent of Exposure .........................................................................................................................15
3.4.
Protocol Deviations ........................................................................................................................16
3.5.
Prior, Concomitant and Subsequent Therapies .............................................................................17
4.
EFFICACY .........................................................................................................................................17
4.1.
Analysis Specifications...................................................................................................................17
4.1.1.
Level of Significance ...................................................................................................................17
4.1.2.
Data Handling Rules ...................................................................................................................19
4.2.
Primary Efficacy Endpoint ..............................................................................................................19
4.2.1.
Definition .....................................................................................................................................19
4.2.2.
Analysis Methods........................................................................................................................20
4.2.3.
Sensitivity Analysis of PFS .........................................................................................................20
4.2.3.1.
Progressive Disease Based on Investigator Assessment.......................................................20
4.2.3.2.
Not Censored for Start of Subsequent Antimyeloma Therapies..............................................20
4.2.3.3.
Censored for Death/PD after Missing More Than One Disease Evaluation............................21
4.2.3.4.
Per-protocol Analysis of PFS...................................................................................................22
4.2.3.5.
Unstratified Analysis of PFS ....................................................................................................22
4.3.
Secondary Endpoints .....................................................................................................................22
4.3.1.
Overall Response Rate (ORR) ...................................................................................................22
4.3.1.1.
Definition..................................................................................................................................22
4.3.1.2.
Analysis Methods.....................................................................................................................22
4.3.2.
VGPR or Better Rate ..................................................................................................................23
4.3.2.1.
Definition..................................................................................................................................23
4.3.2.2.
Analysis Methods.....................................................................................................................23
4.3.3.
CR or Better Rate .......................................................................................................................23
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4.3.3.1.
Definition..................................................................................................................................23
4.3.3.2.
Analysis Methods.....................................................................................................................23
4.3.4.
MRD Negativity Rate ..................................................................................................................23
4.3.4.1.
Definition..................................................................................................................................23
4.3.4.2.
Analysis Methods.....................................................................................................................23
4.3.5.
Overall Survival...........................................................................................................................24
4.3.5.1.
Definition..................................................................................................................................24
4.3.5.2.
Analysis Methods.....................................................................................................................24
4.3.6.
Progression-free Survival on Next Line of Therapy (PFS2) .......................................................25
4.3.6.1.
Definition..................................................................................................................................25
4.3.6.2.
Analysis Methods.....................................................................................................................26
4.3.7.
sCR Rate ....................................................................................................................................26
4.3.7.1.
Definition..................................................................................................................................26
4.3.7.2.
Analysis Methods.....................................................................................................................27
4.3.8.
Time to Disease Progression (TTP) ...........................................................................................27
4.3.8.1.
Definition..................................................................................................................................27
4.3.8.2.
Analysis Methods.....................................................................................................................27
4.3.9.
Time to Response .......................................................................................................................27
4.3.9.1.
Definition..................................................................................................................................27
4.3.9.2.
Analysis Methods.....................................................................................................................28
4.3.10.
Duration of Response .................................................................................................................28
4.3.10.1.
Definition..................................................................................................................................28
4.3.10.2.
Analysis Methods.....................................................................................................................28
4.3.11.
Time to Subsequent Antimyeloma Treatment ............................................................................28
4.3.11.1.
Definition..................................................................................................................................28
4.3.11.2.
Analysis Methods.....................................................................................................................28
4.3.12.
Best M-protein/dFLC Response..................................................................................................29
4.3.12.1.
Definition..................................................................................................................................29
4.3.12.2.
Analysis Methods.....................................................................................................................29
4.4.
Subgroup Analysis of Efficacy Endpoints.......................................................................................29
4.5.
Functional Status and Well-being ..................................................................................................29
4.5.1.
Definition .....................................................................................................................................29
4.5.2.
Analysis Methods........................................................................................................................30
5.
SAFETY .............................................................................................................................................31
5.1.
Adverse Events ..............................................................................................................................31
5.1.1.
Overview of TEAEs.....................................................................................................................32
5.1.2.
All TEAEs....................................................................................................................................32
5.1.3.
Toxicity Grade 3 or 4 TEAEs.......................................................................................................32
5.1.4.
Study Treatment-Related TEAEs................................................................................................32
5.1.5.
Serious Adverse Events (SAEs) .................................................................................................32
5.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications.............................................................33
5.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment.......................................................33
5.1.8.
TEAEs Leading to Discontinuation of All Study Treatments .......................................................33
5.2.
Deaths ............................................................................................................................................33
5.2.1.
Death Due to TEAEs...................................................................................................................33
5.2.2.
All Deaths....................................................................................................................................33
5.3.
Adverse Events of Clinical Interest ................................................................................................34
5.3.1.
Infusion-Related Reactions (IRR)...............................................................................................34
5.3.2.
Infections and infestations...........................................................................................................34
5.3.3.
Peripheral Neuropathies .............................................................................................................34
5.3.4.
Hemorrhage Events....................................................................................................................34
5.3.5.
Tumor Lysis Syndrome...............................................................................................................34
5.3.6.
Second Primary Malignancies ....................................................................................................35
5.3.7.
Adverse Events by Subgroups ...................................................................................................35
5.4.
Clinical Laboratory Tests................................................................................................................35
5.5.
Vital Signs and Physical Examination Findings .............................................................................36
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5.6.
Electrocardiogram (ECG)...............................................................................................................36
5.7.
ECOG Performance Score.............................................................................................................36
6.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS ..........................................37
6.1.
Pharmacokinetics...........................................................................................................................37
6.1.1.
Sampling Timepoints...................................................................................................................37
6.1.2.
Pharmacokinetic Parameters......................................................................................................37
6.1.3.
Analysis Methods........................................................................................................................37
6.2.
Immunogenicity ..............................................................................................................................38
6.2.1.
Sampling Timepoints...................................................................................................................38
6.2.2.
Analysis Methods........................................................................................................................38
6.3.
Pharmacokinetic/Pharmacodynamic Analyses ..............................................................................38
7.
BIOMARKER .....................................................................................................................................38
7.1.
Minimal Residual Disease (MRD) ..................................................................................................39
7.1.1.
Sampling Timepoints...................................................................................................................39
7.1.2.
Analysis Methods........................................................................................................................39
7.2.
Molecular Subtyping.......................................................................................................................39
7.2.1.
Sample collection and characterization ......................................................................................39
7.2.2.
Molecular Subtypes ....................................................................................................................39
7.2.3.
Molecular Risk Subgroup Analysis .............................................................................................40
8.
MEDICAL RESOURCE UTILIZATION..............................................................................................40
REFERENCES............................................................................................................................................41
ATTACHMENT 1:
ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT HEMAR ......................42
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ABBREVIATIONS
AE
adverse event
ALT
alanineaminotransferase
ASCT
Autologous Stem Cell Transplant
AST
aspartateaminotransferase
BSA
body surface area
CI
confidence interval
CR
complete response
CrCL
creatinine clearance
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DOR
duration of response
DPS
data presentation specification
D-VMP
Daratumumab, bortezomib, melphalan, prednisone
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FISH
fluorescence in situ hybridization
FLC
free light chain
IA
interim analysis
ICF
informed consent form
IDMC
Independent Data Monitoring Committee
IMWG
International Myeloma Working Group
IRR
infusion-related reaction
ISS
International Staging System
ITT
intent-to-treat
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
M-protein
monoclonal protein, monoclonal paraprotein
MRD
minimal residual disease
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
NGS
Next generation sequencing
ORR
overall response rate
OS
overall survival
PD
progressive disease
PBMC
peripheral blood mononuclear cell
PFS
progression-free survival
PP
per-protocol
PR
partial response
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SD
stable disease
SD
standard deviation
SOC
system organ class
SPEP
serum protein electrophoresis
     SMQ
Standardized MedDRA Queries
TEAEs
treatment-emergent adverse events
TTR
time to response
TTP
time to disease progression
UPEP
urine protein electrophoresis
VGPR
very good partial response
VMP
Bortezomib, melphalan, prednisone
WBC
white blood cells
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived
variables, and statistical methods for the planned analyses as specified in the
protocol JNJ-54767414MMY3007, Amendment 4.
1.1.
Overview of Trial Design
This is a Phase 3, randomized, open-label, active-controlled, parallel-group, multicenter 
study comparing daratumumab, VELCADE (bortezomib), melphalan and prednisone 
(D-VMP) with VELCADE, melphalan and prednisone (VMP) in subjects with previously
untreated multiple myeloma who are ineligible for high dose chemotherapy and 
autologous stem cell transplant (ASCT). The primary objective is to evaluate if 
daratumumab in combination with VMP prolongs progression-free survival (PFS) 
compared with VMP alone. The secondary objectives are to compare the 2 treatment 
groups with respect to time to disease progression (TTP), overall response rate (ORR), 
very good partial response (VGPR) or better rate, complete response (CR) or better rate, 
MRD negativity rate, progression-free survival on next line of therapy (PFS2), and 
overall survival (OS) and as well as to assess the safety and tolerability of daratumumab 
when administered in combination with VMP.
Approximately 700 subjects (350/arm) will be randomized in a 1:1 ratio to receive either 
D-VMP or VMP. Randomization will be stratified by International Staging System (ISS) 
(I, II, or III) at screening, region (Europe vs. Other), and age (<75 vs ≥75). Within each 
stratum, subjects will be randomized using an equal allocation ratio of 1:1.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up 
Phase. The Screening Phase will be up to 21 days before Cycle 1, Day 1. All subjects will 
receive up to 9 cycles of the VMP regimen (1 cycle = 6 weeks) with or without 
daratumumab.
The Treatment Phase will extend from Day 1 of Cycle 1 to discontinuation of all study 
treatments of a given treatment arm. Subjects in both treatment arms will receive 
1.3 mg/m2 VELCADE by subcutaneous injection (SC) twice weekly (Weeks 1, 2, 4, and 
5) in Cycle 1 followed by once weekly (Weeks 1, 2, 4, and 5) in Cycles 2 to 9. Melphalan 
orally at 9 mg/m2 and prednisone orally at 60 mg/m2 will be self-administered on Day 1-4 
of each VELCADE cycle. For subjects randomized to the D-VMP regimen, 20 mg of 
dexamethasone will substitute for the planned dose of prednisone on Day 1 of each cycle. 
In this setting, dexamethasone will be utilized as the treatment dose of steroid for that
particular day, as well as the required pre-medication prior to daratumumab infusion. 
Daratumumab 16 mg/kg will be administered to subjects in D-VMP regimen by IV 
infusion once every week for 6 weeks (Cycle 1; 1 VELCADE cycle); then once every
3 weeks for 16 additional doses (Cycles 2-9). Measures to prevent infusion-related 
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reactions (IRR) will include pre-infusion medication with dexamethasone, paracetamol, 
and antihistamine before each daratumumab infusion.
After completion of the VMP cycles, subjects in the VMP arm will enter the Follow-up 
Phase. Subjects in D-VMP regimen will continue to receive daratumumab every 4 weeks 
until documented progression, unacceptable toxicity, or the study ends (see below for 
definition). Subjects who need to discontinue treatment with any one component of study 
treatment (VELCADE, melphalan, prednisone, or daratumumab) may continue to receive 
treatment with the other components of study treatment, as assigned. Upon 
discontinuation of daratumumab, subjects in the D-VMP arm will also enter the Follow-
up Phase.
In the Follow-up Phase, subjects who discontinued for reasons other than disease 
progression will continue to have disease evaluations per the Time and Events Schedule, 
which will continue until confirmed progressive disease (PD), death, lost to follow up, 
subsequent antimyeloma therapy, withdrawal of consent, or the study ends, whichever 
occurs first.
Two interim analyses are planned for this study. The first interim analysis, with a purpose 
to evaluate safety, will be performed after a total of approximately 100 subjects have 
been treated for at least 2 cycles or discontinued the study treatment. The second interim 
analysis will be performed when 216 PFS events (60% of the total events) have been 
accumulated. The purpose of this interim analysis is to evaluate cumulative interim safety 
and efficacy data. The significance level at this interim analysis to establish the 
superiority of D-VMP over VMP with regard to PFS will be determined based on the 
observed number of PFS events at the interim analysis, using the O’Brien-Fleming 
boundaries as implemented by the Lan-DeMets alpha spending method. If the 
experimental arm (D-VMP) is numerically worse than the control arm in terms of PFS 
(observed hazard ratio >1 favoring the control arm), then the study may be terminated for 
futility.
The primary PFS analysis will occur when approximately 360 PFS events have been
observed if the second interim analysis does not result in an early stop due to efficacy or 
futility. The date established for the primary PFS analysis will serve as the clinical cut-off 
date, after which data collection in the study will be reduced. Investigators will be 
informed when each interim analysis is to occur. All available data prior to that time will 
be included in each of the respective analyses.
The end of the study will occur when 330 subjects have died, or 5 years after the last 
subject is randomized, whichever comes first. The sponsor will ensure that subjects 
benefiting from treatment with daratumumab will be able to continue treatment after the 
end of the study.
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An Independent Data Monitoring Committee (IDMC) will be commissioned for this 
study to review efficacy and safety results at the planned interim analyses. After the 
interim reviews, they will make recommendations regarding the continuation of the 
study. In addition, the IDMC may also review cumulative safety data every 6 months in 
addition to the planned 2 interim analyses.
Assessment of tumor response and disease progression will be conducted in accordance 
with the International Myeloma Working Group (IMWG) response criteria. An 
assessment of MRD will be conducted on bone marrow samples. Safety evaluations will 
include adverse event monitoring, physical examinations, electrocardiogram (ECG) 
monitoring, clinical laboratory parameters (hematology and chemistry), vital sign 
measurements, and Eastern Cooperative Oncology Group (ECOG) performance status. 
Blood samples will be drawn for assessment of pharmacokinetic parameters and 
immunogenicity.
1.2.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint of this study is PFS. The null hypothesis is that
there is no difference in PFS between daratumumab in combination with VMP and
VMP alone in subjects with newly diagnosed multiple myeloma who are ineligible for 
high dose chemotherapy and ASCT.
The secondary endpoints such as TTP, ORR, VGPR or better rate, CR or better rate, 
MRD negativity rate, PFS2, time to response, duration of response and OS will be 
evaluated as well.
1.3.
Sample Size Determination
The sample size calculation is performed based on the assumption that the median PFS 
for the VMP group in this study is estimated to be approximately 21 months.
Assuming the addition of daratumumab can reduce the risk of the disease progression or 
death by 27.6%, i.e., assuming the hazard ratio (D-VMP vs. VMP) of 0.724, which 
translates to a median PFS of 29 months for the D-VMP arm, a total of 360 PFS events is 
needed to achieve a power of 85% to detect this hazard ratio with a log-rank test (two-
sided alpha is 0.05). With a 20-month accrual period and an additional 21-month follow-
up, the total sample size needed for the study is approximately 700 (350/treatment group) 
subjects. The sample size calculation has taken into consideration an annual dropout rate 
of 5%.
Long-term survival follow-up will continue until 330 deaths have been observed or 
5 years after the last subject is randomized, whichever is first. This study will achieve 
approximately 80% power to detect a 27% reduction in the risk of death (hazard ratio = 
0.73) with a log-rank test (two-sided alpha = 0.05) if 330 death events are observed at the 
study end.
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1.4.
Interim Analyses
Two interim analyses are planned. The first interim analysis has a purpose to evaluate 
safety after a total of approximately 100 subjects treated for at least 2 cycles or
discontinued the study treatment. The second interim analysis is to evaluate the 
cumulative interim safety and efficacy of daratumumab in combination with VMP when
approximately 216 PFS events have been accumulated.  More details about the conduct of 
these interim analyses can be found in a stand-alone IDMC charter. 
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
For analyses of data by cycle, if data are collected by date (e.g., AE onset), the
corresponding study evaluations will be assigned to actual sequential cycles, which are
derived from the study treatment administration data. The start date of a particular cycle 
is defined as the date of the first
scheduled dose of any component of the study
treatment, and the end date of a cycle is the start date of the next cycle minus 1. For the
last cycle, the end date is defined as the end of treatment visit date or the minimum of
last study treatment date plus 30 days and subsequent antimyeloma therapy minus 
1 day, if the end of treatment visit date is not available.
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal
cycle will be used to summarize data. However, due to possible cycle delays,
assessment performed in the same cycle may not be well aligned in time scale for
different subjects. To address this, by-week windowing rules may be applied in the
overtime data summaries by study week.
2.2.
Pooling Algorithm for Analysis Centers
All participating centers in the study will be pooled together for analyses.
2.3.
Study Treatment and Study Drug
Study treatment refers to bortezomib, melphalan, prednisone, and/or daratumumab.
Study drug refers to daratumumab.
2.4.
Study Treatment Dosing Date
Study treatment dosing date is the date on which a subject actually received study
treatment (partial or complete) and will be recorded in the study treatment administration
dataset.
For subjects who receive D-VMP treatment, the first study treatment date is defined as
the earliest
date of non-zero dose of the following administration: bortezomib, 
melphalan, prednisone or daratumumab. The last study treatment date is defined as the
latest date of non-zero dose of the following administration: bortezomib, melphalan,
prednisone or daratumumab.
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For subjects who receive VMP treatment, the first study treatment date is defined as
the earliest
date of non-zero dose of the following administration: bortezomib, 
melphalan or prednisone. The last study treatment date is defined as the latest date
of
non-zero
dose
of
the
following
administration:
bortezomib, melphalan
or
prednisone.
2.5.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or
prior to the first study treatment administration (including time if time is available, with
exception of parameters associated with disease-related efficacy assessment such as
SPEP, UPEP, kappa, lambda, kappa/lambda ratio, serum calcium, and albumin).
2.6.
Unique Lab Value
In general, in instances when there are multiple records at a given visit date for lab
parameters associated with disease assessment, the following rules will be applied to
select the unique lab value for analysis: a.) multiple records from both central and local
lab, central lab value always takes precedence over local lab value; b) multiple records
from central lab, select the latest value by time, visit number, or sequence number as the
unique lab value; c.) multiple records from local lab, select the latest lab value by 
time, visit number, or sequence number as the unique lab value.
2.7.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and
efficacy evaluations. For analysis and reporting purpose, partial dates in adverse event
(AE onset date; AE end date), concomitant therapies (start date; end date), MM
diagnosis date, and start date of subsequent antimyeloma therapy will be imputed.
2.7.1.
Missing/Partial Adverse Event Onset Date
If the onset date of an adverse event is missing completely or partially, the following
imputation rules will be used.

