Clinical trial NCT02874742
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC
Start date: 2016-08-29; Completion date: 2022-04-08
Enrollment: 224 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if the addition of daratumumab to lenalidomide-bortezomib-dexamethasone (RVd) will increase the proportion of participants achieving stringent complete response (sCR), as defined by the International Myeloma Working Group (IMWG) criteria, by the time of completion of post autologous stem cell transplantation (ASCT) consolidation treatment, compared with RVd alone.

Detailed description:

Arms: arm 1: Participants will receive lenalidomide, bortezomib, dexamethasone and daratumumab. arm 2: Participants will receive lenalidomide, bortezomib and dexamethasone.
Interventions: intervention 1: Lenalidomide intervention 2: Bortezomib intervention 3: Dexamethasone intervention 4: Daratumumab
Intervention descriptions: intervention 1: Cycles 1 through 6: lenalidomide 25 (milligram) mg orally on Days 1 through 14 and each cycle is of 21-days followed by maintenance treatment with lenalidomide 10 mg on days 1-21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a tolerability concern. intervention 2: Bortezomib 1.3 mg/m\^2 subcutaneously on Days 1, 4, 8, and 11 during Cycles 1-6. intervention 3: Dexamethasone 40 mg orally every week (20 mg on Days 1, 2, 8, 9, 15, and 16). intervention 4: Daratumumab intravenously at a dose of 16 milligram per kilogram (mg/kg) weekly during induction treatment (Days 1, 8, and 15 of Cycles 1 through 4), and every 3 weeks during consolidation treatment (Day 1 of Cycles 5 and 6), followed by maintenance treatment with daratumumab every 4 or 8 weeks.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 10 January 2019
Janssen Research & Development*
Clinical Protocol
Phase 2, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, Bortezomib, 
and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in 
Subjects With Newly Diagnosed Multiple Myeloma Eligible for High-Dose Chemotherapy and 
Autologous Stem Cell Transplantation
Protocol 54767414MMY2004; Phase 2
Amendment 3
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 Scientific Affairs, LLC.; Janssen Biotech, Inc.; 
Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen 
Infectious Diseases BVBA; 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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved  
Date:
10 January 2019
Prepared by:
Janssen Research & Development  
EDMS number:
EDMS-ERI-101884947
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
ABBREVIATIONS ...................................................................................................................................... 10
SYNOPSIS.................................................................................................................................................. 12
TIME AND EVENTS SCHEDULE – DARA-RVD ....................................................................................... 21
TIME AND EVENTS SCHEDULE - RVD.................................................................................................... 26
STUDY DRUG DOSING SCHEDULE ........................................................................................................ 32
1.
INTRODUCTION................................................................................................................................ 34
1.1.
Background .................................................................................................................................... 34
1.1.1.
Multiple Myeloma........................................................................................................................ 34
1.1.2.
Daratumumab............................................................................................................................. 35
1.1.2.1.
Nonclinical Studies .................................................................................................................. 35
1.1.2.2.
Clinical Studies ........................................................................................................................ 36
1.1.2.2.1.
Pharmacokinetics................................................................................................................. 37
1.1.2.2.2.
Efficacy................................................................................................................................. 37
1.1.2.2.3.
Safety ................................................................................................................................... 39
1.1.3.
Lenalidomide .............................................................................................................................. 43
1.1.4.
Bortezomib.................................................................................................................................. 43
1.1.5.
Dexamethasone.......................................................................................................................... 44
1.1.6.
Combination Therapy: Lenalidomide-Bortezomib-Dexamethasone........................................... 44
1.1.7.
Combination Therapy: Daratumumab-Lenalidomide-Bortezomib-Dexamethasone .................. 45
1.2.
Overall Rationale for the Study...................................................................................................... 46
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 47
2.1.
Objectives and Endpoints .............................................................................................................. 47
2.1.1.
Objectives ................................................................................................................................... 47
2.1.2.
Endpoints.................................................................................................................................... 48
2.2.
Hypothesis ..................................................................................................................................... 50
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 50
3.1.
Overview of Study Design.............................................................................................................. 50
3.2.
Study Design Rationale.................................................................................................................. 55
3.2.1.
Study Phase/Periods, Treatment Groups................................................................................... 55
3.2.2.
Rationale for Daratumumab Dose Selection, Infusion Rate, and Backbone 
Chemotherapy Regimen............................................................................................................. 55
3.2.3.
Rationale for Pharmacokinetics, Immunogenicity, and Biomarker Evaluations ......................... 56
4.
SUBJECT POPULATION.................................................................................................................. 56
4.1.
Inclusion Criteria ............................................................................................................................ 57
4.2.
Exclusion Criteria ........................................................................................................................... 60
4.3.
Prohibitions and Restrictions ......................................................................................................... 63
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 64
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 64
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6.1.
Daratumumab ................................................................................................................................ 65
6.1.1.
Preparation ................................................................................................................................. 65
6.1.2.
Treatment Schedule and Administration .................................................................................... 65
6.1.3.
Guidelines for Prevention and Management of Infusion-Related Reactions.............................. 66
6.1.3.1.
Preinfusion Medication ............................................................................................................ 66
6.1.3.2.
Postinfusion Medication........................................................................................................... 67
6.1.3.3.
Management of Infusion-Related Reactions ........................................................................... 67
6.1.3.3.1.
Infusion-Related Reactions of Grade 1 or Grade 2.............................................................. 68
6.1.3.3.2.
Infusion-Related Reactions of Grade 3 or Higher................................................................ 68
6.1.4.
Dose Modification and Dose Delays........................................................................................... 69
6.1.4.1.
Dose Modification .................................................................................................................... 69
6.1.4.2.
Toxicity Management .............................................................................................................. 69
6.1.4.3.
Interruption or Missed Doses................................................................................................... 70
6.2.
Lenalidomide.................................................................................................................................. 70
6.2.1.
Dose Adjustments of Lenalidomide............................................................................................ 70
6.2.2.
Deep Vein Thrombosis and Pulmonary Embolism..................................................................... 70
6.2.3.
Thrombocytopenia...................................................................................................................... 71
6.2.4.
Neutropenia ................................................................................................................................ 71
6.2.5.
Renal Impairment ....................................................................................................................... 71
6.2.6.
Other Grade 3 or 4 Adverse Events ........................................................................................... 72
6.3.
Bortezomib ..................................................................................................................................... 72
6.3.1.
Dose Adjustments of Bortezomib ............................................................................................... 72
6.3.2.
Neurologic Toxicity ..................................................................................................................... 73
6.4.
Dexamethasone............................................................................................................................. 73
7.
TREATMENT COMPLIANCE............................................................................................................ 75
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 75
8.1.
Recommended Therapies.............................................................................................................. 76
8.1.1.
Bisphosphonate Therapy............................................................................................................ 76
8.1.2.
Therapy for Tumor Lysis Syndrome ........................................................................................... 76
8.1.3.
Prophylaxis for Bacterial Infection .............................................................................................. 77
8.1.4.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 77
8.1.5.
Prophylaxis for Pneumonia......................................................................................................... 77
8.1.6.
Therapy for Pneumocystis Carinii............................................................................................... 77
8.1.7.
Prevention of Steroid Induced Gastritis...................................................................................... 77
8.2.
Permitted Therapies....................................................................................................................... 77
8.3.
Prohibited Therapies...................................................................................................................... 78
9.
STUDY EVALUATIONS .................................................................................................................... 79
9.1.
Study Procedures........................................................................................................................... 79
9.1.1.
Overview..................................................................................................................................... 79
9.1.2.
Screening Phase ........................................................................................................................ 79
9.1.3.
Induction/Consolidation Phase ................................................................................................... 80
9.1.4.
Maintenance Phase.................................................................................................................... 81
9.1.5.
End-of-Treatment........................................................................................................................ 82
9.1.6.
Long-Term Follow-Up Phase...................................................................................................... 82
9.2.
Efficacy Evaluations....................................................................................................................... 83
9.2.1.
Response Categories ................................................................................................................. 83
9.2.2.
Myeloma Protein Measurements in Serum and Urine................................................................ 86
9.2.3.
Serum Calcium Corrected for Albumin....................................................................................... 86
9.2.4.
β2-microglobulin ......................................................................................................................... 87
9.2.5.
Bone Marrow Examination.......................................................................................................... 87
9.2.6.
Minimal Residual Disease Assessment...................................................................................... 87
9.2.7.
Assessment of Lytic Bone Disease ............................................................................................ 88
9.2.8.
Documentation of Extramedullary Plasmacytomas.................................................................... 89
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 89
9.3.1.
Evaluations ................................................................................................................................. 89
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9.3.2.
Analytical Procedures................................................................................................................. 90
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 90
9.3.4.
Immunogenicity Assessments .................................................................................................... 90
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 91
9.5.
Biomarkers ..................................................................................................................................... 91
9.6.
Patient-Reported Outcomes .......................................................................................................... 92
9.7.
Medical Resource Utilization.......................................................................................................... 93
9.8.
Safety Evaluations ......................................................................................................................... 93
9.8.1.
Adverse Events........................................................................................................................... 93
9.8.2.
Clinical Laboratory Tests ............................................................................................................ 94
9.8.3.
Pregnancy Testing (for women of childbearing potential only) .................................................. 94
9.8.4.
Daratumumab Interference With Indirect Antiglobulin Test Results........................................... 95
9.8.5.
Stem Cell Harvest....................................................................................................................... 96
9.8.6.
FEV1 Test................................................................................................................................... 96
9.8.7.
Electrocardiogram and Vital Signs ............................................................................................. 96
9.8.8.
Physical Examination and ECOG Performance Status.............................................................. 96
9.9.
Sample Collection and Handling.................................................................................................... 96
10.
SUBJECT COMPLETION, DISCONTINUATION OF STUDY TREATMENT, AND 
WITHDRAWAL FROMTHE STUDY.................................................................................................. 97
10.1.
Completion ..................................................................................................................................... 97
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study .................................................. 97
10.3.
Withdrawal From the Use of Research Samples........................................................................... 98
11.
STATISTICAL METHODS................................................................................................................. 99
11.1.
Subject Information ........................................................................................................................ 99
11.2.
Sample Size Determination ........................................................................................................... 99
11.3.
Efficacy Analyses ........................................................................................................................... 99
11.4.
Pharmacokinetic Analyses........................................................................................................... 100
11.5.
Immunogenicity Analyses ............................................................................................................ 100
11.6.
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 100
11.7.
Biomarker Analyses ..................................................................................................................... 100
11.8.
Medical Resource Utilization Analyses........................................................................................ 101
11.9.
Patient-Reported Outcomes ........................................................................................................ 101
11.10.
Safety Analyses ........................................................................................................................... 101
11.11.
Interim Analysis............................................................................................................................ 102
11.12.
Independent Data Monitoring Committee .................................................................................... 103
11.13.
Safety Run-in Data Review Committee ....................................................................................... 103
12.
ADVERSE EVENT REPORTING .................................................................................................... 103
12.1.
Definitions .................................................................................................................................... 103
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 103
12.1.2.
Attribution Definitions................................................................................................................ 105
12.1.3.
Severity Criteria ........................................................................................................................ 105
12.2.
Special Reporting Situations........................................................................................................ 106
12.3.
Procedures................................................................................................................................... 106
12.3.1.
All Adverse Events.................................................................................................................... 106
12.3.2.
Serious Adverse Events ........................................................................................................... 107
12.3.3.
Pregnancy................................................................................................................................. 108
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 109
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 109
13.1.
Procedures................................................................................................................................... 109
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 109
14.
STUDY DRUG INFORMATION....................................................................................................... 109
14.1.
Physical Description of Study Drug.............................................................................................. 109
14.2.
Packaging .................................................................................................................................... 110
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14.3.
Labeling........................................................................................................................................ 110
14.4.
Preparation, Handling, and Storage............................................................................................. 110
14.5.
Drug Accountability ...................................................................................................................... 110
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 111
16.
ETHICAL ASPECTS ....................................................................................................................... 111
16.1.
Study-Specific Design Considerations......................................................................................... 111
16.2.
Regulatory Ethics Compliance..................................................................................................... 112
16.2.1.
Investigator Responsibilities ..................................................................................................... 112
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 112
16.2.3.
Informed Consent ..................................................................................................................... 113
16.2.4.
Privacy of Personal Data .......................................................................................................... 114
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 115
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 115
17.1.
Protocol Amendments.................................................................................................................. 115
17.2.
Regulatory Documentation .......................................................................................................... 116
17.2.1.
Regulatory Approval/Notification .............................................................................................. 116
17.2.2.
Required Prestudy Documentation........................................................................................... 116
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 117
17.4.
Source Documentation................................................................................................................. 117
17.5.
Case Report Form Completion .................................................................................................... 118
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 118
17.7.
Record Retention ......................................................................................................................... 119
17.8.
Monitoring .................................................................................................................................... 119
17.9.
Study Completion/Termination..................................................................................................... 120
17.9.1.
Study Completion/End of Study................................................................................................ 120
17.9.2.
Study Termination..................................................................................................................... 120
17.10.
On-Site Audits .............................................................................................................................. 120
17.11.
Use of Information and Publication.............................................................................................. 121
REFERENCES.......................................................................................................................................... 123
ATTACHMENTS....................................................................................................................................... 125
INVESTIGATOR AGREEMENT ............................................................................................................... 152
LAST PAGE.............................................................................................................................................. 152
LIST OF ATTACHMENTS
Attachment 1:
Conversion Table for Glucocorticoid Dose .................................................................. 125
Attachment 2:
Calculated Creatinine Clearance ................................................................................. 126
Attachment 3:
ECOG Performance Status Scale ............................................................................... 127
Attachment 4:
Guideline for Asthma Eligibility Criteria........................................................................ 128
Attachment 5:
Serum Calcium Corrected for Albumin ........................................................................ 129
Attachment 6:
Standard Nomogram for Calculation of Body Surface Area........................................ 130
Attachment 7:
EORTC QLQ-C30 and EORTC QLQ-MY20................................................................ 131
Attachment 8:
EQ-5D-5L..................................................................................................................... 135
Attachment 9:
Protocol Amendments 1 and 2 .................................................................................... 138
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LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1:
Available Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 June 
2017 .......................................................................................................................................... 40
Table 2:
Daratumumab Infusion Rates ................................................................................................... 66
Table 3:
Daratumumab-Related Toxicity Management .......................................................................... 69
Table 4:
Lenalidomide Dose Adjustment for Thrombocytopenia............................................................ 71
Table 5:
Lenalidomide Dose Adjustment for Neutropenia ...................................................................... 71
Table 6:
Lenalidomide Dose Adjustment for Renal Impairment ............................................................. 72
Table 7:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy ................................................................................. 73
Table 8:
Dexamethasone Dose Modification Based on Toxicity ............................................................ 75
Table 9:
International Uniform Response Criteria Consensus Recommendations ................................ 84
Table 10:
Bone Marrow Testing Requirements ........................................................................................ 88
FIGURES
Figure 1:
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents ........................................................................................................ 45
Figure 2:
Dose-dependent Lysis of Multiple Myeloma Cells in Triple Chemotherapy Treatments.......... 46
Figure 3:
Schematic Overview of the Study............................................................................................. 54
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
4 April 2016
Amendment 1
24 May 2017
Amendment 2
5 Feb 2018
Amendment 3
10 Jan 2019
Please note that the following summary describes changes implemented in Protocol Amendment 3. Details of the 
changes implemented in Protocol Amendments 1 and 2 have been moved to Attachment 9; please refer to 
Attachment 9 for further details on the first 2 amendments.
Amendment 3 (10 Jan 2019)
The major reason for this amendment was to allow an accelerated infusion time of daratumumab during the 
maintenance phase of the study based on new information. Other edits were made for clarity and are described 
below.
Applicable Section(s)
Description of Change(s)
Rationale:  Based on a study by Barr et al,1 it has been shown that daratumumab may be administered via rapid 
infusion while maintaining efficacy, safety, and tolerability. Accordingly, as all subjects in the study have now 
entered the maintenance phase, the protocol has been amended to allow subjects the option to receive a rapid 
infusion of daratumumab, if clinically feasible, beginning in Cycle 7 and continuing. 
Synopsis, Objectives
Synopsis, Dosage and 
Administration
Study Drug Dosing 
Schedule, Daratumumab
Section 2.1.1, Objectives
As part of this change, information was added to the protocol related to the 
following:

To give subjects the option to receive daratumumab via rapid infusion,

The rationale as to why the rapid infusion was added, 

New objectives related to the rapid infusion,

When the rapid infusion of daratumumab is to begin,

Instructions on how the rapid infusion is to be administered including volumes 
and infusion times, and

Notification to investigators that a new informed consent form (ICF) must be 
signed prior to modification of daratumumab administration.
Note: References were updated accordingly. In addition, no changes were made to 
endpoints for evaluation or statistical methods as monitoring of safety, serum 
concentrations, and infusion-related reactions (IRRs) related to daratumumab 
administration were already included in the protocol.
Section 3.2.2, Rationale 
for Daratumumab Dose 
Selection
Section 6.1.2, 
Daratumumab Treatment 
Schedule
Table 2, Daratumumab 
Infusion Rates
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Applicable Section(s)
Description of Change(s)
Rationale:  The following changes were made throughout the protocol as applicable for clarity or to correct 
inadvertent errors.
Changes were made 
throughout the protocol as 
applicable. For specific 
details on sections 
impacted, refer to the 
document compare 
version of the protocol.
Per Protocol Amendment 2, subjects were given the option to receive maintenance 
treatment with daratumumab every 4 weeks (the preferred treatment regimen based on 
new information) instead of every 8 weeks as originally planned (refer to Protocol 
Amendment 2 in Attachment 9). As this was an optional change, for transparency, text 
in reference to daratumumab administration during the maintenance phase was 
modified from every 4 weeks to read every 4 or 8 weeks in the current protocol.
As part of this change, the Dara-RVd Time and Events Schedule was updated such 
that procedures to be performed on Day 1 of each cycle during the maintenance phase 
now reads, “Day 1 of each cycle when daratumumab is administered” to emphasize 
that subjects will not be required to return to the study site when daratumumab is not 
being administered.
In addition, although already being conducted at study sites, text was added to clarify 
that subjects must sign a new ICF prior to changing the frequency of daratumumab 
administration in the maintenance phase.
Text was modified to allow for a dose delay in the event of exceptional circumstances, 
while noting that every effort should be made to keep subjects on schedule with 
dosing.
ASCT was removed as a timepoint for assessment from the minimal residual disease 
(MRD) objective for accuracy as shown below:

To assess negative minimal residual disease (MRD) rate following induction, 
ASCT, post-ASCT consolidation, and maintenance treatment
The following endpoint was modified as shown below because relapse from stringent 
complete response (sCR) is not defined in the International Myeloma Working Group 
(IMWG) criteria:

Duration of CR (and sCR) is the duration from the date of initial documentation of 
a CR (or sCR) response, according to the IMWG criteria, to the date of first 
documented evidence of progressive disease, or relapse from CR (or sCR). 
The endpoint describing time to recovery (previously defined as absolute neutrophil 
count >1.0 x 109/L and platelet count >100 x 109/L), was split into 2 separate 
endpoints and modified to be in accordance with the Center for International Blood 
and Marrow Transplant Research criteria as follows:

To assess time to absolute neutrophil count (ANC) recovery, defined as the date of 
the first of 3 consecutive laboratory values (obtained on different days) where the 
ANC is > 0.5 x 109/L 

To assess time to platelet count recovery, defined as the date of the first of 
3 consecutive laboratory values (obtained on different days) where the platelet 
count is > 20 x 109/L and at least 7 days after the most recent prior platelet 
transfusion
The definition of high risk cytogenetic subgroups was modified to match the most 
current scientifically accepted definition, as shown below:

To evaluate the clinical efficacy of D-RVd in high-risk cytogenetic subgroups 
currently defined as: del(1p), gain of 1q, del(17p), t(4;14), and t(14;16), t(14;20)
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The definition of progression-free survival after next-line therapy was modified for 
accuracy as shown below: 

Progression-free survival after next-line therapy will be measured from the start 
of the next therapy randomization to the date of the progressive disease on the 
next line of treatment or death, whichever comes first. Subjects who are still alive 
and have not yet progressed on the next line of treatment will be censored on the 
last date of follow-up.
In the overall study description, text was presented to describe study endpoints. This 
information was already reported in the objectives and endpoints section and was 
deleted here to avoid repetitiveness. Full details of study endpoints will be provided in 
the Statistical Analysis Plan.
Treatment regimens were modified for clarity as follows:
D-RVd group: RVd with daratumumab 16 mg/kg IV weekly during induction 
treatment (Days 1, 8, and 15 of Cycles 1 through 4) and every 3 weeks during 
consolidation treatment (Day 1 of Cycles 5 and 6), followed by every 4 or 8 weeks 
during maintenance treatment. plus oral lenalidomide 10 mg (D-R) daily on Days 
1-21 throughout each 28-day cycle. Beginning at Cycle 10, the lenalidomide dose 
will be increased to 15 mg unless there is a tolerability concern. Subjects will 
receive pre- and postinfusion medications for each dose of daratumumab as 
described in Sections 6.1.3.1 and 6.1.3.2, respectively. 
RVd group: RVd alone as induction and consolidation treatment (Cycles 1 through 
6: lenalidomide 25 mg orally on Days 1 through 14, bortezomib 1.3 mg/m2 
subcutaneously on Days 1, 4, 8, and 11, and oral dexamethasone 40 mg weekly 
[20 mg on Days 1, 2,8, 9, 15, and 16]) followed by maintenance treatment with oral 
lenalidomide 10 mg daily on Days 1-21 throughout each 28-day cycle on Cycles 7 
through 9.  Beginning at Cycle 10, the lenalidomide dose will be increased to 15 
mg unless there is a tolerability concern.
In addition, as part of this change, the description of treatment regimens in the 
synopsis was changed to be identical to that described in the body of the report.
Dose delay for toxicity management of daratumumab with respect to neutropenia was 
clarified as follows:
•  Grade 4 Neutropenia with any grade infection, of any grade
Text was clarified with respect to MRD assessment as follows:
At the time the original protocol was originally written, MRD Minimal residual 
disease assessment is was a relatively new tool in the assessment of patients with 
multiple myeloma.
Note:  Other minor editorial changes were made. None of these changes impacted the conduct of the study and 
therefore are not summarized here.
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ABBREVIATIONS
ALT
alanine aminotransferase 
ANC
absolute neutrophil count
ASCT
autologous stem cell transplantation
AST
aspartate aminotransferase
AUC
area under the curve
-hCG
-human chorionic gonadotropin
BM-MNC
bone marrow mononuclear cell
BUN
blood urea nitrogen
C
Cycle
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CR
complete response
CrCl
creatinine clearance
CRF
case report form(s) (paper or electronic as appropriate for this study)
CT
computed tomography
CYP
cytochrome P450
DC
Discontinuation
DKd
daratumumab+carfilzomib+dexamethasone
DKRd
daratumumab+carfilzomib+lenalidomide+dexamethasone
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
D-R
daratumumab-lenalidomide
DRC
Data Review Committee
DRd
daratumumab-lenalidomide-dexamthasone
D-RVd
daratumumab-lenalidomide-bortezomib-dexamethasone
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders (4th edition)
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EOT
end of treatment
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FISH
fluorescence in situ hybridization
FLC
free light chain
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
HCV
hepatitis C virus
HDT
high-dose chemotherapy
IAT
indirect antiglobulin test
IB
Investigator Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFE
Immunofixation
Ig
Immunoglobulin
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
Intravenous
IMWG
International Myeloma Working Group
IWRS
interactive web response system
KRd
carfilzomib-lenalidomide-dexamethasone
Kd
carfilzomib -dexamethasone
M-protein
monoclonal paraprotein
MDS
myelodysplastic syndrome
MDSC
myeloid-derived suppressor cells
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MedDRA
Medical Dictionary for Regulatory Activities
MRD
minimal residual disease
MRI
magnetic resonance imaging
MRU
medical resource utilization
N
number of subjects
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
not estimable
NK
natural killer
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PC
plasma cell
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic(s)
PO
by mouth
Pom-dex
pomalidomide-dexamethasone
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome
RBC
red blood cell
Rd
lenalidomide and dexamethasone
Reg
Regulatory cells
RVd
lenalidomide-bortezomib-dexamethasone
sCR
stringent complete response
SPEP
serum M-protein quantitation by electrophoresis
SUSAR
suspected unexpected serious adverse reaction
TTP
time to progression
ULN
upper limit of normal
UPEP
urine M-protein quantitation by electrophoresis
US
United States
Vd
bortezomib-dexamethasone
VGPR
very good partial response
VMP
bortezomib-melphalan-prednisone
VTd
bortezomib-thalidomide-dexamethasone
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SYNOPSIS
Title: Phase 2, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, Bortezomib, 
and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects 
With Newly Diagnosed Multiple Myeloma Eligible for High-Dose Chemotherapy and Autologous Stem 
Cell Transplantation
Daratumumab (JNJ-54767414) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that 
binds CD38 expressed on the cell surface in a variety of hematological malignancies, including myeloma 
cells, lymphomas, and leukemias, as well as on other cell types and tissues with various expression levels. 
Daratumumab can induce complement dependent cytotoxicity, antibody-dependent cell-mediated 
cytotoxicity, antibody-dependent cell phagocytosis, direct apoptosis after cross-linking, and can modulate
CD38 enzymatic activity. CD38 is highly expressed on myeloma cells but is expressed at relatively low 
levels on normal lymphoid and myeloid cells and in some tissues of non-hematopoietic origin, making it a 
relevant target for the treatment of multiple myeloma.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to determine if the addition of daratumumab to lenalidomide, bortezomib, and 
dexamethasone (D-RVd) will increase the proportion of subjects achieving stringent complete response 
(sCR), as defined by the International Myeloma Working Group (IMWG) criteria, by the time of 
completion of post-autologous stem cell transplantation (ASCT) consolidation treatment, compared with 
RVd alone.
Secondary Objectives

To evaluate complete response (CR) and sCR rate following induction, ASCT, post-ASCT 
consolidation, and maintenance treatment

To evaluate overall response rate (ORR) and rate of very good partial response (VGPR) or better 
following induction, ASCT, post-ASCT consolidation, and maintenance treatment

To evaluate duration of and time to sCR and time to CR

To evaluate time to VGPR or better

To evaluate time to partial response (PR) or better

To assess negative minimal residual disease (MRD) rate following induction, post-ASCT 
consolidation, and maintenance treatment

To evaluate clinical outcomes including:

Time to progression (TTP)

Progression-free survival (PFS)

Overall survival (OS)

Duration of response

To assess the safety and tolerability of D-RVd

To assess the pharmacokinetics of daratumumab 

To assess the immunogenicity of daratumumab 
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
To evaluate patient-reported outcomes (PROs)

To evaluate stem cell yield after mobilization 

To assess time to absolute neutrophil count (ANC) recovery, defined as the date of the first of 
3 consecutive laboratory values (obtained on different days) where the ANC is > 0.5 x 109/L

To assess time to platelet count recovery, defined as the date of the first of 3 consecutive laboratory 
values (obtained on different days) where the platelet count is > 20 x 109/L and at least 7 days after 
the most recent prior platelet transfusion

To evaluate the tolerability of daratumumab when administered as a rapid infusion during 
maintenance treatment (ie, an accelerated infusion rate whereby 20% of the daratumumab dose is 
administered over 30 minutes and the remaining 80% is administered over 60 minutes for a total 
dose administration time 90 minutes)
Exploratory Objectives

To evaluate PFS on next-line therapy 

To evaluate the clinical efficacy of D-RVd in high-risk cytogenetic subgroups currently defined as 
del(17p), t(4;14), and t(14;16)

To explore immune modulatory effects of D-RVd as compared with RVd through immune profiling 
(NK, T, and B cells) and T-cell receptor sequencing

To collect medical resource utilization (MRU) data that may be used in future economic modeling 
(the construction and reporting of the economic model will be conducted separately from this study)

To evaluate serum concentrations and potential immunogenicity of daratumumab with respect to 
infusion-related reactions (IRRs) in the setting of rapid infusion during maintenance. 
Endpoints
Primary Endpoint
The primary endpoint is the sCR rate by the end of post-ASCT consolidation treatment, defined as the 
proportion of subjects who have achieved sCR, according to the IMWG criteria, by the end of post-ASCT 
consolidation treatment.
Secondary Endpoints
The secondary efficacy endpoints include: 

Following induction treatment (prior to high-dose chemotherapy [HDT]/ASCT), ASCT (prior to start 
of consolidation treatment), post-ASCT consolidation (after Cycle 6), and maintenance treatment: 

Overall CR and sCR rate is defined as the proportion of subjects who achieve CR (or sCR), 
according to the IMWG criteria, by the respective time point.

ORR is defined as the proportion of subjects who achieve PR or better, according to the IMWG 
criteria, by the respective time point. 

VGPR or better rate is defined as the proportion of subjects achieving VGPR or better, 
according to the IMWG criteria, by the respective time point. 

MRD negative rate is defined as the proportion of subjects who achieve MRD negative status 
by the respective time point. 
Note: A subject not tested for MRD will be considered as MRD positive.
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
Duration of CR (and sCR) is the duration from the date of initial documentation of a CR (or sCR) 
response, according to the IMWG criteria, to the date of first documented evidence of progressive 
disease, or relapse from CR. 

Time to CR (and sCR) is the duration from the date of randomization to the date of initial 
documentation of CR (or sCR), which was confirmed by a repeated measurement as required by the 
IMWG criteria. 

Time to VGPR or better is the duration from the date of randomization to the date of initial 
documentation of VGPR or better, which was confirmed by a repeated measurement as required by 
the IMWG criteria. 

Time to PR or better is the duration from the date of randomization to the date of initial 
documentation of PR or better, which was confirmed by a repeated measurement as required by the 
IMWG criteria. 

Time to progression is defined as the duration from the date of randomization to the date of first 
documented evidence of progressive disease according to the IMWG criteria. 

Progression-free survival is defined as the duration from the date of randomization to the date of first 
documented evidence of progressive disease or death, whichever comes first. 

Overall survival is measured from the date of randomization to the date of the subject’s death. 

Duration of response is defined as the duration from the date of initial documentation of a response 
(PR or better) according to the IMWG criteria to the date of first documented evidence of 
progressive disease according to the IMWG criteria. 
Predefined data censoring rules will be applied.
Exploratory Endpoint

Progression-free survival after next-line therapy will be measured from randomization to the date of 
the progressive disease on the next line of treatment or death, whichever comes first. Subjects who 
are still alive and have not yet progressed on the next line of treatment will be censored on the last 
date of follow-up.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
Hypothesis
The primary hypothesis of this study is that D-RVd will improve the sCR rate by the end of post-ASCT 
consolidation treatment compared with RVd alone.
OVERVIEW OF STUDY DESIGN
This is a multicenter, randomized, open-label, active-controlled, Phase 2 study in subjects with newly 
diagnosed multiple myeloma eligible for HDT and ASCT. Initially, there will be a safety run-in phase in 
up-to-16 subjects to assess potential dose-limiting toxicities (DLTs) that may be associated with the 
addition of daratumumab to the RVd regimen. The main study consists of 4 phases: a 28-day screening 
phase; an induction/consolidation phase (which is inclusive of four 21-day induction treatment cycles 
followed by stem cell mobilization, HDT, and ASCT, followed by two 21-day consolidation treatment 
cycles); a 24-month maintenance phase that starts after the post-ASCT consolidation disease evaluation; 
and a long-term follow-up phase. All subjects will be followed in the long-term follow-up phase for at 
least 1 year after last dose of study treatment and will continue until death, withdrawal of consent for 
study participation, or the end of study definition is met. The end of study is defined as when all subjects 
have completed at least 1 year of long-term follow up, or until death or withdrawal of consent for study 
participation, whichever occurs first.
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Initially, a safety run-in phase will be performed at selected study sites. In this safety run-in phase, a total 
of 8 to 16 subjects will be enrolled and assigned to receive D-RVd to assess potential DLTs during Cycle 
1 of treatment. Subjects who are enrolled in the safety run-in phase will have all procedures indicated in 
the TIME AND EVENTS SCHEDULE performed except PRO assessments and MRU data collection.
Dose-limiting toxicities are defined as:

Grade 4 neutropenia lasting more than 7 days.

Grade 4 thrombocytopenia lasting more than 7 days despite transfusion support. 

Grade 3 or higher nonhematological toxicity except: 

Grade 3 nausea, vomiting or diarrhea that can be controlled within 48 hours with maximal 
supportive care.

Grade 3 hyperglycemia that can be controlled within 48 hours with appropriate supportive care.

Asymptomatic Grade 3 or higher electrolyte disturbances that can be controlled with repletion 
within 24 hours. 

Grade 3 maculopapular rash attributable to lenalidomide.

Infusion-related reactions (IRRs):

Any Grade 4 IRR occurring within 48 hours of the infusion of daratumumab.

Any Grade 3 IRR occurring within 48 hours of the infusion of daratumumab that does not 
resolve with a reduced infusion rate or temporarily stopping the infusion, as well as 
administration of supportive care and symptomatic therapy such as a steroid and an 
antihistamine.
Alopecia, lymphopenia, and anemia will not be part of DLT determination.
Up to 16 subjects (minimum 8) will be enrolled in the safety run-in phase. Subjects will be monitored 
according to stopping boundaries specified in the Statistical Methods section. Subjects who experience a 
DLT during the safety run-in will be withdrawn from the study (based on investigator’s judgment and 
best clinical practice). If the stopping boundaries are crossed after 8, 12, or 16 subjects, all subjects will 
be withdrawn from the study, and the study will be stopped. Unless the study is stopped due to DLTs, 
subjects enrolled in the safety run-in phase will continue in the study and follow the visit schedule and 
procedures described for the main study (except PRO assessments and MRU data collection).
Following successful completion of the safety run-in phase, approximately 200 subjects will be randomly 
assigned to 1 of 2 treatment groups (100 per treatment group) in the main study:

D-RVd group: RVd with daratumumab 16 mg/kg intravenous (IV) weekly during induction 
treatment (Days 1, 8, and 15 of Cycles 1 through 4) and every 3 weeks during consolidation 
treatment (Day 1 of Cycles 5 and 6), followed by every 4 or 8 weeks during maintenance treatment.