When month and year are present and the day is missing,

If the onset month and year are the same as the month and year of first
study treatment, the day of first study treatment or the day-component of
the AE end date (possibly imputed) is imputed, whichever is earlier

If the onset month and year are not the same as the month and year of first
study treatment, then the first day of the month is imputed

When only a year is present,

If the onset year is the same as the year of first study treatment. If AE end
date is available and is prior to first study treatment, the day and month of
AE end date are imputed. Otherwise, the day and month of first study
treatment are imputed
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
If the onset year is different from the year of first study treatment, the 1st
of January is imputed

If the onset date is completely missing, the earlier one of the date of first study
treatment and the AE end date is imputed as the onset date.
No imputation will be done for partial or missing AE onset time.
2.7.2.
Missing/Partial Adverse Event End Date
If the end date of an adverse event is missing completely or partially, the following
imputation rules will be used.

If month and year are present and the day of the month is missing, the last day of the
month is imputed.

If only a year is present, the 31st of December is used.

If the imputed date is later than the date of death (if available), the date of death will be 
used as the imputed date instead.

If the year of end date is missing, no imputation will be applied.
No imputation will be done for partial or missing AE end time.
2.7.3.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following
imputation rules will be applied. If the date is completely missing, no imputation will be
performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used. If the
medication was taken prior to study start, and the imputed start date is after first
treatment date, further adjust of the imputed start date as the day prior to first dosing
date; If the medication was taken after study start, and the imputed start date is
prior to first dosing date, further adjust the imputed start date as first dosing
date. Also, adjust the imputed medication end date so that it is on or after first
dosing date.
2.7.4.
Partial Multiple Myeloma Diagnosis Date
For partial date of original multiple myeloma diagnosis, the following imputation rules will
apply:

If only the day is missing, set day=15 and pick minimum of imputed date, date of 
collection and date of randomization.

If both the day and month are missing, set to January 1 and pick minimum of 
imputed date, date of collection and date of randomization.

If year is missing, no imputation will be applied.
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If the imputed date of original diagnosis is after the randomization date, further adjust the 
imputed start date as the day before the randomization date.
2.7.5.
Partial Subsequent Antimyeloma Therapy Start Date
If year or month of subsequent antimyeloma therapy start date is missing or no
components of the start date are present, no imputation will be performed.
If only the day is missing, the following steps apply:

If the month and year of the start date are the same as the month and year of last
dosing date, the day of last dosing date or the day-component of the stop date of
subsequent antimyeloma therapy is imputed, whichever is earlier.

If the start month and year are not the same as the month and year of last dosing date,
the first day of the month is imputed.
No imputation will be applied for missing or partial subsequent antimyeloma therapy
end date.
2.8.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as
mean,
standard deviation (SD), median and range. Categorical variables will be
summarized using frequency and percentage. For time-to-event variables, which is
defined as from the date of randomization to the date of the event, the Kaplan-Meier
method will be used for descriptive summaries. For the calculation of time-to-event
and duration-of-event variables, the difference between the start date and the end date
plus 1 day will be used.
2.9.
Analysis Sets
The following analysis sets are defined.

Intent-to-treat (ITT): defined as subjects who have been randomly assigned to the
D-VMP or VMP group. Analyses of demographics, baseline characteristics, and
efficacy endpoints will be primarily analyzed based on this population.

Safety population: defined as subjects who have received at least 1 administration
of any study treatment (partial or complete). This population will be used for all
safety analyses. The safety analyses grouping will be according to treatment actually
received.

Response-evaluable: defined as subjects who have a confirmed diagnosis of
multiple myeloma and measurable disease at baseline or screening visit. In
addition, subjects must have received at least one administration of study treatment
and have adequate post-baseline disease assessments. Measurable disease is defined
as follows:

IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or 
urine M-protein level ≥200 mg/24 hours; or 
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
IgA, IgD, IgE or IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or 
urine M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in serum or urine: 
Serum immunoglobulin free light chain (FLC) level ≥10 mg/dL and abnormal 
serum immunoglobulin kappa lambda free light chain ratio.
This population will be used as sensitivity analyses for selective response-related 
secondary endpoints such as CR or better rate.

Per-protocol (PP) population: defined as subjects who are randomized and meet all 
eligibility criteria.

Pharmacokinetics-evaluable: defined as subjects assigned to D-VMP group who
received
at
least
1
administration
of
daratumumab
and
have
at
least
1
pharmacokinetic
sample
concentration
value
after
the
first
infusion.
All
pharmacokinetics analyses are based on the pharmacokinetic evaluable population.

Immune response-evaluable: defined as subjects assigned to D-VMP group who
have at least 1 immunogenicity sample obtained after their first daratumumab
administration.

Molecular genetic evaluable: defined as subjects who meet one of the following 
biomarker criteria for risk assessment based on the next generation sequencing 
(NGS) data:

Standard risk: subjects that are negative (=molecular aberration absent) for all 
del17p, t(14;16), t(4;14).

High risk: subjects that are positive (=molecular aberration present) for any of 
del17p, t(14;16), t(4;14).

Cytogenetic evaluable: defined as subjects who meet one of the following 
cytogenetic risk categories: 

Standard risk: subjects that are negative for del17p, t(14;16), t(4;14) by 
FISH/Karyotype.

High risk: subjects that are positive for any of del17p, t(14;16), t(4;14) by 
FISH/Karyotype.
2.10.
Definition of Subgroups
The following pre-specified subgroup analyses are to be performed at the 2nd IA for the
efficacy and safety endpoints. Additional subgroup analyses may be performed, if
requested and deemed necessary by IDMC for their analyses and decision making.
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Table 1:
Subgroup Analyses of Efficacy and Safety Endpoints
Subgroup 
Definition 
Analysis Type 
Sex 
Male, Female 
E, S 
Age 
E: <75 years, ≥75 years
S: <65 years, 65 to <75, ≥75
E, S 
Race 
White, Other 
E, S 
Baseline renal function 
(CrCl): 
E: >60 mL/min; ≤60 mL/min; 
S: <30, 30 to <60, 60 to <90, 
≥90 mL/min
E, S
Baseline hepatic function 
Normal, Impaireda
E, S 
Region 
Europe, Other
E, S
International Staging System 
(ISS) 
I, II, and III 
E 
Type of MM 
IgG, Non-IgG 
E 
Cytogenetic risk
High risk, Standard risk
E 
ECOG performance score 
0, ≥1 
E
E: efficacy (PFS, CR or better rate); S: TEAE 
a Includes mild, moderate and severe. mild: (total bilirubin ≤ ULN and AST > 
ULN) or ULN < total bilirubin ≤ 1.5×ULN; moderate: 1.5×ULN < total bilirubin ≤ 
3×ULN; severe: total bilirubin > 3×ULN
3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
Unless specified otherwise, all demographic and baseline characteristics variables will
be
summarized for the ITT population. No statistical comparison between the
2 treatment groups is planned.
The distribution of subject enrollment will be presented for each treatment group 
according to region and country. A list of subjects who did not meet study 
inclusion/exclusion criteria will be provided. This listing will include subject ID, treatment 
group, category of study selection criteria not met and specific criteria not met.
Subject demographic and baseline characteristic variables: age (<65 years, 65 to
<75 years, and ≥75 years), sex, ethnicity, race, weight (kg), height (cm), body surface 
area (BSA) (m2), and ECOG performance status will be summarized by treatment
group and overall. A listing of subject demographic and baseline characteristics will 
be provided as well.
Baseline disease characteristics including type of multiple myeloma (IgG, IgA, IgM, 
IgD, IgE, light chain only, biclonal, or negative immunofixation), type of measurable
disease ( IgG, IgA, Other (IgD, IgM, IgE and biclonal), Serum and urine, Urine only, or 
Serum FLC), ISS staging at screening by central laboratory assessment (I, II, III), time
since initial MM diagnosis (months), number of lytic bone lesions (None, 1-3, 4-10,
more than 10), presence of diffuse myeloma-related osteopenia (Yes, No), number 
of extramedullary plasmacytomas (Yes, No), bone marrow % plasma cells (<10, 10 –
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30, >30), standard-risk and high-risk cytogenetic abnormalities (del17p, t(4;14), 
t(14;16)), will be summarized and tabulated by treatment group and overall.
A descriptive summary of selected hematology and chemistry laboratory analytes at
baseline will be provided for each treatment group and overall. In addition, baseline
toxicity grade of each selected laboratory analyte in hematology and chemistry panel
will be summarized by treatment group using frequency.
Medical history collected at baseline or screening visit will be summarized by
system-organ class and preferred term for each treatment group and overall.
A summary of stratification factors (ISS staging, region, and age) used in the 
randomization based on IWRS will be provided to evaluate whether or not randomization
process was appropriately executed in the study. The stratified log-rank test and stratified 
cox model use these stratification factors in randomization.
3.2.
Disposition Information
An overview of subject disposition in the study will be provided. The overview
includes a summary of total number of subjects who are randomized to each treatment
group, the number and percentage of subjects who are randomized but not treated in
each treatment group, and total number of subjects who are treated in each treatment
group. For all treated subjects (defined as subjects who have received at least 1
administration of any study treatment), the number and percentage of subjects who
discontinued treatment including reason for discontinuation as
indicated by the
investigators will be summarized. Similar summaries will be presented for
all
randomized subjects who discontinued from study.
A list of subjects who discontinued study treatment will be provided for safety 
population. This listing will include subject ID, treatment group, date of treatment 
discontinuation, study day of last dose, reason for discontinuation as well as the specific 
adverse events (MedDRA preferred term/verbatim term) if discontinuation due to AEs 
and primary cause of death if discontinuation due to death. 
A similar list of subjects who discontinued study will be provided for ITT population.
3.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized and presented based on
the safety population.
The number and percentage of subjects treated within each cycle will be summarized by
treatment group. The maximum number of treatment cycles received for each subject
will be summarized by frequency and descriptive statistics.
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Duration of study treatment, defined as the number of days from the date of the first
administration of study treatment to the date of the last administration of study treatment,
will be summarized.
The number of daratumumab administrations (continuous and categorical variables)
will be summarized for subjects treated with D-VMP. The total dose administered for
daratumumab
(mg/kg), bortezomib (mg/m2), melphalan (mg/m2) and prednisone
(mg/m2) will be summarized overall, by cycle, by high-intensity (Cycle 1) or low-
intensity (Cycles 2-9) for bortezomib, and by Cycle 1, Cycles 2-9 and Cycles 10+for 
daratumumab.
The dose intensity, which is defined as the sum of total dose administered in all cycles
divided by the number of treatment cycles, will be calculated for each study treatment
and summarized accordingly. Additionally, the daratumumab dose intensity will be
summarized for cycles with high-intensity (Cycle 1) or low-intensity (Cycles 2-9 and
Cycles 10+).
The relative dose intensity (%) defined as the ratio of total dose actually received
and total
planned dose (planned dose level times the number of administered
infusions/medications) will be calculated for each study treatment and summarized by
treatment group using descriptive statistics.
The number of subjects with treatment cycle delay, dose delays/skipping for each study 
treatment, dose reduction for bortezomib, melphalan, and prednisone will be summarized 
for each treatment group. The reasons (AE or other) for treatment cycle delay, dose delays 
or skipping for each study treatment as well as dose reduction for bortezomib, melphalan,
and prednisone will also be reported. In addition, a summary of study treatment dose 
modifications by cycle will be provided. 
3.4.
Protocol Deviations
Major protocol deviations will be summarized for the ITT population by the following 
types of deviation for each treatment group:

Entered but did not satisfy inclusion/exclusion criteria

Developed withdrawal criteria but not withdrawn

Received wrong treatment or incorrect dose

Received an excluded concomitant treatment

Efficacy assessment deviation

Safety assessment deviation

Other – protocol non-compliance
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All major protocol deviations will be summarized. A listing of subjects with major 
protocol deviations including subject ID, type of deviation, and reasons for deviation will 
also be provided. 
3.5.
Prior, Concomitant and Subsequent Therapies
With the study population of newly diagnosed subjects with multiple myeloma who are 
not candidates for high dose chemotherapy and ASCT, prior systemic use of 
corticosteroids is limited to a short course of emergency use to treat multiple myeloma
symptoms. If any, a listing of all prior systemic use of corticosteroids will be provided.   
Concomitant medications collected in the CRF page during the study will be
summarized by therapeutic class, pharmacologic class, and drug name for each
treatment group. A similar summary will be provided for subjects who received growth
factor support, pre-infusion medication and post-infusion medication, respectively. In 
addition, systemic steroids as concomitant medication use during the study will be 
summarized. Additionally, prophylactic antiviral medication use will be tabulated.
The total number of subjects who received subsequent antimyeloma therapy will be
reported for safety population in each treatment group. A summary of subsequent 
antimyeloma therapy will be presented by therapeutic class, pharmacologic class and drug 
name. In addition, for subjects who received subsequent antimyeloma therapy, their best 
response to the first subsequent antimyeloma therapy will be summarized.
4.
EFFICACY
A validated computerized algorithm, which is based on the IMWG response criteria
(Durie 2006, Rajkumar 2011)1,3 and has been used and validated by an independent
review committee (IRC) in Study
MMY2002, also used in MMY3003 and 
MMY3004, will be used to determine response and disease progression for each
subject. Unless specified otherwise, relapse from CR by positive immunofixation or
trace amount (defined as less than 0.5 g/dL) of M-protein is not considered to be
progressive
disease
in
the
IMWG response
criteria.
As
a
sensitivity analysis,
investigator assessment of response and disease progression using the IMWG response
criteria will also be performed.
4.1.
Analysis Specifications
4.1.1.
Level of Significance
All statistical hypothesis tests and 95% confidence intervals presented will be 2-sided.
The primary hypothesis is to be tested at the 0.05 significance level (overall). The exact
significance level at the second interim analysis is to be determined by the observed
number of
events per the O’Brien-Fleming alpha spending function. Assuming
216 PFS events are observed at the second interim analysis, the alpha to be spent will
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be 0.0076 (2-sided) for the interim analysis and 0.0476 (2-sided) for the primary PFS 
analysis (360 PFS events occur). If the observed two-sided p-value is smaller than this
significance level as specified above, the superiority of D-VMP versus VMP with 
respect to PFS will be established.
If the primary endpoint of PFS is statistically significant, the following secondary 
endpoints ordered below will be sequentially tested, each with an overall two-sided alpha 
of 0.05, by utilizing a hierarchical testing approach as proposed by Tang and Geller 19994
that strongly controls Type I error rate: 
1)
ORR
2)
VGPR or better rate
3)
CR or better rate 
4)
MRD negativity rate
5)
OS.
These secondary endpoints will be tested at the second IA and the primary PFS analysis. 
The primary PFS analysis will be skipped if PFS is positive at the second IA. If this is the 
case, the protocol will be amended to add an analysis for secondary endpoints at a similar 
timing as the planned primary PFS analysis (note that OS will also be tested at its 
protocol-specified final analysis). The significance level at the second interim and the 
primary PFS analyses will be determined by the alpha-spending function specific to 
endpoints:  

For ORR, VGPR or better rate, CR or better rate, and MRD negativity rate, the 
information fraction is expected to be 80% at the second IA.  The O’Brien-Fleming 
alpha-spending function as implemented by the Lan-DeMets method will be used for 
alpha spending: 0.0244 (two-sided) at the second IA and 0.0428 (two-sided) at the 
primary PFS analysis.