RVd group: RVd alone as induction and consolidation treatment (Cycles 1 through 6: lenalidomide 
25 mg orally on Days 1 through 14, bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, and 11, 
and oral dexamethasone 40 mg weekly [20 mg on Days 1, 2, 8, 9, 15, and 16]) followed by 
maintenance treatment with oral lenalidomide 10 mg daily on Days 1-21 throughout each 28-day 
cycle on Cycles 7 through 9. Beginning at Cycle 10, the lenalidomide dose will be increased to 
15 mg unless there is a tolerability concern. 
Subjects will be stratified at randomization by International Staging System Stage I, II, or III disease 
(β-2 microglobulin and albumin) and creatinine clearance (CrCl [30-50 mL/min and >50 mL/min]). 
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Daratumumab and RVd are to be administered as described in Dosage and Administration and in the 
Study Drug Dosing. After 4 cycles of induction study treatment, subjects will undergo stem cell 
mobilization and then proceed to HDT and ASCT, which will be performed according to institutional 
standards. If the decision is made by the investigator not to pursue HDT and ASCT, subjects will be 
discontinued from study treatment and enter the long-term follow-up phase; subjects who do not undergo 
HDT and ASCT will not receive consolidation or maintenance treatment on protocol. 
Consolidation treatment may commence when engraftment is complete and when in the opinion of the 
investigator the subject is fit enough to tolerate subsequent systemic therapy (60-100 days post-ASCT). 
At the start of consolidation treatment, both groups will receive the same dosages of lenalidomide, 
bortezomib, and oral dexamethasone that were tolerated at the end of induction treatment. Subjects will 
be evaluated for the primary endpoint (post-ASCT consolidation sCR). MRD will be assessed by next-
generation sequencing, regardless of treatment group, as detailed in the TIME AND EVENTS 
SCHEDULE. After the post-ASCT consolidation disease evaluation, subjects will enter the 24-month 
maintenance phase of the study. Following completion of the last cycle of the maintenance phase, 
subjects may continue lenalidomide as per local standard of care.
Subjects will receive study treatment through completion of the 24-month maintenance phase, or until 
confirmed disease progression, discontinuation of study treatment due to an unacceptable drug toxicity, or 
other reasons. Unless a subject withdraws consent for study participation, or is lost to follow-up, an EOT 
visit is to be scheduled 30 days after the last dose of all components of the study treatment have been 
discontinued, or as soon as possible before the start of next-line therapy. After completion of the EOT 
visit, subjects will enter the long-term follow-up phase of the study. Subjects who enter the long-term 
follow-up phase before disease progression will return to the site every 12 weeks for disease evaluation 
and other follow-up assessments (ie, other malignancies, start of next-line therapy, and survival), until 
confirmed disease progression, death, the start of a new treatment for multiple myeloma, withdrawal of 
consent for study participation, or the end of study, whichever occurs first (see TIME AND EVENTS 
SCHEDULE). After confirmed disease progression or the start of a new treatment for multiple myeloma, 
subjects will return to the site or be contacted by telephone every 12 weeks for follow-up assessments (ie, 
other malignancies, next-line therapy, progressive disease on next-line therapy, and survival, as 
applicable). Following disease progression on the next-line therapy, subjects will only be followed for 
survival.
Throughout the study, subjects will be monitored closely for adverse events, laboratory abnormalities, and 
clinical response. 
To measure functional status, well-being, and symptoms, the EORTC QLQ-C30, EORTC QLQ-MY20,
and the EQ-5D-5L instruments will be completed by subjects throughout the study. Medical resource 
utilization data will also be collected.
A Data Review Committee will be established to review safety data after 8, 12, and 16 subjects in the 
safety run-in phase complete Cycle 1 (or discontinue before the end of Cycle 1) and will use stopping 
boundaries described in the Statistical Methods section. If the study is not stopped due to DLTs in the 
safety run-in phase, one interim safety analysis is planned for the safety run-in cohort after all subjects are 
treated for at least 4 cycles or discontinue study participation.
An independent Data Monitoring Committee (DMC) will meet periodically to review interim safety data
during the main study. One planned interim safety analysis will occur after at least 50 subjects are treated 
for at least 4 cycles and undergo stem cell mobilization (or are evaluated for mobilization feasibility) in 
the main study or have discontinued before completing 4 cycles / stem cell mobilization / feasibility.
SUBJECT POPULATION
Potential subjects, 18 to 70 years of age, inclusive, who are eligible for HDT and ASCT, have documented 
multiple myeloma, have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 
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1, or 2, and have not had prior systemic therapy for multiple myeloma, are eligible for enrollment. 
Potential subjects will not be eligible if they have been diagnosed or treated for malignancy other than 
multiple myeloma (with exception of malignancies treated with curative intent and no known disease for 
≥3 years or adequately treated non-melanoma skin cancer, lentigo maligna, or in situ malignancies 
[including but not limited to, cervical, breast] with no evidence of disease), are exhibiting clinical signs of 
or have a known history of meningeal or central nervous system involvement by multiple myeloma, have
known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) <50% 
of predicted normal, have known moderate or severe persistent asthma within the past 2 years or currently 
have uncontrolled asthma of any classification, have clinically significant cardiac disease, or have plasma 
cell leukemia, Waldenström’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, monoclonal protein, and/or skin changes), or light-chain amyloidosis.
DOSAGE AND ADMINISTRATION
All induction and consolidation cycles are 21 days (Cycles 1-6). All subjects will receive RVd with or 
without daratumumab, based on random assignment, during induction and consolidation cycles. At the 
start of the consolidation phase (ie, Cycle 5 Day 1), both groups will receive the same dosages of 
lenalidomide, bortezomib, and oral dexamethasone that were tolerated at the end of induction treatment.
Maintenance treatment cycles are 28 days in duration with lenalidomide given on Days 1-21; the D-RVd 
group will receive daratumumab every 4 or 8 weeks. Maintenance treatment will continue until disease 
progression or up to a maximum of 2 years. The start of a cycle will be the day of the first full dose of 
either daratumumab or lenalidomide, depending on the treatment group and study phase. The start of each 
cycle may occur within ±3 days (induction), ±14 days (consolidation), or ±14 days (maintenance) of the 
scheduled day to accommodate the schedule of the site or subject. Every effort should be made to keep a 
subject on schedule with dosing; however, in exceptional circumstances, dose delay may be considered.
Daratumumab (16 mg/kg) will be administered as an IV infusion weekly during induction treatment in 
Cycles 1 to 4 (Days 1, 8, and 15), every 3 weeks during consolidation treatment in Cycles 5 and 6 
(Day 1), and every 4 or 8 weeks during maintenance treatment in Cycle 7 and beyond for 24 months.
Beginning on Cycle 7 Day 1 and onward, if clinically feasible, subjects in the D-RVd will be given the 
option to be converted from the standard infusion rate of daratumumab to the accelerated infusion rate 
(90-minute rapid infusion) of daratumumab. For each daratumumab standard infusion or accelerated 
infusion, protocol specified pre- and post-infusion medications will be administered. No daratumumab 
dose modification (increase or decrease) will be permitted; dose delays are allowed to recover from 
toxicity. Subjects who miss ≥3 consecutive planned doses of daratumumab for reasons other than toxicity 
will be withdrawn from treatment.
In Cycles 1 through 6, lenalidomide will be administered at a dose of 25 mg orally each day on Days 1 
through 14 of each 21-day cycle. During maintenance treatment in Cycle 7 and beyond, lenalidomide 
10 mg will be administered daily on Days 1-21 throughout each 28-day cycle. Beginning at Cycle 10, the 
lenalidomide dose will be increased to 15 mg unless there is a tolerability concern. Following completion 
of the last cycle of the 24-month maintenance phase, subjects may continue lenalidomide as per local 
standard of care. Lenalidomide dose adjustment should be instituted for subjects with a CrCl 
≤50 mL/min. To be enrolled in the study, subjects must have CrCl ≥30 mL/min. If during treatment a 
subject’s renal status changes, the dose should be adjusted accordingly. 
Bortezomib 1.3 mg/m2 will be administered as a subcutaneous injection twice weekly (Days 1, 4, 8, and 
11) during the 21-day induction and consolidation cycles (Cycles 1-6). On daratumumab infusion days, 
bortezomib will be administered at the end of the daratumumab infusion. Neither group will receive 
bortezomib after the first 6 cycles of D-RVd or RVd.
Oral dexamethasone will be administered at a total dose of 40 mg weekly (ie, 20 mg on Days 1, 2, 8, 9,
15, and 16) during the 21-day induction and consolidation cycles (Cycles 1-6). For subjects in the D-RVd 
group, the dexamethasone 20 mg oral or IV (only if oral is not available) dose administered as a 
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preinfusion medication on daratumumab infusion days (Days 1, 8, and 15) replaces the oral 
dexamethasone dose for that day. In the maintenance phase, dexamethasone, 20 mg orally (or IV), will be 
administered to subjects in the D-R group as a pre-infusion medication prior to daratumumab.
Subjects who need to temporarily interrupt treatment due to toxicity or discontinue treatment with any 
one component of study treatment (lenalidomide, bortezomib, dexamethasone, or daratumumab, as 
applicable depending on the study phase) may continue to receive treatment with the other components of 
study treatment, as assigned.
EFFICACY EVALUATIONS
Disease evaluations must be performed on Day 1 of every cycle according to the TIME AND EVENTS 
SCHEDULE. Note that an additional disease evaluation occurs on Day 21 of Cycle 4 and the day after 
Day 21 of Cycle 6 (with a 7-day window) to assess end of Cycle 4 and end of Cycle 6 response, 
respectively. Disease response and progression will be based on assessments according to the IMWG 
guidelines. Efficacy evaluations include: monoclonal paraprotein (M-protein) measurements (serum and 
urine), immunofixation (IFE; serum and urine), serum free light chain (FLC), serum calcium corrected for 
albumin, examination of bone marrow aspirate or biopsy, skeletal survey (assessment of lytic bone 
disease), and documentation of extramedullary plasmacytomas. Minimal residual disease in the bone 
marrow aspirate will also be assessed.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
For all subjects who receive daratumumab (D-RVd during induction/consolidation and/or D-R during 
maintenance), serum concentration of daratumumab as well as the immunogenicity (anti-daratumumab
antibodies) will be determined from venous blood samples collected according to the TIME AND 
EVENTS SCHEDULE. 
BIOMARKER EVALUATIONS 
Blood and bone marrow aspirate samples for biomarker studies will be collected from all subjects. 
Biomarker evaluations will focus on the assessment of MRD (in bone marrow aspirates). Minimal 
residual disease will be evaluated in subjects who achieve CR or sCR (including subjects with VGPR or 
better and suspected daratumumab interference). In addition to evaluating MRD, biomarker assessments
may also monitor changes in immune cell subpopulations in bone marrow aspirates and whole blood.
Blood and bone marrow aspirate samples will be collected at screening and following treatment, as 
detailed in the TIME AND EVENTS SCHEDULE. Baseline bone marrow aspirate samples will be 
subjected to DNA and RNA sequencing to establish the myeloma clone for MRD monitoring. In addition 
to evaluating MRD, a whole blood sample will be collected from subjects, as outlined in the TIME AND 
EVENTS SCHEDULE for processing to plasma and PBMCs and monitoring changes in immune cell 
subpopulations. 
SAFETY EVALUATIONS
Safety evaluations will include adverse event monitoring, clinical laboratory parameters (hematology and 
serum chemistry; testing for hepatitis C virus reactivation for subjects with a history of hepatitis C), 
pregnancy testing, electrocardiogram monitoring, vital sign measurements, physical examinations, and 
ECOG performance status. Since daratumumab interferes with the indirect antiglobulin test (IAT), 
subjects in the daratumumab group will receive an 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.
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STATISTICAL METHODS
Sample Size Determination
Historical data suggest that the post-consolidation sCR rate is approximately 35% for RVd therapy. To 
detect an absolute 15% increase in post-consolidation sCR rate with 80% power using a 1-sided 
likelihood ratio test at the 10% significance level, 200 subjects need to be randomized with a 1:1 
randomization ratio, assuming a 5% non-evaluable rate.
Efficacy Analyses
Analysis of the primary and secondary efficacy variables will be based on the response-evaluable 
population, which includes all randomized subjects who have measurable disease, receive at least 1 dose 
of study treatment, and have at least 1 efficacy evaluation assessment.
Response to study treatment and progressive disease will be evaluated by a validated computer algorithm
to calculate IMWG response. Rate of sCR achieved after post-ASCT consolidation will be tabulated. 
Treatment comparison will be made using the Cochran-Mantel-Haenszel test. The difference in 
post-ASCT consolidation sCR rate and its 2-sided 95% confidence interval will be provided. Other binary 
endpoints, including overall CR, sCR, ORR, VGPR or better rate following induction, ASCT, post-ASCT 
consolidation, and maintenance, and MRD-negative rate after consolidation, will be analyzed similarly. 
Time-to-event efficacy endpoints, including duration of CR, sCR, TTP, PFS, OS, and time to next-line 
anti-myeloma treatment, will be descriptively summarized using the Kaplan-Meier method. Except for 
duration of CR and sCR, treatment comparisons will be made via a log-rank test, and treatment effects, 
measured by hazard ratios, will be estimated via a Cox regression model with treatment as the sole 
explanatory variable in the model. 
The primary analysis will be performed after all randomized subjects have completed the post-ASCT 
consolidation disease evaluation or have been discontinued from study treatment by this time point. 
A second analysis will be performed after all randomized subjects complete the maintenance phase or 
have been discontinued from study treatment by this time point. A final data cutoff and analysis, to update 
secondary endpoints and safety, will occur at the end of study when all subjects have completed at least 
1 year of long-term follow up, or until death or withdrawal of consent for study participation, whichever 
occurs first.
All data, including efficacy and safety, from subjects enrolled in the safety run-in phase during the study
will be summarized and presented separately from the randomized portion of the study (main study) using 
similar methods. 
Safety Analyses
During the safety run-in phase for D-RVd, DLTs in Cycle 1 will be monitored in cohorts of 4 subjects, 
after the first 8 subjects have completed Cycle 1 or discontinued due to DLT, using the Bayesian 
approach of Thall, Simon, Estey as extended by Thall and Sung. The prior probability of DLT in Cycle 1 
for the D-RVd regimen is modeled by beta distribution (Beta(0.25, 0.75)). This distribution has the same 
mean as the maximum acceptable DLT in Cycle 1 of 0.25, and an Effective Sample Size of 1. The 
decision criteria applied will be to stop if Prob{p(DLT) >0.25| data}>0.95; ie, the posterior probability of 
the unknown DLT rate being >0.25 given the observed data is more than 0.95.
Subjects will be monitored according to the following stopping boundaries for DLT.
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Clinical Protocol 54767414MMY2004 Amendment 3
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Approved, Date: 10 January 2019
Stop the study if there are this many toxicities total:
Number of Subjects 
(in complete cohorts of 4)
Number of Toxicities
8
≥5
12
≥6
16
≥8
All safety analyses will be based on the safety analysis set, which includes all randomized subjects who 
receive at least 1 dose of study treatment.
Treatment-emergent adverse events are adverse events with onset during the induction/consolidation or 
maintenance treatment phase or that are a consequence of a pre-existing condition that has worsened since 
baseline. 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. These will be provided using the same formats as those used for adverse events.
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
21
Approved, Date: 10 January 2019
TIME AND EVENTS SCHEDULE – DARA-RVD
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1
(Cycles 
1-4)
D21
(C4 
only)
D1
Procedures
Informed consenti
X
Eligibility criteria
X
Demographics/Medical Historyj
X
Height
X
Chest x-ray
Xk
Spirometry (FEV1)
Xk,l
ECOG performance status
X
X
X
X
D1 of each cycle when daratumumab is 
administered (ie, D1 every 4 weeks or 
D1 every 8 weeks depending on the 
subject’s daratumumab dosing cycle)
X
12-lead ECG
Xk
C5 only
As clinically indicated
Physical examination
X
X
X
D1 of each cycle when
daratumumab is administered
Neurological examinationm
X
X
X
As clinically indicated
Weightn
X
X
X
X
D1 of each cycle when
daratumumab is administered
Vital signso
X
D1, D8, 
D15
X
D1 of each cycle when
daratumumab is administered
Blood type/indirect antiglobulin test
Xq
Laboratory Assessments
For D1 of Cycles 1-6, the following 2 central laboratory kits must be completed: assessment kit and disease evaluation kit 
Local 
laboratory
Pregnancy test 
(Women of childbearing 
potential only) 
Serum -hCG pregnancy tests: within 10-14 days before and again within 24 hours before first dose of C1D1; weekly during 
Cycle 1, then monthly in subsequent cycles in women with regular menstrual cycles, or every 2 weeks in women with irregular 
menstrual cycles. A serum (-hCG) or urine pregnancy test is also required at the EOT visit. Testing must continue as per standard 
of care in follow-up phase for subjects remaining on lenalidomide.
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
22
Approved, Date: 10 January 2019
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1
(Cycles 
1-4)
D21
(C4 
only)
D1
Hematologyr,s
X
D 1, D8, 
D15
X
X
D1 of each cycle when
daratumumab is administered
X
Serum chemistryr,t
X
X
X
X
D1 of each cycle when
daratumumab is administered
X
Send to central 
laboratory
Daratumumab PK
(D-RVd/D-R group only)
C1, C4 
only u
X u
Posttreatment 
Weeks 4 and 8
Anti-daratumumab antibodies 
(Immunogenicity) 
(D-RVd/D-R group only)v
No additional sample required; taken from PK sample (see Section 9.3.4)
C1, C4 
predose
C5 predose
Posttreatment 
Weeks 4 and 8
HCV viral load w
X
Every 3 months during induction and consolidation
Every 4 months during maintenance 
Study Drug Administration
Randomizationx
X
Study drug dosing
See Study Drug Dosing Schedule
PRO Assessments and MRU (The initial set up of the ePRO device and administration of the first questionnaire for each subject are to be completed on C1D1 (and subsequent 
D1 visits) before any study-specific procedures are performed.)
PRO assessments and MRU data collection will not be performed at any time during the study for subjects enrolled in safety run-in phase.
EORTC QLQ-C30 
C1-C3
only
X
C5 only
X
6, 12, 18, and 24 months after start of 
maintenance
X
X
EORTC QLQ-MY20
C1-C3
only
X
C5 only
X
X
X
EQ-5D-5L
C1-C3
only
X
C5 only
X
X
X
MRU
X
X
X
D1 of each cycle when
daratumumab is administered e
X
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
23
Approved, Date: 10 January 2019
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1
(Cycles 
1-4)
D21
(C4 
only)
D1
Disease Evaluations: To be performed on Day 1 of each cycle during induction, consolidation and every 8 weeks during maintenance phase.
Note that an additional disease evaluation occurs on Day 21 of Cycle 4 and the day after Day 21 of Cycle 6 (with a 7-day window) to assess end of Cycle 4 and end of 
Cycle 6 response, respectively. Refer to Section 9.2 for details on efficacy evaluations. 
Send to 
central 
laboratory
β2-microglobulin, LDH
X
Blood and 24-hour urine samples: In addition to the time points below, samples will also be collected whenever CR or sCR is suspected. 
Only 1 blood and 1 24-hour urine sample are required to perform the following tests: 
Send to 
central
laboratory
SPEP y
X
X
X
X
X
D1 of odd cycles (7, 9, 11, etc) e
X
Q12
wks
UPEP
X
X
X
X
X
X
Serum QIgz
X
X
X
X
X
X
Serum IFEy
X
X
X
X
X
Performed whenever CR or sCR is 
suspected or maintained for all subjects.
X
Urine IFE
X
X
X
X
X
X
Serum FLC assay
X
X
X
X
X
Performed whenever CR or sCR is 
suspected or maintained for all subjects
For subjects without measurable disease 
in serum or urine, also performed on D1 
of each odd cycle
X
Bone marrow aspirate/biopsy sample and blood samples (additional details are provided in Table 10).
Local laboratory
Cytogenetics-FISH 
(aspirate)aa
X bb
Send to 
central 
laboratorycc
MRD (aspirate)
Xbb
at first evidence of suspected CR or sCR (including subjects with VGPR or better and 
suspected daratumumab interference) 
after induction / before stem cell collection
at post-ASCT consolidation disease evaluation
at 12 and 24 months (3 weeks) during maintenance
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
24
Approved, Date: 10 January 2019
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1
(Cycles 
1-4)
D21
(C4 
only)
D1
Biomarker (CyTOF, PBMC, 
and plasma) (blood)dd
X
X
X
X
Immunophenotyping (blood)dd
X
X
X
X
Send to local 
laboratory
PC clonality assay 
(immunohistochemistry, 
immunofluorescence or flow 
cytometry)
Xbb
At first evidence of suspected CR or sCR (including subjects with VGPR or better and 
suspected daratumumab interference)
after induction / before stem cell collection
at post-ASCT consolidation disease evaluation
at 12 and 24 months (3 weeks) during maintenance
Morphology (aspirate and 
biopsy)ee
Xbb
Assessment of lytic bone disease
Xk
As clinically indicated to document response or progression; see Section 9.2.7 for details.
X
Extramedullary plasmacytomas
(subjects with history; physical or radiologic 
examination, as applicable)
Xk
X
C5 only
X
6, 12, and 24 months (3 weeks) 
after start of maintenance 
(within 14 days before scheduled visit)
X
Follow-up After EOT
Other malignancy
Q12 wks
Q12 wks
Next-line therapy and start/stop date
Survival
Date of PD on next-line therapy
Ongoing Subject Review
Adverse events
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment in the 
maintenance phase with the exception of adverse events related to mobilization and ASCT procedures; see Section 12 for 
detailed instructions. 
Concomitant medications
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment; 
see Section 8 for detailed instructions. During the mobilization and stem cell transplantation procedures, concomitant 
medications related to the planned procedures do not need to be reported in the eCRF. However, concomitant medications 
related to the mobilization and transplantation procedures should be documented by providing a copy of the medication order 
set.
ASCT = autologous stem cell transplantation; -hCG = -human chorionic gonadotropin; BUN = blood urea nitrogen; C = cycle; CR = complete response; D = day; D-R = daratumumab 
and lenalidomide; D-RVd = daratumumab, lenalidomide, bortezomib, and dexamethasone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end-of-
treatment; FEV1 = Forced Expiratory Volume (in 1 second); FISH = fluorescence in situ hybridization; FLC = free light chain; FU = follow-up; HCV = hepatitis C virus; HDT = high-
dose chemotherapy; ICF = informed consent form; IFE = immunofixation; Ig = immunoglobulin; LDH = lactic acid dehydrogenase; M-protein = monoclonal paraprotein; 
MRD = minimal residual disease; MRU = medical resource utilization; PBMC = peripheral blood mononuclear cell; PC = plasma cell; PD = progressive disease; PK = pharmacokinetic; 
PRO = patient-reported outcome; Q12wks = every 12 weeks; QIg = quantitative immunoglobulin; RVd = lenalidomide, bortezomib, and dexamethasone; sCR = stringent complete 
response; SPEP = serum M-protein quantitation by electrophoresis; UPEP = urine M-protein quantitation by electrophoresis; VGPR = very good partial response.
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
25
Approved, Date: 10 January 2019
NOTE: Subjects who are enrolled in the safety run-in phase will have all procedures performed except PRO assessments and MRU data collection.
a)
Induction and consolidation cycles are 21 days in duration; there will be a maximum of 4 induction cycles and 2 consolidation cycles. Maintenance therapy cycles are 28 days in 
duration. The start of each cycle may occur within ±3 days during induction, ±14 days during consolidation, and ±14 days during maintenance of the scheduled day to accommodate 
the schedule of the site or subject. Every effort should be made to keep a subject on schedule with dosing; however, in exceptional circumstances, dose delay may be considered.
For C4D21 procedures, a window of +7 days will be allowed; must be performed before ASCT. For C5D1 procedures, a window of -7 days will be allowed.
If a D-RVd subject opts to remain on the every 8-week daratumumab maintenance dosing schedule, it is not necessary for that subject to return for office visits for D1 procedures 
during cycles when they are not receiving a daratumumab infusion. These subjects will continue to come to the clinic for D1 of daratumumab dosing cycles only.
For those D-RVd subjects consenting to every 4-week daratumumab dosing, central laboratory disease evaluation samples (SPEP, UPEP, etc.) will continue to be collected every 
other cycle during maintenance (D1 of odd cycles). All other necessary evaluations (vital signs, ECOG etc.) are to be conducted monthly on D1 of every cycle during maintenance or 
as otherwise specified in the protocol.
b) Stem cell mobilization, HDT, and ASCT will be performed according to institutional standards. Subjects who do not undergo HDT and ASCT will not receive consolidation or 
maintenance treatment on protocol; however, they will have EOT assessments then enter the long-term follow-up phase.
c)
Consolidation therapy may commence when engraftment is complete and when in the opinion of the investigator the subject is fit enough to tolerate subsequent systemic therapy and 
should start in the 60 to 100 days post-ASCT.
d) The post-ASCT consolidation disease evaluation (primary endpoint) should be performed the day after completion of C6D21 (+7 day window; 100 to 150 days post-ASCT). 
e)
If C7D1 is started within the 14 days following the post-ASCT consolidation disease evaluation, C7D1 collection of MRU data and disease evaluations do not need to be repeated.
f)
Subjects will receive study treatment through completion of the 24-month maintenance phase, or until confirmed disease progression, discontinuation of study treatment due to an 
unacceptable drug toxicity, or other reasons. Unless a subject withdraws consent for study participation, or is lost to follow-up, an EOT visit is to be scheduled 30 days after the last 
dose of all components of the study treatment have been discontinued, or as soon as possible before the start of next-line therapy. Lenalidomide will be continued as per local 
standard of care at the end of the maintenance phase, the EOT visit should be performed 30 days after all other study treatment is permanently discontinued or as soon as possible 
before the start of next-line therapy.
g) Before disease progression, subjects will return to the site for assessments until confirmed disease progression, death, the start of a new treatment for multiple myeloma, withdrawal 
of consent for study participation, or the end of study, whichever occurs first. Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat 
investigation. Clinical judgment should prevail; however, repeat assessments after 1 to 3 weeks can be used as a general guideline. After confirmed disease progression or the start of 
a new treatment for multiple myeloma, subjects will return to the site or be contacted by telephone for follow-up assessments until death, withdrawal of consent for study 
participation, or the end of study, whichever occurs first. Following disease progression on the next-line therapy, subjects will only be followed for survival.
h) Subjects will be followed in the long-term follow-up phase for at least 1 year after last dose of study treatment and will continue until death, withdrawal of consent for study 
participation, or the end of study definition is met. The end of study is defined as when all subjects have completed at least 1 year of long-term follow up, or until death or withdrawal 
of consent for study participation, whichever occurs first.
i)
Must be signed before any study-related procedures are performed.
j)
Medical history including surgery or procedures planned prior to entry into the study.
k)   Acceptable for screening if performed as part of standard of care within 42 days before randomization.
l)
Pulmonary function testing (spirometry) is required only for subjects with chronic obstructive pulmonary disease or asthma. FEV1 should be measured for subjects with chronic 
obstructive pulmonary disease or asthma. 
m) General neurological exam focused on sensory peripheral neuropathy.
n) Each subject’s dose will be calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. If a subject’s weight changes by more than 10% from C1D1 or 
the most recent weight used for dose calculation, the dose of all study treatments should be re-calculated. Weight to be recorded on all daratumumab dosing days.
o)   Temperature, pulse/heart rate, respiratory rate, and blood pressure. Measured in sitting position. For all infusions except C1D1 (see note below), measured immediately before the 
start of and at the end of daratumumab infusion. Day 15 vital signs are required only for subjects in D-RVd arm.
p) For C1D1 only: immediately before the start of daratumumab infusion; at 0.5, 1, 1.5, 2, and 3.5 hours after the start of the infusion and then every 2 hours through duration of 
infusion; at end of infusion; and 0.5 and 1 hour after the end of the infusion.
q) To be performed once randomization to D-RVd is known, prior to dosing with daratumumab. A wallet card with the subject’s blood type will be provided to subjects randomly 
assigned to D-RVd group.
r)
For C1D1, there is no need to repeat the tests if they have been performed within the past 3 days. Laboratory evaluations may be performed up to 2 days before other infusion days. 
Perform at additional time points, as clinically indicated.
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
26
Approved, Date: 10 January 2019
s)
On-site or accredited local laboratory must be used for hematology laboratory assessments. Results of local hematology tests must be evaluated before each study drug administration
to guide treatment decisions. Hematology panel: hemoglobin, white blood count with absolute neutrophils and lymphocytes, red blood cell count, and platelet count.
t)
Serum chemistry panel: sodium, potassium, creatinine and creatinine clearance (must be calculated per protocol, see Section 9.8), glucose, aspartate aminotransferase, alanine 
aminotransferase, total bilirubin, alkaline phosphatase, BUN, calcium and albumin-adjusted calcium, and albumin.
u) If the sampling falls on a dosing day, 1 sample is to be collected before the start of (window -2 hours) the daratumumab infusion and 1 sample is to be collected immediately after the 
end of (window +2 hours) the daratumumab infusion. 
v) 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 
determination of anti-daratumumab antibodies.
w) Subjects who completed treatment for hepatitis C at least 6 months prior to screening and have no detectable circulating hepatitis C virus (HCV) at screening, may participate in the 
study. Such subjects will be required to undergo regular assessment for HCV reactivation, as shown and will be withdrawn from the study if they test positive at any time during the 
study.
x)   Randomization will be performed up to 72 hours before the first dose of study treatment on C1D1.
y) If daratumumab interference is suspected based on SPEP and IFE results, additional reflex IFE testing will be performed by the central laboratory.
z)
All subject’s samples will be tested for IgG, IgA, and IgM. Subjects with IgE or IgD myeloma will have samples tested for IgE or IgD.
aa) FISH testing to include del(1p), gain of 1q, del(17p), t(4;14), t(14;16), and t(14;20).
bb) Acceptable for screening if performed as part of standard of care within 28 days before randomization.
cc) A fresh aspirate and biopsy are preferred at screening; if not available, obtain non-decalcified clot sections (block or slides) or aspirate smear slides. 
At all visits, during the bone marrow aspirate procedure, the first aspirate sample that is drawn will be sent to the central laboratory to determine MRD. All bone marrow aspirates to 
be sent to the central laboratory should be at least 2 mL. Additional bone marrow aspirate samples may be taken and used for local laboratory testing.
dd) An additional blood sample for biomarker and immunophenotyping analyses will be collected at the time of disease progression.
ee) Bone marrow biopsy and aspirate are required at screening and aspirate will be requested at time of disease progression, if feasible. For all other assessments, only bone marrow 
aspirates are required.
TIME AND EVENTS SCHEDULE - RVD
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease 
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1 
(Cycles 
1-4)
D21 
(C4 
only)
D1
Procedures
Informed consenti
X
Eligibility criteria
X
Demographics/Medical Historyj
X
Height
X
Chest x-ray
Xk
Spirometry (FEV1)
Xk,l
ECOG performance status
X
X
X
X
Day 1 of odd cycles (7, 9, 11, etc)
X
12-lead ECG
Xk
C5 only
As clinically indicated
Physical examination
X
X
X
Day 1 of odd cycles (7, 9, 11, etc)
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
27
Approved, Date: 10 January 2019
Neurological examinationm
X
X
X
As clinically indicated
Weightn
X
X
X
X
Day 1 of odd cycles (7, 9, 11, etc)
Vital signso
X
D1, D8
X
Day 1 of odd cycles (7, 9, 11, etc)
Laboratory Assessments
For D1 of Cycles 1-6, the following 2 central laboratory kits must be completed: assessment kit and disease evaluation kit
Local 
laboratory
Pregnancy test 
(Women of childbearing 
potential only) 
Serum -hCG pregnancy tests: within 10-14 days before and again within 24 hours before first dose of C1D1; weekly during Cycle 
1, then monthly in subsequent cycles in women with regular menstrual cycles, or every 2 weeks in women with irregular menstrual 
cycles. A serum (-hCG) or urine pregnancy test is also required at the EOT visit. Testing must continue as per standard of care in 
follow-up phase for subjects remaining on lenalidomide.
Hematologyr,s
X
D1, D8, 
D15
X
X
Day 1 of odd cycles (7, 9, 11, etc)
X
Serum chemistryr,t
X
X
X
X
Day 1 of odd cycles (7, 9, 11, etc)
X
HCV viral load w
X
Every 3 months during induction and consolidation
Every 4 months during maintenance 
Study Drug Administration
Randomizationx
X
Study drug dosing
See Study Drug Dosing
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease 
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1 
(Cycles 
1-4)
D21 
(C4 
only)
D1
PRO Assessments and MRU (The initial set up of the ePRO device and administration of the first questionnaire for each subject are to be completed on C1D1 (and 
subsequent D1 visits) before any study specific procedures are performed.) 
PRO assessments and MRU data collection will not be performed at any time during the study for subjects enrolled in safety run-in phase.
EORTC QLQ-C30 
C1-C3 
only
X
C5 only
X
6, 12, 18, and 24 months after start of 
maintenance
X
X
EORTC QLQ-MY20
C1-C3 
only
X
C5 only
X
X
X
EQ-5D-5L
C1-C3 
only
X
C5 only
X
X
X
MRU
X
X
X
D1 of odd cycles (7, 9, 11, etc)e
X
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
28
Approved, Date: 10 January 2019
Disease Evaluations: To be performed on Day 1 of each cycle during induction, consolidation and every 8 weeks during maintenance phase.
Note that an additional disease evaluation occurs on Day 21 of Cycle 4 and the day after Day 21 of Cycle 6 (with a 7-day window) to assess end of Cycle 4 and end 
of Cycle 6 response, respectively. Refer to Section 9.2 for details on efficacy evaluations. 
Send to 
central 
laboratory
β2-microglobulin, LDH
X
Blood and 24-hour urine samples: In addition to the time points below, samples will also be collected whenever CR or sCR is suspected. 
Only 1 blood and 1 24-hour urine sample are required to perform the following tests: 
Send to 
central
laboratory
SPEP y
X
X
X
X
X
D1 of odd cycles (7, 9, 11, etc)e
X
Q12
wks
UPEP
X
X
X
X
X
X
Serum QIgz
X
X
X
X
X
X
Serum IFEy
X
X
X
X
X
Performed whenever CR or sCR is 
suspected or maintained for all 
subjects.
X
Urine IFE
X
X
X
X
X
X
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease 
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1 
(Cycles 
1-4)
D21 
(C4 
only)
D1
Serum FLC assay
X
X
X
X
X
Performed whenever CR or sCR is 
suspected or maintained for all subjects
For subjects without measurable 
disease in serum or urine, also 
performed on D1 of odd cycles (7, 9, 
11, etc)e
X
Bone marrow aspirate/biopsy sample and blood samples (additional details are provided in Table 10). 
Local laboratory Cytogenetics-FISH 
(aspirate)aa
X bb
NCT02874742