For OS, a modified linear alpha spending function will be used to determine the alpha 
level at three looks (second IA, primary PFS analysis, and final OS analysis). The 
alpha level will be 0.0001 for the first OS look, and linear spending function will be 
used to determine the alpha level for the second and last looks. For example, if 59% 
targeted OS events are observed at the second look, the corresponding alpha level will 
be 0.0295.
If the null hypothesis for any of these endpoint fails to be rejected at the second interim
analysis, then any subsequent endpoint(s) listed above will not be tested until the
next analysis time point (e.g., primary PFS analysis), if applicable. If the null hypothesis
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for an endpoint is rejected at the second interim analysis, it will remain being rejected
and will not be re-tested at any subsequent time points, if any.
4.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
4.2.
Primary Efficacy Endpoint
The primary efficacy endpoint is progression-free survival (PFS) based on the 
computerized algorithm.
4.2.1.
Definition
PFS is defined as the duration from the date of randomization to either progressive
disease, according to the IMWG response criteria, or death, whichever occurs first.
Subjects who start subsequent antimyeloma therapies for multiple myeloma without
disease progression will be censored at the last disease assessment before the start of
subsequent therapies. Subjects who withdrew consent from the study before disease
progression will be censored at the last disease assessment. Subjects who are lost to
follow-up will be censored at the last disease assessment before subjects are lost to
follow-up. Subjects who have not progressed and are still alive at the cutoff date for 
analysis will be censored at the last disease assessment. Subjects without any post-
baseline disease assessment will be censored at the randomization.
Determination of dates of PFS event and dates for censoring is summarized in 
Table 2 as follows.
Table 2:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Disease progression prior to start
of subsequent antimyeloma
therapy
Earliest date that indicates disease
progression
PFS event
Death prior to start of
subsequent antimyeloma
therapy
Date of death
PFS event
No post-baseline disease assessment
Randomization
Censored
Other (e.g., withdrawal of consent to
study participation, lost to follow-up,
start of subsequent antimyeloma therapy
etc.)
Date of last disease assessment
prior to withdrawal of consent to
study participation, lost to follow-
up, or subsequent antimyeloma
treatment
Censored
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4.2.2.
Analysis Methods
Analysis of PFS will be based on the ITT population. The Kaplan-Meier method will be
used to estimate the distribution of overall PFS for each treatment group. The median
PFS with 95% CI will be provided. In addition, the number and percentage of subjects
who had a PFS event or were censored will be reported. The Kaplan-Meier PFS curve
will also be plotted by treatment group.
The primary treatment comparison of the distribution of overall PFS will be based on a
stratified log-rank test. The p-value from a stratified log-rank test will be reported. 
Hazard ratio and its 95% confidence interval will be estimated based on a stratified Cox’s 
regression model with treatment as the sole explanatory variable. Stratification factors 
used in the analyses include ISS staging (I, II, III), region (Europe vs other), and age 
(<75 years vs ≥75 years).
In addition, 12, 18 and 24-months of PFS rate with 95% CI will be estimated by
Kaplan-Meier method and reported for each treatment group.
Additionally, reasons for PFS censoring will be summarized for ITT population.
4.2.3.
Sensitivity Analysis of PFS
The following sensitivity analysis is planned to evaluate the robustness of the primary
endpoint analysis of PFS.
4.2.3.1.
Progressive Disease Based on Investigator Assessment
A sensitivity analysis of PFS, in which progressive disease is based on investigator
assessment according to the IMWG response criteria, will be performed in a similar
manner as described in the Section 4.2.2.
The PFS definition used in the sensitivity analysis is similar to that defined in the
Section 4.2.1, except for date of progressive disease and date of censoring. The date of
progressive disease is the date of initial disease progression recorded in the Disease
Progression CRF page or earliest date of confirmed progressive disease recorded in the
Evaluation of Response CRF page, based on investigator assessment. Similarly, the
censoring date is the latest date of disease response recorded in the Evaluation of 
Response CRF page, based on investigator assessment.
In addition, reasons for PFS and censoring based on investigator assessment will be
summarized for ITT population.
4.2.3.2.
Not Censored for Start of Subsequent Antimyeloma Therapies
A sensitivity analysis of PFS derived from the algorithm by not censoring data due to
start of subsequent antimyeloma therapies for subjects, who have not developed a
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confirmed progressive disease, will be performed in a similar manner as described in
Section 4.2.2. 
The PFS definition used in the sensitivity analysis is similar to that defined in
Section 4.2.1, except for censoring date due to start of subsequent antimyeloma
therapies. Subjects who start subsequent antimyeloma therapies for multiple myeloma
without disease progression will NOT be censored at the last disease assessment
before the start of subsequent therapies. If there is no confirmed progressive disease,
the subjects will be censored at the last disease assessment before subjects are lost to 
follow-up or withdrawal of consent to study.
Determination of dates of PFS event and dates for censoring is summarized in Table 3 as
follows.
Table 3:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Disease progression
Earliest date that indicates disease
i
PFS event
Death
Date of death
PFS event
No post-baseline disease
assessment
Randomization
Censored
Other (e.g., withdrawal of
consent to study participation,
lost to follow-up, start of
subsequent antimyeloma
therapy etc.)
Date of last disease assessment prior to
withdrawal of consent to study
participation, lost to follow-up
Censored
4.2.3.3.
Censored for Death/PD after Missing More Than One Disease
Evaluation
A sensitivity analysis of PFS derived from the algorithm by censoring for death or
progression after missing two or more consecutive evaluations will be performed in a
similar manner as described in Section 4.2.2.
The PFS definition used in the sensitivity analysis is similar to that defined in
Section 4.2.1, except for death or progression after missing more than one disease
evaluation. For any PFS (death or progression) event identified by the computer
algorithm, if the event date and the latest date of scheduled disease evaluation (includes
serum M-protein, urine M-protein, serum FLC and corrected calcium only) immediately
preceding the event differs more than 1.25 cycles for year 1 (Cycle 1 to Cycle 9),
2.5 cycles for the second year, and 5 cycles thereafter, which indicates that subject
missed at least one scheduled disease evaluation, then this event will not be
considered as a PFS event in the sensitivity analysis. Instead, the subject will be
censored at the date of last disease evaluation (includes serum M-protein, urine
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M-protein, serum FLC and corrected calcium only) prior to the PFS event originally
identified.
4.2.3.4.
Per-protocol Analysis of PFS
A sensitivity analysis of PFS derived from the algorithm based on Per-protocol 
population will be performed in a similar manner as described in Section 4.2.2 .
4.2.3.5.
Unstratified Analysis of PFS
A sensitivity analysis of PFS by using unstratified log-rank test and unstratified Cox’s
regression model will be performed in a similar manner as described in Section 4.2.2.
4.3.
Secondary Endpoints
Secondary efficacy endpoints include overall response rate (ORR), VGPR or better rate, 
CR or better rate, MRD negativity rate, OS, PFS2, sCR rate, TTP, time to and duration of 
response, time to subsequent antimyeloma treatment, and proportion of subjects with best
M-protein/dFLC responses (maximal reduction of 100%, ≥90% or ≥50% from baseline).
4.3.1.
Overall Response Rate (ORR)
4.3.1.1.
Definition
ORR is defined as the proportion of subjects who achieve a partial response or better
(i.e., PR, VGPR, CR, or sCR) based on the computerized algorithm, according to IMWG
response criteria, during or after the study treatment but before the start of subsequent
antimyeloma therapy.
4.3.1.2.
Analysis Methods
ORR will be calculated for each treatment group based on the ITT and response-
evaluable population. The number and percentage of subjects in the following response 
categories will be presented by treatment group: stringent complete response (sCR), 
complete response (CR), sCR+CR, very good partial response (VGPR), VGPR or better 
(sCR+CR+VGPR), partial response (PR), overall response (sCR+CR+VGPR+PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). The corresponding 95% 
exact CI will be provided.
Stratified CMH test will be used to test treatment difference in ORR, VGPR or better 
rate, CR or better rate. The CMH estimate of odds ratio and its 95% confidence interval 
and p-value for testing treatment difference will be reported. Stratification factors used in 
the analysis include ISS staging (I, II, III), region (Europe vs. Other), and age (<75 years 
vs. ≥75 years).
A sensitivity analysis, which disease response is based on investigator assessment
according to the IMWG response criteria, will be performed in a similar manner as
described above.
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4.3.2.
VGPR or Better Rate
4.3.2.1.
Definition
VGPR or better rate is defined as the proportion of subjects with a response of
VGPR or better (i.e., VGPR, CR or sCR) based on the computerized algorithm,
according to IMWG response criteria, during or after the study treatment but before the 
start of subsequent antimyeloma therapy.
4.3.2.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.3.1.2 for ORR
analysis.
4.3.3.
CR or Better Rate
4.3.3.1.
Definition
CR or better rate is defined as the proportion of subjects with a response of CR or better
(i.e., CR or sCR) based on the computerized algorithm, according to IMWG response
criteria, during or after the study treatment but before the start of subsequent antimyeloma
therapy.
4.3.3.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.3.1.2 for ORR 
analysis.
4.3.4.
MRD Negativity Rate
For this study, three threshold values, 10-4, 10-5 and 10-6, will be used to evaluate MRD 
negativity status and its predictive value for PFS.
4.3.4.1.
Definition
MRD negativity rate is defined as the proportion of subjects who have negative MRD by 
bone marrow aspirate at any time point after the randomization and before disease 
progression or starting subsequent therapy. MRD positive subjects include subjects of 
which all tested samples were found to be MRD positive or ambiguous. Subjects with 
missing or unevaluable MRD status will be considered as MRD positive.   
4.3.4.2.
Analysis Methods
The MRD negativity rate will be calculated for each treatment group based on the ITT
population. The corresponding 95% exact CI will be provided. Reasons for missing or 
unevaluable MRD status will be tabulated by treatment group.
For each threshold value, the stratified CMH estimate of odds ratio and its 95% 
confidence interval and p-value from Fisher’s exact test will be used to test if the MRD 
negativity rate is the same between the two treatment groups in the previously untreated 
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myeloma setting. Stratification factors used in the analysis include ISS staging (I, II, III), 
region (Europe vs. Other), and age (<75 years vs. ≥75 years). For the purpose of 
hierarchical testing, the threshold value of 10-5 will be employed.
In addition, time point analysis of MRD negativity rate will be performed at 12, 18, 24 
and 30 months after the first dose of study treatment. Time to MRD negativity will be 
descriptively summarized by treatment groups, as well as the proportion of subjects with 
durable MRD negativity (i.e., lasted at least 12 months after the start of any MRD 
negativity) if sufficient data becomes available.
Exploratory analyses correlating MRD negativity with long-term clinical endpoints (e.g. 
PFS) are described in Section 7.1.2. 
4.3.5.
Overall Survival
4.3.5.1.
Definition
Overall survival (OS) is measured from the date of randomization to the date of