JNJ-54767414 (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
29
Approved, Date: 10 January 2019
Send to 
central 
laboratorycc
MRD (aspirate)
Xbb
at first evidence of suspected CR or sCR
after induction / before stem cell collection
at post-ASCT consolidation disease evaluation
at 12 and 24 months (3 weeks) during maintenance
Biomarker (CyTOF, PBMC, 
and plasma) (blood)dd
X
X
X
X
Immunophenotyping 
(blood)dd
X
X
X
X
Send to local 
laboratory
PC clonality assay 
(immunohistochemistry, 
immunofluorescence or flow 
cytometry)
Xbb
At first evidence of suspected CR or sCR )
after induction / before stem cell collection
at post-ASCT consolidation disease evaluation
at 12 and 24 months (3 weeks) during maintenance
Morphology (aspirate and 
biopsy)ee
Xbb
Assessment of lytic bone disease
Xk
As clinically indicated to document response or progression; see Section 9.2.7 for details.
X
Extramedullary plasmacytomas
(subjects with history; physical or radiologic 
examination, as applicable)
Xk
X
C5 only
X
6, 12, and 24 months (3 weeks) 
after start of maintenance 
(within 14 days before scheduled visit)
X
Follow-up After EOT
Other malignancy
Q12 wks
Q12 wks
Next-line therapy and start/stop date
Survival
Date of PD on next-line therapy
Screening 
Phase
Within 28 days 
before 
randomization
Induction/Consolidation Phase
Maintenance Phasea
(Cycles 7e-32)
EOTf
(30 days 
[±7 days] 
after last 
dose)
FUg,h
Phase
Inductiona
(Cycles 1-4)
ASCTb
Consolidation 
(Cycles 5-6)a,c
(start 60-100 
days post-
ASCT)
Post-ASCT
Consolidation 
Disease 
Evaluationd
(+7 day 
window after 
C6D21)
Pre-PD
Post-PD
D1 
(Cycles 
1-4)
D21 
(C4 
only)
D1
Ongoing Subject Review
Adverse events
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment in the 
maintenance phase with the exception of adverse events related to mobilization and ASCT procedures; see Section 12 for 
detailed instructions. 
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Concomitant medications
Continuous from the time of signing of ICF until 30 days after last dose of any component of the study treatment; 
see Section 8 for detailed instructions. During the mobilization and stem cell transplantation procedures, concomitant 
medications related to the planned procedures do not need to be reported in the eCRF. However, concomitant medications 
related to the mobilization and transplantation procedures should be documented by providing a copy of the medication order 
set.
ASCT = autologous stem cell transplantation; -hCG = -human chorionic gonadotropin; C = cycle; CR = complete response; D = day; D-R = daratumumab and lenalidomide;
D-RVd = daratumumab, lenalidomide, bortezomib, and dexamethasone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end-of-treatment; 
FEV1 = Forced Expiratory Volume (in 1 second); FISH = fluorescence in situ hybridization; FLC = free light chain; FU = follow-up; HDT = high-dose chemotherapy; ICF = informed 
consent form; IFE = immunofixation; Ig = immunoglobulin; LDH = lactic acid dehydrogenase; M-protein = monoclonal paraprotein; MRD = minimal residual disease; MRU = medical 
resource utilization; PBMC = peripheral blood mononuclear cell; PC = plasma cell; PD = progressive disease; PK = pharmacokinetic; PRO = patient-reported outcome; Q12wks = 
every 12 weeks; QIg = quantitative immunoglobulin; RVd = lenalidomide, bortezomib, and dexamethasone; SPEP = serum M-protein quantitation by electrophoresis; UPEP = urine 
M-protein quantitation by electrophoresis; VGPR = very good partial response.
NOTE: Subjects who are enrolled in the safety run-in phase will have all procedures performed except PRO assessments and MRU data collection.
a)
Induction and consolidation cycles are 21 days in duration; there will be a maximum of 4 induction cycles and 2 consolidation cycles. Maintenance therapy cycles are 28 days in 
duration. The start of each cycle may occur within ±3 days during induction, ±14 days during consolidation, and ±14 days during maintenance of the scheduled day to accommodate 
the schedule of the site or subject. Every effort should be made to keep a subject on schedule with dosing; however, in exceptional circumstances, dose delay may be considered.
For C4D21 procedures, a window of +7 days will be allowed; must be performed before ASCT. For C5D1 procedures, a window of -7 days will be allowed.
b) Stem cell mobilization, HDT, and ASCT will be performed according to institutional standards. Subjects who do not undergo HDT and ASCT will not receive consolidation or 
maintenance treatment on protocol; however, they will have EOT assessments then enter the long-term follow-up phase. 
c)
Consolidation therapy may commence when engraftment is complete and when in the opinion of the investigator the subject is fit enough to tolerate subsequent systemic therapy 
and should start in the 60 to 100 days post-ASCT. 
d) The post-ASCT consolidation disease evaluation (primary endpoint) should be performed the day after completion of C6D21 (+7 day window; 100 to 150 days post-ASCT). 
e)
If C7D1 is started within the 14 days following the post-ASCT consolidation disease evaluation, C7D1 collection of MRU data and disease evaluations do not need to be repeated.
f)
Subjects will receive study treatment through completion of the 24-month maintenance phase, or until confirmed disease progression, discontinuation of study treatment due to an 
unacceptable drug toxicity, or other reasons. Unless a subject withdraws consent for study participation, or is lost to follow-up, an EOT visit is to be scheduled 30 days after the last 
dose of all components of the study treatment have been discontinued, or as soon as possible before the start of next-line therapy. Lenalidomide will be continued as per local 
standard of care at the end of the maintenance phase, the EOT visit should be performed 30 days after all other study treatment is permanently discontinued or as soon as possible 
before the start of next-line therapy.
g) Before disease progression, subjects will return to the site for assessments until confirmed disease progression, death, the start of a new treatment for multiple myeloma, withdrawal 
of consent for study participation, or the end of study, whichever occurs first. Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat 
investigation. Clinical judgment should prevail; however, repeat assessments after 1 to 3 weeks can be used as a general guideline. After confirmed disease progression or the start 
of a new treatment for multiple myeloma, subjects will return to the site or be contacted by telephone for follow-up assessments until death, withdrawal of consent for study 
participation, or the end of study, whichever occurs first. Following disease progression on the next-line therapy, subjects will only be followed for survival. 
h) Subjects will be followed in the long-term follow-up phase for at least 1 year after last dose of study treatment and will continue until death, withdrawal of consent for study 
participation, or the end of study definition is met. The end of study is defined as when all subjects have completed at least 1 year of long-term follow up, or until death or 
withdrawal of consent for study participation, whichever occurs first.
i)
Must be signed before any study-related procedures are performed.
j)
Medical history including surgery or procedures planned prior to entry into the study.
k)   Acceptable for screening if performed as part of standard of care within 42 days before randomization.
l)
Pulmonary function testing (spirometry) is required only for subjects with chronic obstructive pulmonary disease or asthma. FEV1 should be measured for subjects with chronic 
obstructive pulmonary disease or asthma. 
m) General neurological exam focused on sensory peripheral neuropathy
n) Each subject’s dose will be calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. If a subject’s weight changes by more than 10% from C1D1 
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or the most recent weight used for dose calculation, the dose of all study treatments should be re-calculated. 
o)   Temperature, pulse/heart rate, respiratory rate, and blood pressure. Measured in sitting position. For all infusions except C1D1 (see note below), measured immediately before the 
start of and at the end of daratumumab infusion. 
p) Left blank for consistency across Time and Event Schedules.
q) Left blank for consistency across Time and Event Schedules.
r)
For C1D1, there is no need to repeat the tests if they have been performed within the past 3 days. Laboratory evaluations may be performed up to 2 days before other infusion days. 
Perform at additional time points, as clinically indicated. 
s)
On-site or accredited local laboratory must be used for hematology laboratory assessments. Results of local hematology tests must be evaluated before each study drug 
administration to guide treatment decisions. Hematology panel: hemoglobin, white blood count with absolute neutrophils and lymphocytes, red blood cell count, and platelet count.
t)
Serum chemistry panel: sodium, potassium, creatinine and creatinine clearance (must be calculated per protocol, see Section 9.8), glucose, aspartate aminotransferase, alanine 
aminotransferase, total bilirubin, alkaline phosphatase, BUN, calcium and albumin-adjusted calcium, and albumin.
u) Left blank for consistency across Time and Event Schedules.
v) Left blank for consistency across Time and Event Schedules.
w) Subjects who completed treatment for hepatitis C at least 6 months prior to screening and have no detectable circulating hepatitis C virus (HCV) at screening, may participate in the 
study. Such subjects will be required to undergo regular assessment for HCV reactivation, as shown and will be withdrawn from the study if they test positive at any time during the 
study.
x)   Randomization will be performed up to 72 hours before the first dose of study treatment on C1D1.
z)
All subject’s samples will be tested for IgG, IgA, and IgM. Subjects with IgE or IgD myeloma will have samples tested for IgE or IgD.
aa) FISH testing to include del(1p), gain of 1q, del(17p), t(4;14), t(14;16), and t(14;20).
bb) Acceptable for screening if performed as part of standard of care within 28 days before randomization.
cc) A fresh aspirate and biopsy are preferred at screening; if not available, obtain non-decalcified clot sections (block or slides) or aspirate smear slides. 
At all visits, during the bone marrow aspirate procedure, the first aspirate sample that is drawn will be sent to the central laboratory to determine MRD. All bone marrow aspirates to 
be sent to the central laboratory should be at least 2 mL. Additional bone marrow aspirate samples may be taken and used for local laboratory testing.
dd) An additional blood sample for biomarker and immunophenotyping analyses will be collected at the time of disease progression.
ee) Bone marrow biopsy and aspirate are required at screening and aspirate will be requested at time of disease progression, if feasible. For all other assessments, only bone marrow 
aspirates are required.
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STUDY DRUG DOSING SCHEDULE
Notes
Induction
Consolidation
Maintenance
EOT
Cycle 1-4
(21-day cycles)
Cycle 5-6a
(21-day cycles)
Cycle 7-32
(28-day cycles)
D1
D8
D15
D1
D1
Refer to the TIME AND EVENTS SCHEDULE for important information regarding hematology, serum chemistry, weight, and vital signs assessments related to dosing.
Ongoing Review
Diary review
Accountability/exposure check
X
X
X
X
Day 1 of odd cycles
when daratumumab 
is administered
X
Preinfusion Medications: Only for the Daratumumab group (D-RVd [induction/consolidation phase]/D-R [maintenance phase]); administer approximately 1 hour prior to 
daratumumab infusion; oral preinfusion medications may be administered within 3 hours prior to daratumumab infusion. For subjects with a higher risk of respiratory 
complications, see Section 6.1.3.2 for postinfusion medications.
Dexamethasone
Dexamethasone 20 mg PO or IV (only if oral is not available). 
Substitutions for dexamethasone allowed, see Attachment 1.
X
X
X
X
D1 of each cycle
when daratumumab 
is administered
Antihistamine
Diphenhydramine 25-50 mg or equivalent, PO or IV.
X
X
X
X
D1 of each cycle only 
for D-R group when 
daratumumab is 
administered
Acetaminophen Acetaminophen 650-1,000 mg PO or IV equivalent
X
X
X
X
D1 of each cycle only 
for D-R group when 
daratumumab is 
administered
Montelukast
Montelukast 10 mg PO, at C1D1 approximately 1 hour or less 
before the daratumumab infusion. An additional 10 mg PO can be 
given the day before infusion at the discretion of the investigator.
May be omitted for any daratumumab dose after the second 
infusion if the subject has no respiratory symptoms.
X
X
As clinically indicated
Study Treatment Administration, D-RVd group and RVd group in induction/consolidation phase and D-R group and lenalidomide group in maintenance phase
Daratumumab
(D-RVd/D-R 
group, only)
Refer to Section 6.1.2 and the SIPPM for recommendations on 
daratumumab infusion rate. Note: Subject’s weight will be recorded 
on all daratumumab dosing days.
D-RVd treatment group: Beginning at Cycle 7 Day 1 and onward, if 
clinically feasible, subjects will be given the option to receive an 
accelerated 90-minute infusion of daratumumab.
16 mg/kg IV
Days 1, 8, 15 of Cycles 1-4
Day 1 of Cycles 5-6
16 mg/kg IV every 
4 or 8 weeksb (Day 1 
of each applicable 
cycle)
Lenalidomidec
Dispense on Day 1 for self-administration.
25 mg PO dailya,d
Day 1-14 of Cycles 1-6
10 mg PO dailye
Days 1-21.
Beginning at Cycle 
10, the dose will be 
increased to 15 mg 
unless there is a 
tolerability concern
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Bortezomib
Administer by SC injection. Dose may be delayed up to 48 hours.
Doses that need to be withheld are skipped and will not be made up 
later in the cycle. For subjects who experience SC injection-site 
reactions, IV injection allowed. Note: Each subject’s dose will be 
calculated based on the subject’s weight at Cycle 1 Day 1 rounded to 
the nearest kilogram. Dose should be readjusted if weight 
changes >10% from value on C1D1.
1.3 mg/m2 SCa
Days 1, 4, 8, and 11 during Cycles 1-6
-
Dexamethasone Dispense on Day 1 for self-administration.
Substitutions for dexamethasone allowed, see Attachment 1.
20 mg POa
Days 1, 2, 8, 9, 15, and 16 during Cycles 1-6. 
Not required in D-RVd group on daratumumab infusion days, since 
the subject will receive PO dexamethasone as a pre-medication prior 
to daratumumab infusion.
D-R group: pre-
infusion medication 
(see above). 
CrCl = creatinine clearance; D = day; D-R = daratumumab and lenalidomide; D-RVd = daratumumab, lenalidomide, bortezomib, and dexamethasone; EOT = end-of-treatment; ICF = 
informed consent form; IV = intravenous; PO = oral; REMS = Risk Evaluation and Mitigation Strategy; RVd = lenalidomide, bortezomib, and dexamethasone; SC = subcutaneous; 
SIPPM = study site investigational product and procedures manual.
a
The doses of RVd that were tolerated by a subject at the end of induction should be used at the start of the consolidation phase.
b     Subjects who signed the original ICF stating that daratumumab maintenance was to be administered every other month and who do not agree to the revised daratumumab 
maintenance administration every month will be permitted to receive daratumumab every other month. However, every effort should be taken to ensure that the subject understands 
the benefit of the monthly daratumumab maintenance schedule.
c     Due to the potential of birth defects or embryo-fetal death associated with the use of lenalidomide, investigators and subjects must adhere to the lenalidomide REMS program that can 
be accessed at http://www.revlimidrems.com/.
d
Lenalidomide dose adjustment should be instituted for subjects with a CrCl ≤50 mL/min: CrCl 30-50 mL/min, 10 mg every 24 hours (escalate the dose to 15 mg after 2 cycles if the 
subject tolerates the 10 mg dose without dose-limiting toxicity); CrCl <30 mL/min (not requiring dialysis), 15 mg every 48 hours; CrCl <30 mL/min (requiring dialysis), 5 mg once 
daily (on dialysis days, administer the dose after dialysis). 
e
Following completion of the maintenance phase, subjects may continue lenalidomide as per local standard of care. 
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1.
INTRODUCTION
Daratumumab (JNJ-54767414) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal 
antibody that binds CD38 expressed on the cell surface in a variety of hematological 
malignancies, including myeloma, lymphomas, and leukemias, as well as on other cell types and 
tissues with various expression levels.3 The mechanisms of action of daratumumab comprise 
immune-mediated effects, including complement-dependent cytotoxicity, antibody-dependent 
cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis by means of 
cross-linking. Moreover, daratumumab also induces immunomodulatory effects via several 
different pathways that contribute to killing CD38+ immune cells that modulate T cell activity, 
namely myeloid-derived suppressor cells (MDSC) and regulatory T (TReg), and B (BReg) cells
(Krejcik 2016).13 Daratumumab’s converging mechanisms of actions are hypothesized to lead 
synergistically to the deep responses observed in patients with multiple myeloma.
Daratumumab by intravenous (IV) injection is approved in the United States (US), European 
Union, and other countries for the treatment of patients with multiple myeloma who have 
received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an 
immunomodulatory agent (IMiD) or who are double-refractory to a PI and an IMiD. On 
21 November 2016, the US Food and Drug Administration (FDA) approved daratumumab in 
combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the 
treatment of patients with multiple myeloma who have received at least one prior therapy. In 
June 2017, the US FDA approved daratumumab in combination with pomalidomide and 
dexamethasone for the treatment of patients with multiple myeloma who have received at least 2
prior therapies including lenalidomide and a proteasome inhibitor.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator’s Brochure for daratumumab. The term “sponsor” used 
throughout this document refers to the entities listed in the Contact Information page(s), which 
will be provided as a separate document.
1.1.
Background
1.1.1.
Multiple Myeloma
Multiple myeloma, a malignant disorder of the plasma cells, is characterized by uncontrolled and 
progressive proliferation of a plasma cell clone. Patients with multiple myeloma produce a 
monoclonal protein, also known as paraprotein (comprising monoclonal protein [M-protein] and 
free light chain [FLC]), which is an immunoglobulin (Ig) or a fragment of one that has lost its 
function.14,21 The proliferation of myeloma cells causes displacement of the normal bone 
marrow.
Normal Ig levels are compromised, leading to susceptibility to infections. 
Hypercalcemia, renal insufficiency or failure, and neurological complications are frequently 
reported side effects of the disease.21   
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Treatment choices for multiple myeloma vary with age, performance status, comorbidity, 
aggressiveness of the disease, and related prognostic factors.21 Current treatments include 
combination chemotherapy, proteasome inhibitors (bortezomib [and carfilzomib in the United 
States (US)]), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and 
high-dose chemotherapy
(HDT)
with melphalan supported by autologous stem cell 
transplantation (ASCT). 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 HDT and ASCT. For those not considered suitable for HDT and 
ASCT, treatment is longer and consists of multi-agent combinations including alkylating agents 
(melphalan and cyclophosphamide), anthracyclines (doxorubicin), vincristine, glucocorticoids, 
or combinations of these agents.
Although treatments for multiple myeloma have improved significantly over the last 10 years, 
the vast majority of patients have multiple relapses and ultimately succumb to complications of 
the disease.
1.1.2.
Daratumumab
1.1.2.1.
Nonclinical Studies
In mouse xenograft models, daratumumab reduced tumor growth in both preventive and 
therapeutic settings. Daratumumab had no effect on proliferation of human peripheral blood 
mononuclear cells (PBMCs), and cytokine release was similar to other marketed therapeutic 
antibodies. Hence, daratumumab can recruit multiple effector mechanisms to facilitate the lysis 
of malignant cells in vitro and in vivo. In-vitro studies, using bone marrow mononuclear cells 
from patients with multiple myeloma (MM), demonstrated increased killing of tumor cells when 
daratumumab was combined with lenalidomide or bortezomib as well as with both lenalidomide 
and bortezomib. Additionally, the upregulation of CD38 by pomalidomide or lenalidomide can 
enhance the activity of anti-CD38 antibodies including daratumumab. These observations 
suggest a strong potential for the treatment of CD38-expressing malignancies using 
daratumumab as monotherapy and in combinations.
The potential toxicity of daratumumab was evaluated in a repeat dose study in chimpanzees. The 
primary toxicities identified in chimpanzees were infusion-related reactions during the first, but 
not subsequent, daratumumab infusions and thrombocytopenia. The binding affinity of 
daratumumab is ≥15-fold higher for chimpanzee platelets than for human platelets, suggesting 
that thrombocytopenia may be less pronounced in humans. Depletion of specific lymphocyte 
phenotypic cell populations, as expected, based on the intended pharmacological effect of 
daratumumab, was observed in chimpanzees. No genotoxicity, chronic toxicity, carcinogenicity, 
or reproductive toxicity testing has been conducted. 
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1.1.2.2.
Clinical Studies
As of 30 June 2017, daratumumab is being evaluated in 21 ongoing and completed company-
sponsored clinical studies in subjects across the multiple myeloma disease continuum, ie, 
smoldering multiple myeloma, previously untreated multiple myeloma, relapsed/refractory 
multiple myeloma, and other diseases including myelodysplastic syndrome (MDS), lung cancer, 
natural killer (NK)/T-cell lymphoma and non-Hodgkin lymphoma. Approximately 2,700 
subjects have been treated with daratumumab monotherapy or combination therapy in 14 clinical 
studies that contribute study-specific safety summaries to the current daratumumab Investigator 
Brochure (IB; version 14, dated 5 October 2017). Of these subjects, daratumumab has been 
administered to approximately 1,160 subjects as monotherapy in Studies GEN501, MMY1002, 
and MMY2002, SMM2001, LYM2001, MMY1004 (SC) and MMY3010. Daratumumab as 
combination therapy has been administered to approximately 1,533 subjects in Studies GEN503, 
MMY1001, MMY1005, MMY3003, MMY3004, MMY3007, and MMY3008.

Monotherapy studies in subjects with relapsed/refractory multiple myeloma are: 

GEN501, MMY1002, MMY1004, MMY2002, SMM2001, MMY3010

Combination therapy studies are: 

Subjects with previously untreated and relapsed/refractory multiple myeloma: 
o
MMY1001: daratumumab in combination with bortezomib-dexamethasone (Vd), 
bortezomib-thalidomide-dexamethasone (VTd), bortezomib-melphalan-prednisone 
(VMP), 
carfilzomib-lenalidomide-dexamethasone 
[KRd] 
in 
subjects 
with 
previously untreated multiple myeloma and pomalidomide dexamethasone [Pom-
dex] and carfilzomib-dexamethasone [Kd])

Subjects with relapsed/refractory multiple myeloma: 
o
GEN503: daratumumab in combination with lenalidomide-dexamethasone (Rd)
o
MMY1005: daratumumab in combination with Vd (in Japan)
o
MMY3003: daratumumab in combination with Rd 
o
MMY3004: daratumumab in combination with Vd 

Subjects with previously untreated multiple myeloma:
o
MMY3007: daratumumab in combination with VMP
o
MMY3008: daratumumab in combination with Rd 

Monotherapy Non-Hodgkin’s Lymphoma

LYM2001
Limited safety data are available for ongoing clinical studies in untreated multiple myeloma 
(Studies MMY3007, MMY3008), smoldering multiple myeloma (Study SMM2001), and for an 
early-access study (Study MMY3010). 
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In addition, there are 7 other ongoing clinical studies in subjects with multiple myeloma, natural 
killer/T cell lymphoma, MDS, and lung cancer; however, data from those studies are preliminary 
and not included in the current daratumumab IB.
Daratumumab IV Monotherapy Studies 

MMY1003: Subjects with relapsed/refractory multiple myeloma

NKT2001: Subjects with relapsed/refractory natural killer/Tcell lymphoma

MDS2002: Daratumumab or talacotuzumab in Subjects with MDS 
Daratumumab IV Combination Therapy

MMY1006: daratumumab in combination with Rd in newly diagnosed MM

MMY2004: daratumumab in combination with RVd in newly diagnosed MM

MMY2012: daratumumab in combination with CyBorD in relapsed/refractory and newly 
diagnosed MM