death due to any cause. Subjects who withdraw consent from the study or are lost to
follow-up will be censored at the time of withdrawal or lost to follow-up. Subjects who
are still alive at the cutoff date for the analysis will be censored at the last known alive.
The date of last known alive will be determined by the maximum collection/assessment
date from among selected data domains within the clinical database.
4.3.5.2.
Analysis Methods
OS, including 12, 24, and 36-months survival rate, will be analyzed for the ITT
population. The Kaplan-Meier method will be used to estimate the distribution of OS
for each treatment group. Median OS with 95% CI will be provided. In addition, the
number and percentage of subjects who had died or were censored will be reported.
Additionally, the survival rate with 95% CI at 12, 24 and 36 -months will be estimated
using Kaplan-Meier method for each treatment group.
Due to the expected small number of death events at the second interim analysis, the
distribution of OS for the 2 treatment groups will be compared based on an un-stratified
log-rank test. A p-value from an un-stratified log-rank test will be reported. Hazard ratio
and its 95% confidence interval will be estimated based on an un-stratified Cox’s
regression model with treatment as the sole explanatory variable.
If the null hypothesis of OS is not rejected at the second interim analysis, for OS at the 
primary PFS analysis when 360 PFS events observed, the alpha to be spent will be 
determined by a linear alpha spending function based on the observed number of deaths 
at that time, i.e., the cumulative alpha to be spent will be the total alpha (0.05) multiplied 
by the proportion of the observed number of deaths out of the total planned number of 
deaths (330, expected at time of the final OS). See Section 4.1.1 for more details on alpha 
spending and type I error control. 
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If a large number of subjects crossed over to receive daratumumab treatment, at the final 
OS analysis, exploratory analysis may be performed that adjust for the effect of 
crossover, such as an analysis based on the inverse-probability-of-censoring weighting 
(IPCW) by Robins (2000)5 or the accelerated failure time model with iterative parameter 
estimation method described by Branson and Whitehead (2002).6 If a large number of 
patients are censored, the rank preserving structural failure time model described by 
Robins and Tsiatis (1991)7 may also be considered in the overall assessment of the 
survival endpoint.
4.3.6.
Progression-free Survival on Next Line of Therapy (PFS2)
4.3.6.1.
Definition
PFS2 is defined as the duration from randomization to progression on the next line of 
subsequent antimyeloma therapy or death due to any cause, whichever comes first. 
Disease progression on next line of treatment will be based on investigator judgment. 
For those subjects who progress on study treatment, but are still alive and not yet 
progressed on the next line of therapy, they will be censored on the date of last follow-up. 
Subjects who withdraw consent or lost to follow-up prior to any subsequent antimyeloma 
therapy will be censored at the date of last disease assessment during the course of study. 
Subjects without any post-baseline follow-up will be censored at the randomization.
Determination of dates of PFS2 event and dates for censoring is summarized in Table 4 as 
follows:
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Table 4:
PFS2 Event and Censoring Method
Situation 
Date of Progression or Censoring 
Outcome 
No post-baseline disease 
assessment 
Randomization 
Censored 
No death on study 
treatment and withdrew or 
lost to follow-up when 
next line of subsequent 
antimyeloma therapy not 
yet started
Date of last disease assessment on 
study treatment
Censored
Death when next line of 
subsequent antimyeloma
therapy not yet started 
Date of death 
PFS2 event 
No disease progression on 
study treatment, and no 
disease progression and no 
death after the start of next 
line of subsequent 
antimyeloma therapy
Date of last disease assessment on 
study treatment
Censored
Disease progression on 
study treatment, and no 
disease progression and no 
death after the start next 
line of subsequent 
antimyeloma therapy
The start date of 2nd line of 
subsequent antimyeloma therapy if 
any (the one after the next line of 
subsequent therapy) minus 1 day, or 
date of last follow-up, whichever 
occurs first
Censored 
Disease progression (or 
death) after the start of 
next line of subsequent 
antimyeloma therapy
Earliest date that indicates 
progression on the next line of 
subsequent antimyeloma therapy (or 
date of death).  If both occurred, pick 
the minimum between the two dates. 
PFS2 event 
4.3.6.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.2.2 for PFS analysis.
4.3.7.
sCR Rate
4.3.7.1.
Definition
sCR rate is defined as the proportion of subjects with a response of sCR based on the 
computerized algorithm, according to IMWG response criteria, during or after the study
treatment but before the start of subsequent antimyeloma therapy.
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4.3.7.2.
Analysis Methods
sCR rate will be calculated for each treatment group based on the ITT and response-
evaluable population. The corresponding 95% exact CI will be provided.
4.3.8.
Time to Disease Progression (TTP)
4.3.8.1.
Definition
TTP is defined as the time between the date of randomization and the date of first
documented evidence of confirmed PD, as defined in the IMWG response criteria,
or death due to PD, whichever occurs first. Subjects who start subsequent antimyeloma
therapies for multiple myeloma without disease progression will be censored at the
last disease assessment before the start of subsequent therapies. Subjects who
withdraw consent to study or are lost to follow-up or die without disease progression
will be censored at the last disease assessment. Subjects who have not progressed at
the cutoff date for analysis will be censored at the last disease assessment. Subjects
without any post-baseline disease assessment will be censored at the randomization.
Determination of dates of TTP event and dates for censoring is summarized in Table 5 as 
follows.
Table 5:
TTP Event and Censoring Method
Situation 
Date of Progression or 
Censoring 
Outcome 
Disease progression prior to start of 
subsequent antimyeloma therapy 
Earliest date that indicates 
disease progression 
TTP event 
Death due to disease progression prior to 
start of subsequent antimyeloma therapy 
Date of death 
TTP event 
No post-baseline disease assessment 
Randomization 
Censored 
Other (e.g., withdrawal of consent to 
study participation, lost to follow-up, start 
of subsequent antimyeloma therapy etc.) 
Date of last disease assessment 
prior to subsequent antimyeloma
treatment 
Censored 
4.3.8.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.2.2 for PFS analysis.
4.3.9.
Time to Response
4.3.9.1.
Definition
Time to response (i.e., time to first response) is defined as the time between the date of
randomization and the first efficacy evaluation that the subject has met all criteria for
PR or better based on the computerized algorithm for patients who had PR or better as 
their best response.
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4.3.9.2.
Analysis Methods
For subjects who achieve a confirmed response, descriptive statistics (n, mean, SD,
median, and range) will also be provided to summarize time to response, time to VGPR 
or better response and time to CR or better response.
4.3.10.
Duration of Response
4.3.10.1.
Definition
Duration of response (DOR) is defined for subjects with a confirmed response (PR or
better) as the time between first documentation of response and disease progression
based on the computerized algorithm, according to IMWG response criteria, or death
due to PD, whichever occurs first. Responders without disease progression will be
censored at the censoring time point for TTP.
4.3.10.2.
Analysis Methods
No formal statistical comparison of DOR between the 2 treatment groups is planned.
Analysis of DOR will be based on subjects who achieved a confirmed response of
PR or better. Median DOR with 95% CI will be estimated based on the Kaplan-
Meier method for each treatment group. The Kaplan-Meier duration of response curve
will be plotted by treatment group.
4.3.11.
Time to Subsequent Antimyeloma Treatment
4.3.11.1.
Definition
Time to subsequent antimyeloma treatment is defined as the time from randomization to
the start of subsequent antimyeloma treatment. Death due to PD without start of
subsequent therapy will be considered as event. Subjects who withdrew consent to study
or are lost to follow, or die due to causes other than disease progression will be
censored at the date of death or the last date known to be alive.
4.3.11.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of time to subsequent
antimyeloma
treatment
for
the
ITT
population.
Median
time
to
subsequent
antimyeloma treatment with 95% CI will be tabulated for each treatment group. In
addition, a Kaplan-Meier curve for time to subsequent antimyeloma treatment will be
plotted. The hazards ratio and its 95% CI will be obtained through a stratified Cox’s
regression model with treatment as the sole explanatory variable. Treatment comparison 
will be made via a stratified log-rank test.
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4.3.12.
Best M-protein/dFLC Response
4.3.12.1.
Definition
Best M-protein response is defined as the maximal percent reduction or the lowest
percent increase from baseline in serum M-protein for subjects with measurable heavy
chain at baseline or urine M-protein for subjects without measurable heavy chain, but
with measurable light chain disease at baseline.
For subjects without measurable heavy chain and light chain disease at baseline, best
response in serum FLC is defined as the maximal percent reduction or the lowest
percent increase from baseline in the difference between involved and uninvolved serum
FLC level.
4.3.12.2.
Analysis Methods
The number and percentage of subjects in each response category, along with
presentation of ≥90% reduction and ≥50% reduction will be tabulated for each treatment
group.
4.4.
Subgroup Analysis of Efficacy Endpoints
For assessment of internal consistency and investigation of homogeneity of the
treatment effect across subgroups, subgroup analyses of the primary and selected
secondary efficacy endpoints will be conducted based on pre-specified subgroups
defined in Section 2.10.
A forest plot of subgroup analysis on PFS and selected secondary endpoints (e.g. CR or 
better rate) will be generated, respectively.
4.5.
Functional Status and Well-being
4.5.1.
Definition
Functional status and well-being will be assessed using two PRO measures, the
EORTC- QLQ-C30 and the EQ-5D-5L. The EORTC QLQ-C30 and EQ-5D-5L will be 
scored based on the instrument developer guidelines.
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical
functioning, role functioning, emotional functioning, cognitive functioning, and social
functioning), 1 Global Health Status scale, 3 symptom scales (fatigue, nausea and
vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation,
diarrhea, and financial difficulties). The recall period is 1 week (the past week).
The instrument contains 28 items using a Likert scale with 4 response options: “Not at
All,” “A Little,” “Quite a Bit,” and “Very Much” (scored 1 to 4). Two additional items
use response options (1 to 7): 1 = Very Poor, to 7 = Excellent. All scale and item scores
will be linearly transformed to be in the range from 0 to 100 according to the algorithm in
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EORTC QLQ-C30 scoring manual, version 3.0 (Fayers 2001).2 A higher score
represents a higher ("better") level of functioning, or a higher ("worse") level of
symptoms.
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the
EQ-5D-5L will be used to generate utility scores for use in cost effective analyses. The
EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care,
usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating
“health today” with anchors ranging from 0 (worst imaginable health state) to 100 (best
imaginable health state). The scores for the 5 separate questions are categorical and
cannot be analyzed as cardinal numbers. However, the scores for the 5 dimensions are
used to compute a single utility score ranging from zero (0.0) to 1 (1.0) representing the
general health status of the individual.
4.5.2.
Analysis Methods
Compliance rates for completion of EORTC QLQ-C30 and EQ-5D-5L at each time point
will be generated based on number of expected.
Key PRO endpoints