LUC2001: daratumumab in combination with atezolizumab in NSCLC
As of 30 June 2017, the final analysis had occurred for Studies MMY2002, GEN501, MMY1002 
and MMY1005. The primary analysis had occurred for Studies GEN503, MMY1001, 
MMY3003, and MMY3004. The following studies are ongoing: SMM2001, MMY3010,
GEN503, MMY3007, MMY3008 and LYM2001. 
1.1.2.2.1.
Pharmacokinetics
Daratumumab Intravenous (IV) Administration
Over the dose range from 1 to 24 mg/kg as monotherapy or 1 to 16 mg/kg in combination with 
other treatments, increases in area under the curve (AUC) were more than dose-proportional. 
Clearance was rapid at low doses and slower at higher doses; clearance also decreased with 
multiple doses. This PK profile was consistent with target-mediated disposition indicating target 
saturation at higher doses. The PK of daratumumab was similar following monotherapy and 
combination therapies in multiple myeloma. The mean ± SD estimated terminal half-life of 
daratumumab associated with linear clearance was 18 ± 9 days when administered as 
monotherapy and 23 ± 12 days when administered as combination therapy.
1.1.2.2.2.
Efficacy
A total of 148 subjects relapsed /refractory multiple myeloma treated with 16 mg/kg 
monotherapy daratumumab were included in the combined analysis of Study GEN501 and Study 
MMY2002. The overall response rate (ORR) for the combined data set was 31% after a median 
duration of follow-up of 20.7 months, the Kaplan-Meier based median OS was 20.1 months.
Daratumumab IV Combination Therapy
Clinical benefit in relapsed/refractory multiple myeloma with daratumumab IV in combination 
with Rd and Vd was demonstrated by a significant improvement in progression free survival 
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(PFS) which corresponds to clinically meaningful reductions in the risk of disease progression or 
death. Clinical benefit in relapsed/refractory multiple myeloma with daratumumab IV in 
combination Pd in heavily pretreated subjects resulted in deep and durable responses, as 
exemplified by a high ORR, complete response or better rate, and minimal residual disease 
(MRD) negativity rates.
Primary efficacy analysis data for Studies GEN501, MMY2002, GEN501+MMY2002 (pooled 
monotherapy efficacy analysis), GEN503, MMY1002, MMY3003, MMY3004, MMY1001, 
MMY1005, and LYM2001 are provided in the Investigator Brochure. 
Efficacy results for Study MMY2002 and Study GEN501 Part 2 (Part 1 was the dose-escalation 
phase of this first-in-human study), single-arm, open-label studies in which subjects with 
relapsed and refractory multiple myeloma were administered 16 mg/kg of daratumumab by 
intravenous (IV) route as monotherapy weekly for 8 weeks, every 2 weeks for an additional 
16 weeks, and every 4 weeks thereafter until disease progression or unacceptable toxicity. 
Response and progressive disease assessment in both studies were evaluated based on the 
International Myeloma Working Group (IMWG) criteria. Efficacy results from the primary 
analysis of 148 subjects receiving daratumumab 16 mg/kg in Study MMY2002 (n = 106) and 
Study GEN501 Part 2 (n = 42) were integrated. After a median duration of follow-up of 20.7 
months, the median overall survival (OS) was 20.1 months and an overall response rate (ORR)
of 31%. Within the individual studies, the ORR was 36% in Study GEN501 and 29% in 
Study MMY2002.
In Study GEN503, a Phase 1/2, open-label, dose-escalation study of DRd in subjects with 
relapsed/refractory MM, efficacy results from the primary analysis of 13 subjects (Part 1) and 32 
subjects (Part 2) receiving daratumumab 16 mg/kg showed an ORR of 88% and very good 
partial response of 53% after a median follow up of 7.8 months. Efficacy results from the final 
analysis showed ORR of 81% and very good partial response (VGPR) or better of 69% after 
median follow-up of 32.5 months. Median PFS has not been established in this study. 
In Study MMY1002, a Phase 1 open-label, single-arm study in 9 Japanese subjects with 
relapsed/refractory MM who received daratumumab at a dose of 16 mg/kg, efficacy results from 
the primary analysis showed ORR of 60% after median follow-up of 9.9 months. The median 
PFS was 9.5 months and median duration of response was 7.7 months. In Study MMY3003, 
daratumumab 
in 
combination 
with 
lenalidomide 
and 
dexamethasone
(DRd)
in 
relapsed/refractory MM, the primary analysis showed a significant improvement in PFS and 
ORR for subjects in the DRd group, compared with the lenalidomide/dexamethasone (Rd) group. 
This represents a 63% reduction in the risk of disease progression or death for the DRd group 
compared with the Rd group. The ORR for the DRd group was 91% and 75%% for the Rd 
group. In Study MMY3004, daratumumab in combination with bortezomib and dexamethasone 
(DVd) in subjects with relapsed/refractory MM, the primary analysis showed a significant 
improvement 
in 
PFS
for 
subjects 
in 
the 
DVd 
group, 
compared 
with 
the 
bortezomib/dexamethasone (Vd) group. This represents a 61% reduction in the risk of disease 
progression or death for the DVd group compared with the Vd group. The ORR was significant 
for the DVd group (79%) compared with the Vd group (60%). 
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In Study MMY1001, daratumumab in combination with various background treatment regimens 
for multiple myeloma in either newly diagnosed subjects or those who received prior therapies, 
the primary analysis showed ORR of 59% (median follow up time 9.8 months). 
In Study MMY1005, nonrandomized study to evaluate the safety and tolerability of DVd in 8 
Japanese subjects with relapsed/refractory multiple myeloma, primary analysis showed ORR of 
100% (median follow up duration 5.5 months), VGPR or better 50% and clinical benefit 
(including overall response plus MR) of 100%. Median time to response was 0.9 months and 
median duration of response was 4.1 months.
In Study LYM2001, efficacy and safety of daratumumab in subjects with relapsed/refractory
MCL, DLBCL or FL. Primary analysis after median duration of treatment of 35 days (DLBCL), 
70 days (FL) and 36 days (MCL) showed overall best response rated: DLBCL:7%; FL 12.5% 
MCL: 0. 
1.1.2.2.3.
Safety
The safety results from all ongoing studies of daratumumab are summarized (through June 2017) 
in Table 1, below. 
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Table 1:
Available Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 June 2017
Study Number (N 
exposed to dara)
Safety Results
Daratumumab Monotherapy Trials
MMY2002, GEN501, and 
MMY1002
(Relapsed/Refractory MM, 
156) 
Integrated analysis

Most common TEAEs: fatigue (40%), nausea and anemia (28% each), back 
pain (26%), cough (24%), neutropenia (23%), pyrexia (22%), upper respiratory 
tract infection (22%), and thrombocytopenia (21%). 

Grade 3/4 TEAEs in 57% of subjects; most common were anemia (17%), 
thrombocytopenia (14%), neutropenia (12%), lymphopenia and pneumonia 
(6%), leukopenia and hypertension (5% each), hypercalcemia (3%).

TEAEs leading to DC of study treatment in 4% of subjects; none considered 
drug related. 

SAEs in 34% of subjects; most common were pneumonia (6%) and pyrexia, 
general physical health deterioration, and hypercalcemia (3% each).

Deaths due to progressive disease (7%), and 3 (2%) due to TEAEs 
(cardiorespiratory arrest in the setting of H1N1 influenza, general physical 
health deterioration secondary to aspiration pneumonia, and pneumonia).  
None of the fatal TEAEs were considered related to daratumumab.
SMM2001 (smoldering 
MM, 122)

SAEs were reported for 15 subjects (24% in the long intense, 2% in 
intermediate, and 10% in short intense treatment groups). No IRRs or deaths.
MMY1004 -
Relapsed/Refractory MM
(subcutaneous 
administration, 53)

A total of 8 subjects received dara-MD 1200 mg and 45 subjects received dara-
MD 1800 mg.

Most common TEAEs (≥20% of all subjects): upper respiratory tract infection 
(1200 mg: 38%; 1800 mg: 22%), insomnia (1200 mg: 38%; 1800 mg: 11%), 
decreased appetite (1200 mg: 38%; 1800 mg: 7%), thrombocytopenia (1200 mg:
38%; 1800 mg: 18%), viral upper respiratory tract infection (1200 mg: 25%; 
1800 mg: 13%), vomiting (1200 mg: 25%; 1800 mg: 13%), hyperuricaemia 
(1200 mg: 25%; 1800 mg: 2%), hypokalaemia (1200 mg: 25%; 1800 mg: 4%), 
blood creatinine increased (1200 mg: 25%; 1800 mg: 4%), anemia (1200 mg: 
25%; 1800 mg: 33%), fatigue (1200 mg: 25%; 1800 mg: 20%), pyrexia (1200 
mg: 25%; 1800 mg: 27%), diarrhea (1200 mg: 25%; 1800 mg: 22%), headache
(1200 mg: 25%; 1800 mg: 18%), cough (1200 mg: 25%; 1800 mg: 13%), 
epistaxis (1200 mg: 25%; 1800 mg: 4%), hypertension (1200 mg: 25%; 1800 
mg: 7%), rhinitis allergic (1200 mg: 25%; 1800 mg: 2%), nasal congestion 
(1200 mg: 25%; 1800 mg: 2%), rectal hemorrhage (1200 mg: 25%; 1800 mg: 
0%), and asthenia (1200 mg: 13%; 1800 mg: 20%),

Grade 3/4 TEAEs: in 63% and 49% of subjects in the 1200 mg and 1800 mg
cohorts, respectively. The most frequently reported Grade 3 or 4 TEAEs were in 
the Blood and Lymphatic System Disorders System Organ Class (SOC), 
reported in 38% and 31% of subjects in the 1200 mg and 1800 mg cohorts, 
respectively. Two of 8 (25%) subjects in the 1200 mg cohort and 4% in the 
1800 mg cohort had Grade 3 or 4 hypertension.

SAEs: SAEs were reported in 26% of all subjects: 50% and 31% of subjects in 
the 1200 mg and 1800 mg cohorts, respectively. The most frequently reported 
serious TEAEs were in the Infections and Infestations SOC (1200 mg: 38%, 
1800 mg: 16%), the Nervous System Disorders SOC (1200 mg: 13%, 1800 mg: 
4%), and the Respiratory, thoracic and mediastinal disorders (1200 mg: 13%, 
1800 mg: 2%). 

No TEAEs leading to DC of study treatment. One subject in the dara-MD 
1800 SC cohort died within 30 days of the last dose of study drug from 
progressive disease.
MMY3010
(Relapsed/Refractory MM, 
687)

SAEs in 38% of subjects; most common were pneumonia (4%), hypercalcemia 
(3%), pyrexia (3%), dyspnea (2%), thrombocytopenia (2%), acute kidney injury 
(2%), and back pain (2%).  

Deaths: Forty-eight subjects (7%) reported TEAEs with an outcome of death. 
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Table 1:
Available Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 June 2017
Study Number (N 
exposed to dara)
Safety Results
LYM2001 (non-Hodgkin’s 
lymphoma, 36)

All subjects had at least 1 or more TEAE. Most common TEAEs were reported 
from SOC of respiratory, thoracic and mediastinal disorders; cough (DLBCL 
cohort: 47%; FL cohort: 38%; MCL cohort: 80%); SOC of gastrointestinal 
disorders: abdominal pain (DLBCL cohort: 13%; FL cohort: 31%; MCL cohort: 
20%), and nausea (DLBCL cohort: 33%; FL cohort: 6%; MCL cohort: 40%), 
and SOC of general disorders and administration site conditions; fatigue 
(DLBCL cohort: 27%; FL cohort: 19%; MCL cohort: 20%), and pyrexia
(DLBCL cohort: 13%; FL cohort: 25%; MCL cohort: 40%)

SAEs in 15 subjects.  All SAEs were reported in 1 subject each, except for 
febrile neutropenia, pneumonia, general physical health deterioration, and 
pyrexia (2 subjects each).

Deaths in 4 subjects: 2 due to progressive disease and 2 due to an adverse event 
(chronic kidney disease and pneumonia).

IRRs – none.
Daratumumab Combination Trials
GEN503 and MMY3003
(integrated; dara in 
combination with 
lenalidomide and 
dexamethasone (318)

Most common TEAEs (DRd treatment group): neutropenia (64%), diarrhea 
(53%), upper respiratory tract infection (37%), fatigue (37%), anemia (36%), 
cough (34%), muscle spasms (31%), constipation (31%), thrombocytopenia 
(29%), viral upper respiratory tract infection (29%), nausea (28%), and pyrexia 
(25%). 

Grade 3/4 TEAEs (DRd treatment group): 89%; most common, neutropenia 
(58%), anemia (16%), and thrombocytopenia (14%).  

TEAEs leading to DC of treatment in 13% of subjects in the DRd treatment 
group; most common were pneumonia (4 subjects, 1.3%), general physical 
health deterioration (3 subjects, 0.9%), and septic shock (2 subjects, 0.6%).

SAEs (DRd treatment group) in 63% of subjects; most common were 
pneumonia (13%), influenza, febrile neutropenia (4%) and pyrexia (4% each), 
and bronchitis, pulmonary embolism, lower respiratory tract infection, diarrhea 
(3% each).

Deaths (DRd treatment group):7% of subjects died within 30 days of the last 
dose of study drug: 21 due to TEAEs and 1 due to disease progression.
MMY1001
(dara in combination with 
pomalidomide and 
dexamethasone, 240)

Most common TEAEs: neutropenia (81%), anemia (55%), fatigue (52%), 
diarrhea (50%), thrombocytopenia (43%), cough (41%), leukopenia (39%), 
constipation (36%), nausea (34%), dyspnea (33%), pyrexia (33%), upper 
respiratory tract infection (32%), muscle spasms (29%), vomiting (28%), 
arthralgia (26%). 

Grade 3 or 4 TEAEs in 99% of subjects; most common were neutropenia 
(79%), anemia (28%), leukopenia (24%), thrombocytopenia (19%), 
lymphopenia (14%), and pneumonia and fatigue (13% each). 

TEAEs leading to DC of treatment in 16% of subjects (no single AE reported 
in >1 subject). 

SAEs in 57% of subjects; most common were pneumonia (12%), sepsis (7%), 
febrile neutropenia (5%), fall (4%), anemia, dyspnea, small intestinal 
obstruction, and urinary tract infection (3% each).

Deaths:  9% of subjects died during study treatment or within 30 days after the
last dose of study drug; 7 due to AEs and 2 deaths due to disease progression.
MMY1001 (Dara plus 
bortezomib and 
dexamethasone, 30)

SAEs were reported for 3 subjects in the DVd arm (Hyperglycemia [1 subject], 
soft tissue infection, pneumonia, prerenal failure, diarrhea, respiratory failure 
[1 subject], laboratory test interference [1 subject]. In DVMP arm, SAEs were 
reported in 1 subject (cardiac failure). No subjects in the D-VTd arm were 
reported to have SAEs.

No deaths reported.
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Table 1:
Available Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 June 2017
Study Number (N 
exposed to dara)
Safety Results
MMY1001 (Dara in 
combination with 
carfilzomib/dexamethasone 
+/- lenalidomide DKd = 
20, DKRd = 20)

AEs of Interest – Cardiac Events: In the DKd arm, cardiac disorder TEAEs of 
interest were reported in 15% of subjects; 4 (5%) subjects had a Grade 3 or 
Grade 4 event. No cardiac disorder TEAEs of Grade 5 was reported. In the 
DKRd arm, cardiac disorder TEAEs of interest were reported in 41% of 
subjects, with 1 subject (5%) having a Grade 3 or Grade 4 event (congestive 
heart failure) that was also an SAE. No Grade 5 events were reported.

SAEs reported in 32% of subjects in the DKd arm (n=85); most common was 
pneumonia (7%).  SAEs were reported in 46% of subjects in the DKRd arm
(n=22).  The most frequently reported SAEs were pulmonary embolism (n=3; 
14%) and influenza and pyrexia (n=2; 9% each).  All other SAEs were reported 
in 1 subject each. 

One death in the DKd arm due to progressive disease.
MMY1005 (Dara in 
combination with 
bortezomib and 
dexamethasone; Japan, 8)

SAEs in 3 subject each (herpes zoster, prostate cancer, nasopharyngitis).

No IRRs.

No deaths.
MMY3004 (Dara in 
combination with 
bortezomib and 
dexamethasone, 243)

Most common TEAEs were thrombocytopenia (60%), peripheral sensory 
neuropathy (50%), diarrhea (35%), upper respiratory tract infection (33%), 
anemia (28%), and cough (28%).

Grade 3/4 AEs were reported in 81% of subjects; most common were 
thrombocytopenia (46%), anemia (15%), and neutropenia (14%).

TEAEs leading to DC of treatment were reported for 10% of subjects; most 
common were pneumonia (4 subjects; 2%), and cardiac failure congestive 
(2 subjects; 0.8%).

SAEs in 50% of subjects; most common were pneumonia (10%), and anemia, 
bronchitis, thrombocytopenia, atrial fibrillation, upper respiratory tract infection, 
and pyrexia (3% each). 

Deaths:15 subjects died within 30 days of the last dose of study drug; 13 deaths 
were due to TEAEs and 2 were due to disease progression.
MMY3007 (Dara in 
combination with 
bortezomib, melphalan and 
prednisone, 700)

Most common TEAEs were thrombocytopenia (51%), neutropenia (51%), 
anemia (33%), peripheral sensory neuropathy (31%), diarrhea (24%), pyrexia 
(22%), nausea (21%), upper respiratory tract infection (20%) and constipation 
(18%). 

Grade 3/4 TEAEs were reported in 74% of subjects, with neutropenia (39%) 
and thrombocytopenia (36%) being the most frequently reported.

SAEs were reported in 37% of subjects, with pneumonia being the most 
frequent (7%).  

Deaths: Thirty-eight (5%) subjects had a Grade 5 TEAE. 
MMY3008 (Dara in 
combination with 
lenalidomide and 
dexamethasone, 729)

Most common TEAEs were neutropenia (39%), diarrhea (34%), constipation 
(33%), fatigue (28%), anemia (25%), nausea and edema peripheral (24% each), 
insomnia (22%), muscle spasms (21%), and asthenia (20%). 

Grade 3/4 TEAEs were reported in 70% of subjects, with neutropenia being the 
most frequently reported (32%). 