EORTC-QLQ-C30 global health status/quality of life subscale

EQ-5D-5L VAS and utility score.
The change from baseline at each time point will be summarized descriptively by
treatment group. Line plot of mean with standard error over time will be displayed
by treatment group. A mixed effects model with repeated measures analysis will be 
conducted estimating change from baseline at each time point between two treatments. 
ITT subjects who have a baseline value and at least one post-baseline value are included in 
the analysis. Change from baseline will be fitted to a mixed effects model including 
subjects as a random effect, and baseline value, treatment group, time in month, treatment-
by-time interaction, and stratification factors as fixed effects.
A distribution based method will be used to define improvement/worsening in scores, i.e., 
half SD away from the mean score at baseline combining both treatment groups. 
Time to improvement will be summarized by using descriptive statistics such as mean, 
standard deviation (SD), median and range.
Time to worsening will be estimated using Kaplan-Meier methods. The hazard ratio for D-
VMP relative to VMP and its associated 95% confidence interval (CI) will be calculated 
based on the stratified Cox proportional hazards model by the stratification factor at 
randomization. Death due to disease progression will be considered as worsening. Subjects 
who have not met the definition of worsening will be censored at the last PRO assessment. 
Subjects without baseline assessment or post-baseline assessment will be censored at date 
of randomization.
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Secondary PRO endpoints
These may include other QLQ-C30 scales:

functional scales: physical, role, cognitive, emotional, and social

symptom scales: fatigue, pain, and nausea and vomiting

single-item score: dyspnea, loss of appetite, insomnia, constipation, diarrhea, and
financial difficulties.
The change from baseline at each time point may be summarized descriptively by
treatment group. Line plot of mean with standard error over time may be displayed by
treatment group.
Time to improvement/worsening and the mixed effect model analysis, as described
for the key PRO endpoints, may be performed as appropriate.
5.
SAFETY
Safety assessment will be evaluated through AEs and clinical
hematology and
chemistry laboratory tests. Safety analyses will be based on the safety population and 
presented by the actual treatment received.
5.1.
Adverse Events
All adverse events whether serious or non-serious, will be reported from the time a signed
and dated informed consent form (ICF) is obtained until 30 days after the last dose of
study treatment, until the subject withdraws consent for study participation, or until
the subject starts subsequent antimyeloma therapy, whichever occurs first. AEs will
be recorded in standard medical terminology and graded according to the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),
Version 4.03. For AE reporting, the verbatim term used in the CRF by investigators to
identify adverse events will be coded using the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary.
Unless otherwise specified, at each level (e.g., system organ class and/or preferred
term) of subject summarization in reporting the incidence of the AE, a subject is
counted once if one or more events were recorded. For summarizing new onset events, 
all event records of the same preferred term from the same subject are to be linked by the 
onset date and the end date. If an event is followed by another event of the same preferred 
term with an onset date (or date/time) the same as or 1 day (or 1 minute if applicable) 
after the end date (or date/time) of the previous record and any features of the adverse 
event (i.e.: toxicity grades/seriousness/action taken) are different between these two 
records, these 2 records should be linked together and considered as one event. A Grade 5 
event will be linked to previous event of the same preferred term if the onset date of 
Grade 5 record is the same or one day after the end date of previous record.
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All summaries of AEs will be based on treatment-emergent adverse events (TEAEs),
which are defined as any AE that occurs after start of the first study treatment through
30 days after the last study treatment; or the day prior to start of subsequent
antimyeloma therapy, whichever is earlier; or any AE that is considered drug-related
(very likely, probably, or possibly related) regardless of the start date of the event; or
any AE that is present at baseline but worsens in toxicity grade or is subsequently
considered drug-related by the investigator.
The incidence of TEAEs will be summarized overall, by MedDRA system organ class
(SOC) and preferred term, by toxicity grade, and by relationship to study treatment
administration. Specifically, the following AE summaries will be presented by treatment
group:
5.1.1.
Overview of TEAEs
An overview of TEAEs reported through the study will be provided for each treatment
group. The overview will include summaries of subjects with TEAEs, with TEAEs
related to study treatment, with TEAEs of maximum toxicity Grade of 1 to 5, SAEs,
TEAEs leading to discontinuation of any study treatment, and deaths due to TEAE.
5.1.2.
All TEAEs

Incidence of TEAEs by MedDRA SOC and preferred term

Most commonly reported (>10%) TEAE by MedDRA SOC and preferred term 
5.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity Grade 3 or 4 TEAEs, by MedDRA SOC and preferred term

List of subjects with any toxicity Grade 3 or 4 TEAEs.

Most commonly reported (>5%) Grade 3 or 4 TEAE by MedDRA SOC and 
preferred term 
5.1.4.
Study Treatment-Related TEAEs

Incidence of TEAEs considered by the investigator to be related to study
treatment, by MedDRA SOC, preferred term and relationship to study treatment

Incidence of TEAEs with toxicity Grade 3 or 4 considered by the investigator to be
related to study treatment, by MedDRA SOC and preferred term and relationship to
study treatment.
5.1.5.
Serious Adverse Events (SAEs)

Incidence of treatment-emergent SAEs, by MedDRA SOC and preferred term

Incidence of treatment-emergent SAEs considered by the investigator to be related
to study treatment, by MedDRA SOC, preferred term and relationship to treatment
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
Most commonly reported (>2%) SAEs by MedDRA SOC and preferred term 

List of subjects with any treatment-emergent SAEs
5.1.6.
TEAEs Leading to Cycle Delays or Dose Modifications
Incidence of TEAEs leading to treatment cycle delays or dose modifications will be
summarized by MedDRA SOC and preferred term. The summaries will be presented by
all grades and Grade 3 or 4 for each treatment. This table will include TEAEs leading to
cycle delays or dose modification of at least one of the study treatments, the dose
modifications include dose delays, dose skipping, or dose reduction (applicable to
bortezomib, melphalan and steroids).
5.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment
A summary of number of subjects who discontinued any study treatment because of 1
or more TEAEs by MedDRA system-organ class and preferred term will be provided.
The summaries will be presented by all grades and Grade 3 or 4 for each treatment
group. The AEs leading to discontinuation of any study treatment are based on AEs
recorded in the AE CRF page with an action taken of drug withdrawal for any study
treatment.
5.1.8.
TEAEs Leading to Discontinuation of All Study Treatments
A summary of number of subjects who discontinued all study treatment because of
1 or more TEAEs by MedDRA system-organ class and preferred term will be
provided. The summaries will be presented by all grades and Grade 3 or 4 for each
treatment group. This table includes AEs leading to discontinuation of all study
treatment for those subjects indicated as having discontinued study treatment due to an
adverse event on the end of treatment CRF page.
A listing of subjects who discontinued all study treatment because of TEAEs will be 
provided.
5.2.
Deaths
5.2.1.
Death Due to TEAEs
The number of subjects who died due to treatment-emergent adverse events will be
summarized by preferred term and relationship to study treatment for each treatment
group. The TEAEs included in this table are AEs with outcome death or toxicity Grade
of 5 recorded in the AE CRF page.
A listing of subjects who died due to treatment-emergent adverse events will be provided.
5.2.2.
All Deaths
A summary of all death and cause of death will be tabulated overall and by treatment
group. Specifically, the number of subjects who died during the study will be
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summarized for the ITT population. The primary cause of death collected on the death
information CRF page will be reported. If the primary cause of death is an AE, the
number of subjects who have a related AE and unrelated AE will be further reported.
The similar summaries will be presented for subjects who died within 30 days of last 
study treatment dose and within 60 days of first study treatment dose, respectively.
5.3.
Adverse Events of Clinical Interest
5.3.1.
Infusion-Related Reactions (IRR)
Subjects
with
any
IRR
associated
with
daratumumab
administration
will
be
summarized by MedDRA system-organ class and preferred term. The summaries will be
presented by all grades, Grade 3, 4, and 5. In addition, the total number of subjects with
an IRR in more than 1 infusion will be reported. Additionally, the timing of an IRR
associated with daratumumab administration will be evaluated through a summary of an
IRR by event onset time.
A listing of subjects with Grade 3 or higher treatment-emergent IRR associate with 
daratumumab administration will be provided. In addition, subjects with treatment-
emergent IRR results in discontinuation of daratumumab will be listed.
5.3.2.
Infections and infestations
Infections and infestations refer to adverse events with SOC of infections and 
infestations. A summary of number of subjects with 1 or more toxicity Grade 3 or 4
treatment-emergent infections
and
infestations by MedDRA
preferred
term
and
relationship to treatment will be provided. Additional summary analyses may include 
by onset time (i.e., ≤6 months vs. 6- ≤12 months vs. >12 months).
5.3.3.
Peripheral Neuropathies
Peripheral neuropathies (PNs) refer to adverse events with high level term (HLT) of 
peripheral neuropathies NEC. Incidences of PNs will be summarized by MedDRA high
level term and preferred term. The summaries will be presented by all grades and 
Grade 3 or 4 for each treatment group.
5.3.4.
Hemorrhage Events
Hemorrhage events refer to the adverse events defined by Standardized MedDRA 
Queries (SMQ) with the first subcategory SMQ of hemorrhage terms (exclude laboratory 
terms). Incidences will be summarized by MedDRA system-organ class and preferred 
term. The summaries will be presented by all grades and maximum toxicity grade for
each treatment group.
5.3.5.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) events refer to the adverse events defined by narrow 
Standardized MedDRA Queries (SMQ) of tumor lysis syndrome (haemorrhagic tumour
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necrosis, tumour lysis syndrome, or tumour necrosis). A listing of subjects who reported
any treatment-emergent TLSs during the study will be provided.
5.3.6.
Second Primary Malignancies
A listing of subjects who reported second primary malignancies during the study will be 
provided. This listing will include diagnosis, study day of diagnosis, recurrence of a
prior existing malignancy (yes, no) and pathology diagnosis (biopsy, aspirate, etc.)
information whenever a second primary malignancy is observed. In addition, cumulative
study treatment exposure, the treatment for second primary malignancy and the outcome
information will also be presented in the listing. Second primary malignancies will be 
clinically reviewed and categorized as cutaneous/non-invasive, non-cutaneous/invasive or 
hematologic malignancies, which will be summarized accordingly.  
5.3.7.
Adverse Events by Subgroups
The following subgroup analysis of adverse events will be performed based on subgroups
specified in Section 2.10:

Overview of TEAEs

All TEAEs

Toxicity Grade 3 or 4 TEAEs

SAEs.
5.4.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory
analytes:
Hematology panel:

hemoglobin

platelet count

white blood cell (WBC) count with absolute neutrophils and lymphocytes
Blood chemistry panel: 

alkaline phosphatase

creatinine

uric acid

glucose

bilirubin

aspartate aminotransferase (AST)
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
alanine aminotransferase (ALT)

sodium

potassium

corrected calcium

lactate dehydrogenase (LDH)

creatinine clearance.
Blood samples for serum hematology are taken at the screening visit, on Days 1, 8,
15, and 22 of Cycles 1, Days 1 and 22 of Cycles 2-9, Day 1 every 4 weeks of
Cycles 10+, and at the End-of-Treatment visit. Blood sample for biochemistry are taken
at the screening visit, on Days 1, and 22 of Cycles 1-9, on Day 1 every 4 weeks of 
Cycle 10+ and at the End-of-Treatment visit.
Descriptive statistics (mean, SD, median, range) will be used to summarize observed
laboratory values and change from baseline in observed value at each scheduled visit for 
each treatment group. Line plot of mean with standard error for each laboratory analyte 
over time will be displayed by treatment group for hemoglobin, neutrophils, lymphocytes, 
platelets, WBC, AST, ALT, creatinine, and creatinine clearance.
The worst toxicity grade in hematology and chemistry during the treatment will be
summarized by treatment group and toxicity grade. Shift tables from baseline to worst
toxicity grade during the treatment will be provided for each laboratory analyte listed
above. These tables will summarize the number of subjects with each baseline CTC
grade and changes to the maximum CTC grade.
5.5.
Vital Signs and Physical Examination Findings 
Baseline weight and vital signs (systolic and diastolic blood pressure, heart rate, and 
temperature) values will be summarized. 
Post baseline physical examination findings were collected as AEs, and therefore will not 
be summarized.
5.6.
Electrocardiogram (ECG)
Electrocardiograms (ECG) will be performed at Screening, Day 1 of Cycle 1, Cycle 3, and 
Cycle 6 immediately after end of daratumumab infusion, and End-of-Treatment visit.
The number and percentage of subjects with normal or abnormal 12-lead ECG results will 
be summarized.    
5.7.
ECOG Performance Score
ECOG performance status, which evaluates the effect of the disease status on the 
activities of daily living, will be assessed at Screening, every 3 months in the first year 
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from Cycle 1 Day 1, thereafter every 6 months until PD, 8 weeks and 16 weeks post-PD.
Descriptive statistics will be used to summarize ECOG performance status at baseline, 
and post-baseline visits (including change from baseline), worst score during treatment 
(including change from baseline) for each treatment group. Shift table from baseline to 
worst score during the treatment may be provided.
6.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
Unless specified otherwise, descriptive statistics (e.g., number of observations, mean,
SD,
median,
and
range)
will
be
used
to
summarize
pharmacokinetics
and
pharmacodynamics data. In addition, coefficient variation and geometric mean will be
provided in the pharmacokinetic concentration summary.
6.1.
Pharmacokinetics
6.1.1.
Sampling Timepoints
For subjects assigned to D-VMP, blood samples to assess serum concentration
(pharmacokinetics) of daratumumab will be obtained at Day 1 of Cycle 1, 3 and 6, End-
of-Treatment and Post-Treatment Week 8. On a daratumumab dosing day, blood
samples need to be collected before (up to 2 hours but not after the start of infusion)
and immediately after (up to 2 hours but not before the end of infusion) daratumumab
administration.
6.1.2.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:

Minimum observed concentration (Cmin) - the concentration observed immediately
before infusion.

Maximum observed concentration (Cmax) – the concentration observed after the end
of infusion.
For daratumumab, the pharmacokinetic evaluations include Cmin and Cmax.  
6.1.3.
Analysis Methods
Pharmacokinetic
analyses
will
be
performed
on
the
pharmacokinetic-evaluable
population. All serum concentrations below the lowest quantifiable concentration or
missing
data
will
be
labeled
as
such
in
the
concentration
data
presentation.
Concentrations below the lowest quantifiable concentration will be treated as zero in the
summary statistics. All subjects and samples excluded from the analysis will be clearly
documented in the study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at
each sampling time point. Plot of mean (±SD) daratumumab serum peak and trough
concentrations over time will be provided.
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If
sufficient
data
are
available,
population
pharmacokinetic
analysis
of
serum
concentration-time data of daratumumab may be performed using nonlinear mixed-
effects modeling.
If population
pharmacokinetic
analysis
is
conducted,
it
may
include data from other clinical studies; details will be provided in a population
pharmacokinetic analysis plan and results will be presented in a separate report.
6.2.
Immunogenicity
6.2.1.
Sampling Timepoints
Samples to assess the generation of antibodies to daratumumab (immunogenicity) will be
obtained from all subjects in the D-VMP group at Cycle 1 Day 1 predose, End-of 
Treatment, and Post-Treatment Week 8. In addition, any time an infusion-related reaction
is observed during the study, an unscheduled blood sample should be drawn as soon
as possible after the reaction for potential immune response analysis.
6.2.2.
Analysis Methods
The incidence of antibodies to daratumumab (immunogenicity) will be summarized for
all subjects who receive a dose of daratumumab and have appropriate samples for
detection of antibodies to daratumumab. In addition, subjects who are positive for
antibodies to daratumumab will also be listed.  A listing of daratumumab concentrations
at the time of each immunogenicity sample will also be provided.  
6.3.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, other pharmacokinetic/pharmacodynamic modeling may
be performed, including exploring the relationship between serum concentrations of
daratumumab and endpoints of clinical efficacy. If analysis is conducted, details and
results of the analysis will be presented in a separate report.
7.
BIOMARKER
Biomarker studies are designed to identify markers predictive of response (or resistance)
to daratumumab. Planned analyses are based on the availability of clinically valid assays
and may be deferred if emerging study data show no likelihood of providing useful
scientific information. Results of biomarker analyses may be presented in a separate
report.
Minimal residual disease (MRD) will be assessed for all subjects who achieve a CR/sCR.
Molecular subtyping will be done through next generation sequencing (NGS) to
evaluate
daratumumab
response
rates
in
risk-stratified
multiple
myeloma
subpopulations.
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7.1.
Minimal Residual Disease (MRD)
Bone marrow aspirates will be collected at baseline from all patients, as well as on 
treatment in those subjects who attain or suspect to have a CR/sCR to monitor MRD.
MRD will be monitored using ClonoSEQ Assay 2.0 on bone marrow aspirate.
7.1.1.
Sampling Timepoints
For all subjects, a fresh bone marrow aspirate will be obtained at baseline, as well as on 
treatment for subjects who were suspected to have a CR/sCR, at the time of the suspected 
CR/sCR, and 4 landmark time points: 12, 18, 24 and 30 months (+2 months) after first 
dose of study treatment. 
7.1.2.
Analysis Methods
Details on MRD negativity rate analyses are described in Section 4.3.4.
In addition, exploratory landmark analyses will be conducted to correlate MRD
negativity results (as either binary or continuous values) with long-term clinical
endpoints such as PFS. Subgroup analysis of PFS by MRD negativity status may also be 
performed. Similar analysis may be performed for subjects who achieved CR or better. 
7.2.
Molecular Subtyping
7.2.1.
Sample collection and characterization
Viable, frozen CD138+ bone marrow aspirate samples were collected at baseline for 
DNA/RNA sequencing analysis.  Peripheral blood mononuclear cell (PBMC) samples 
were collected at baseline to use as controls.
7.2.2.
Molecular Subtypes
A portion of the bone marrow aspirate samples collected as specified in the Section 7.2.1
will be utilized for translocation/mutation/genomic analysis using whole exome-
sequencing and RNA-sequencing to assess whether specific molecular subtypes having 
chromosomal aberrations such as del17p, t(4;14), t(14;16), are responsive to 
daratumumab treatment. PBMC samples will be sent for whole exome sequencing and 
used as controls for mutation and copy number analysis. Examples of molecular subtypes
are:

DNA sequence

del17p

amp1q

RNA sequence

t(4;14)

t(14;16).
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7.2.3.
Molecular Risk Subgroup Analysis
To determine if daratumumab combined with VMP (D-VMP) will lead to improved 
clinical responses in standard as well as high-risk molecular subgroups, over VMP the 
following exploratory analysis will be conducted by using the similar analysis methods 
specified in Sections 4.3.1.2 and 4.2.2.

To evaluate ORR for subjects in high-risk molecular subgroup and subjects with 
specific molecular subtypes such as del17p, t(14;16), t(4;14).

To evaluate MRD negativity rate for subjects in standard-risk and high-risk 
molecular subgroups.

To evaluate PFS and OS for subjects in high-risk molecular subgroup and subjects 
with specific molecular subtyping such as del17p, t(14;16), t(4;14).
Subgroup exploratory analysis of ORR and PFS by molecular risk within treatment 
group, as well as between molecular subgroups across treatment group will be conducted.
8.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization (excluding study infusion administration) will be 
descriptively summarized by treatment group. Frequencies of hospitalization, outpatient
visits, type of hospitalization or outpatient visit, reasons for hospitalization or outpatient 
visit, durations of hospitalization or outpatient visit will be calculated and tabulated.
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REFERENCES
1.
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for
multiple myeloma. Leukemia 2006;20:1467–1473. Corrigenda/Erratum in: Leukemia. 2007;
21:1134-1135.
2.
Fayers P, Aaronson N, Bjordal K, Curran D, Groenvold M, on behalf of the EORTC Quality 
Of Life Study Group. EORTC QLQ-C30 Scoring Manual: Third Edition. 2001. ISBN 2-
9300 64-22-6.
3.
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform
reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1.
Blood. 2011; 4691-4695.
4.
Tang and Geller, Closed Testing Procedures for Group Sequential Clinical Trials with 
Multiple Endpoints, Biometrics, Dec;55(4):1188-92.
5.
Robins JM, Finkelstein DM. Correcting for non-compliance and dependent censoring in an 
AIDS clinical trial with Inverse Probability of Censoring Weighted (IPCW) log-rank tests. 
Biometrics 2000; 56:779-788.
6.
Branson M and Whitehead J. Estimating a treatment effect in survival studies in which 
patients switch treatment. Stat Med 2002; 21:2449-2463.
7.
Robins JM and Tsiatis AA. Correcting for non-compliance in randomized trials using Rank 
Preserving Structural Failure Time models. Commun Statist Theory Meth 1991; 20: 2609-
2631.
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ATTACHMENT 1:
ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT 
HEMAR
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