SAEs were reported in 50% of subjects; most common were pneumonia (6%), 
pyrexia and pulmonary embolism (3% each).  

Deaths Thirty-four subjects (5%) had a Grade 5 TEAE. .
TEAE = treatment emergent adverse event; dara = daratumumab; DC = discontinuation; DKd = 
daratumumab+carfilzomib+dexamethasone; DKRd
= daratumumab+carfilzomib+lenalidomide+dexamethasone; 
IRR = infusion-related reaction; MM = multiple myeloma; N = number of subjects; SAE = serious adverse event.
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1.1.3.
Lenalidomide
Lenalidomide is an immunomodulatory drug that is thought to mediate antimyeloma activity by 
3 main mechanisms: 1) direct antitumor effect; 2) inhibition of the microenvironment support for 
tumor cells; and 3) an immunomodulatory role.12 Importantly, it has also been shown that 
lenalidomide causes upregulation of natural killer (NK) cells in myeloma12 and enhances the 
effector cells of antibody-dependent cell-mediated cytotoxicity, which is one mechanism of 
action of daratumumab shown in preclinical studies.29,30
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey 
study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during 
pregnancy, it may cause birth defects or embryo-fetal death. Lenalidomide can cause significant 
neutropenia and thrombocytopenia. There is a significantly increased risk of deep vein 
thrombosis and pulmonary embolism, as well as risk of myocardial infarction and stroke in 
patients with multiple myeloma who receive lenalidomide with dexamethasone. Higher 
incidences of secondary primary malignancies were observed in controlled trials of subjects with 
multiple myeloma receiving lenalidomide. Additionally, administration of lenalidomide has been 
associated with hepatotoxicity (hepatic failure including fatalities); allergic reactions, including 
fatalities (hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis); 
tumor lysis syndrome including fatalities; and impaired stem cell mobilization (a decrease in the 
number of CD34+ cells collected after treatment [>4 cycles]). Most common adverse reactions 
(≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, peripheral edema, insomnia, 
muscle cramp/spasms, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, 
cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor.25
1.1.4.
Bortezomib 
Bortezomib is a proteasome inhibitor. It is a reversible inhibitor of the chymotrypsin-like activity 
of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that 
degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in 
regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis 
within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect 
multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms 
can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety 
of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical 
tumor models, including multiple myeloma. In addition, bortezomib-based treatment regimens 
have demonstrated significant improvements in response, progression-free survival (PFS), and 
OS compared with non-bortezomib-based therapy for multiple myeloma, both in newly 
diagnosed transplant ineligible patients and those suitable for induction and transplant.8,28
Administration of bortezomib has been associated with peripheral neuropathy, hypotension, 
cardiac toxicity (worsening of and development of cardiac failure), pulmonary toxicity (acute 
respiratory syndromes), posterior reversible encephalopathy syndrome, gastrointestinal toxicity 
(nausea, diarrhea, constipation, and vomiting), thrombocytopenia, neutropenia, tumor lysis 
syndrome, hepatic toxicity, and embryo-fetal risk. Most commonly reported adverse reactions 
(incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, 
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peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, 
lymphopenia, rash, pyrexia, and anorexia.35
1.1.5.
Dexamethasone 
Dexamethasone is a corticosteroid used to decrease the nausea and vomiting associated with 
chemotherapy.2 Common adverse reactions include hyperglycemia, increased appetite and 
weight gain, irritability, insomnia, impaired wound healing, and cataracts and osteoporosis with 
long-term use. 
For further information regarding lenalidomide, bortezomib, and dexamethasone, refer to the
individual prescribing information.7,25,35
1.1.6.
Combination Therapy: Lenalidomide-Bortezomib-Dexamethasone
In an important proof of concept study, Richardson and colleagues26 published a Phase 1/2 study 
assessing the combination of lenalidomide, bortezomib, and dexamethasone (RVd) for newly 
diagnosed subjects with multiple myeloma, regardless of eligibility for HDT and ASCT. 
Sixty-six subjects were treated on this single-arm study. A partial response (PR) or better was 
achieved by 100% of subjects (N=66), with favorable tolerability. Complete response (CR) was 
achieved in 19 subjects (29%) with an additional 7 subjects (11%) in near CR. Importantly, this 
study showed that RVd was a feasible induction regimen prior to ASCT. Twenty-eight subjects 
(42%) proceeded to undergo ASCT. Stem cell harvesting and engraftment were not adversely 
impacted by the 3-drug induction regimen.
More recently, the Intergroupe Francophone du Myélome conducted a Phase 2 study of RVd in 
newly diagnosed subjects with multiple myeloma who were eligible for ASCT.27 In this study, 
31 subjects received 3 cycles of RVd followed by stem cell harvest and transplantation, followed 
by an additional 2 consolidation cycles of RVd, and lastly an additional year of lenalidomide 
maintenance therapy. The overall response after 3 cycles of induction therapy was 94% with 
3 subjects achieving sCR (10%) and an additional 4 subjects in CR (13%). Interestingly, 4 out of 
25 tested were minimal residual disease (MRD) negative by flow cytometry. The best response 
at any time during the study was sCR in 15 (48%) subjects, CR in 3 (10%) subjects, and 21 out 
of 31 (68%) subjects achieved MRD negative status by flow cytometry.
Although RVd is a commonly given front-line regimen in the United States, the sCR rate 
demonstrated was approximately 10% to 15%. In a recent publication by Kapoor and 
colleagues,11 the authors correlate the achievement of sCR to long-term outcomes including time 
to progression (TTP) and OS. Specifically, median TTP of subjects achieving sCR was 
significantly longer (50 months) than TTP of subjects achieving CR or near CR (20 months and 
19 months, respectively). Furthermore, subjects attaining sCR were found to have a 5-year OS 
rate of 80% compared with subjects at CR (53%) or near CR (47%). 
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1.1.7.
Combination Therapy: Daratumumab-Lenalidomide-Bortezomib-
Dexamethasone
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-study 
GMB3003-070). 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 bortezomib, even in samples from subjects that were refractory to 
lenalidomide and bortezomib treatment. Treatment
of BM-MNC with lenalidomide or 
bortezomib resulted in 10% and 18% lysis, respectively. A combination of lenalidomide and 
bortezomib resulted in 25% lysis of BM-MNC. When daratumumab was added to either 
lenalidomide or bortezomib, a 2-fold increase in lysis was observed compared with lenalidomide 
or bortezomib alone. When daratumumab was added to combinations of dexamethasone, 
lenalidomide, and bortezomib or to bortezomib, prednisone, and dexamethasone, the cell lysis 
was significantly increased (p<0.001) compared with the triple combination alone (no 
daratumumab).34 Refer to Figure 1 and Figure 2.
Figure 1:
Daratumumab-Enhanced Multiple Myeloma Cell Killing by Key Multiple Myeloma 
Chemotherapeutic Agents
BORT = bortezomib; DARA = daratumumab; LEN = lenalidomide; MM = multiple myeloma. 
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Figure 2:
Dose-dependent Lysis of Multiple Myeloma Cells in Triple Chemotherapy Treatments
DARA = daratumumab; RVD = combination lenalidomide, bortezomib, and dexamethasone; MM = multiple 
myeloma; MPV = bortezomib, prednisone, and dexamethasone. 
P-values were calculated by a paired t-test. *P<0.05, ***P<0.001.
Thus, in this ex vivo clinical setting, daratumumab-mediated multiple myeloma tumor cell 
killing was demonstrated to be significantly augmented by stimulating effector cells. Preclinical 
data, both the literature and the sponsor’s own ex vivo studies, support the combination of 
daratumumab with lenalidomide and bortezomib in the treatment of multiple myeloma.
1.2.
Overall Rationale for the Study
To date, targeting multiple myeloma cells by a combination-therapy approach has demonstrated 
superior clinical response as compared with that of single agents.5 In theory, targeting both the 
tumor cells and the surrounding stromal compartment upon which the tumor is dependent should 
lead to higher efficacy. Targeted immunotherapy based on monoclonal antibodies against 
relevant tumor antigens has shown to be not only feasible, but also an effective approach in 
treating hematological malignancies when combined with chemotherapy agents. The future of 
successful multiple myeloma treatment lies in both the development of novel agents targeting the 
multiple myeloma cells or the bone marrow microenvironment, and the development of 
rationally-based combination therapies. The addition of daratumumab to RVd induction therapy
(D-RVd) could potentially improve initial disease control and long-term outcomes. Based upon 
the pre-clinical synergism observed, and promising clinical data in the relapsed/refractory 
setting, the D-RVd combination will be investigated in this study in newly diagnosed, transplant-
eligible patients.
Based on the current safety data from ongoing daratumumab studies, and the safety information 
in the label for lenalidomide and for bortezomib, the expected safety profile of daratumumab in 
this combination therapy study is considered manageable. See the daratumumab Investigator’s 
Brochure for additional data. The safety profile of daratumumab in combination with other 
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agents is consistent with the known safety profiles of the backbone therapies (bortezomib, 
lenalidomide, pomalidomide, dexamethasone, melphalan, prednisone, thalidomide). With the 
exception of IRRs, the addition of daratumumab to standard multiple myeloma treatment 
regimens did not seem to add toxicity to the safety profiles previously reported with these 
backbone regimens. 
2.
OBJECTIVES, Endpoints, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objective
The primary objective is to determine if the addition of daratumumab to RVd will increase the 
proportion of subjects achieving sCR, as defined by the IMWG criteria, by the time of 
completion of post-ASCT consolidation treatment, compared with RVd alone.
Secondary Objectives
The secondary objectives are:

To evaluate CR and sCR rate following induction, ASCT, post-ASCT consolidation, and 
maintenance treatment

To evaluate overall response rate (ORR) and rate of VGPR or better following induction, 
ASCT, post-ASCT consolidation, and maintenance treatment

To evaluate duration of and time to sCR and time to CR

To evaluate time to VGPR or better

To evaluate time to PR or better

To assess negative MRD rate following induction, post-ASCT consolidation, and 
maintenance treatment

To evaluate clinical outcomes including:

Time to progression

Progression-free survival

Overall survival 

Duration of response

To assess the safety and tolerability of D-RVd 

To assess the pharmacokinetics of daratumumab 

To assess the immunogenicity of daratumumab 
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
To evaluate patient-reported outcomes (PROs)

To evaluate stem cell yield after mobilization 

To assess time to absolute neutrophil count (ANC) recovery, defined as the date from 
transplant to the first of 3 consecutive laboratory values (obtained on different days) where 
the ANC is > 0.5 x 109/L.

To assess time to platelet count recovery, defined as the date from transplant to the first of 
3 consecutive laboratory values (obtained on different days) where the platelet count is > 20 
x 109/L and at least 7 days after the most recent prior platelet transfusion

To evaluate the tolerability of daratumumab when administered as a rapid infusion during 
maintenance treatment (ie, an accelerated infusion rate whereby 20% of the daratumumab 
dose is administered over 30 minutes and the remaining 80% is administered over 
60 minutes for a total dose administration time of 90 minutes)
Exploratory Objectives
The exploratory objectives are:

To evaluate PFS on next-line therapy

To evaluate the clinical efficacy of D-RVd in high-risk cytogenetic subgroups: del(17p), 
t(4;14), and t(14;16), 

To explore immune modulatory effects of D-RVd as compared with RVd through immune 
profiling (NK, T, and B cells) and T-cell receptor sequencing 

To collect medical resource utilization (MRU) data that may be used in future economic 
modeling (the construction and reporting of the economic model will be conducted 
separately from this study)

To evaluate serum concentrations and potential immunogenicity of daratumumab with 
respect to IRRs in the setting of rapid infusion during maintenance. 
2.1.2.
Endpoints
Primary Endpoint
The primary endpoint is the sCR rate by the end of post-ASCT consolidation treatment, defined 
as the proportion of subjects who have achieved sCR, according to the IMWG criteria, by the 
end of post-ASCT consolidation treatment.
Secondary Endpoints
M-protein levels need to meet the definition of disease progression (see Table 9: International 
Uniform Response Criteria Consensus Recommendations) for subjects to have disease 
progression. Disease evaluations will continue beyond relapse from CR until disease progression 
is confirmed.
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The secondary efficacy endpoints include: 

Following induction treatment (prior to HDT/ASCT), ASCT (prior to start of consolidation 
treatment), post-ASCT consolidation (after Cycle 6), and maintenance treatment: 

Overall CR and sCR rate is defined as the proportion of subjects who achieve CR (or 
sCR), according to the IMWG criteria, by the respective time point.

ORR is defined as the proportion of subjects who achieve PR or better, according to the 
IMWG criteria, by the respective time point. 

VGPR or better rate is defined as the proportion of subjects achieving VGPR or better, 
according to the IMWG criteria, by the respective time point. 

MRD negative rate is defined as the proportion of subjects who achieve MRD negative 
status by the respective time point. 
Note: A subject not tested for MRD will be considered as MRD positive.

Duration of CR (and sCR) is the duration from the date of initial documentation of a CR (or 
sCR) response, according to the IMWG criteria, to the date of first documented evidence of 
progressive disease, or relapse from CR. For subjects who have not progressed or relapsed, 
data will be censored at the last disease evaluation before the start of any subsequent 
anti-myeloma therapy.

Time to CR (and sCR) is the duration from the date of randomization to the date of initial 
documentation of CR (or sCR), which was confirmed by a repeated measurement as 
required by the IMWG criteria. For subjects who have not achieved CR (or sCR), data will 
be censored at the date of progressive disease or the last disease evaluation before the start 
of any subsequent anti-myeloma therapy, whichever comes first.

Time to VGPR or better is the duration from the date of randomization to the date of initial 
documentation of VGPR or better, which was confirmed by a repeated measurement as 
required by the IMWG criteria. For subjects who have not achieved VGPR or better, data 
will be censored at the date of progressive disease or the last disease evaluation before the 
start of any subsequent anti-myeloma therapy, whichever comes first.

Time to PR or better is the duration from the date of randomization to the date of initial 
documentation of PR or better, which was confirmed by a repeated measurement as required 
by the IMWG criteria. For subjects who have not achieved PR or better, data will be 
censored at the date of progressive disease or the last disease evaluation before the start of 
any subsequent anti-myeloma therapy, whichever comes first.

Time to progression is defined as the duration from the date of randomization to the date of 
first documented evidence of progressive disease according to the IMWG criteria. Subjects 
who have not progressed will be censored at the last date of the disease evaluation before the 
start of any subsequent anti-myeloma therapy.

Progression-free survival is defined as the duration from the date of randomization to the 
date of first documented evidence of progressive disease or death, whichever comes first. 
First documented evidence of progressive disease must have been confirmed by a repeat 
measurement as required by the IMWG criteria. Subjects who have not progressed nor died 
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by the data cutoff will be censored at the last date of the disease evaluation before the start 
of any subsequent anti-myeloma therapy.

Overall survival is 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.

Duration of response is defined as the duration from the date of initial documentation of a 
response (PR or better) according to the IMWG criteria to the date of first documented 
evidence of progressive disease according to 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.
Exploratory Endpoint

Progression-free survival after next-line therapy will be measured from randomization to the 
date of the progressive disease on the next line of treatment or death, whichever comes first. 
Subjects who are still alive and have not yet progressed on the next line of treatment will be 
censored on the last date of follow-up.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The primary hypothesis of this study is that D-RVd will improve the sCR rate by the end of 
post-ASCT consolidation treatment compared with RVd alone.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter, randomized, open-label, active-controlled, Phase 2 study in subjects with 
newly diagnosed multiple myeloma eligible for HDT and ASCT. Initially, there will be a safety 
run-in phase in up-to-16 subjects to assess potential dose-limiting toxicities (DLTs) that may be 
associated with the addition of daratumumab to the RVd regimen. The main study consists of 4
phases: a 28-day screening phase; an induction/consolidation phase (which is inclusive of four 
21-day induction treatment cycles followed by stem cell mobilization, HDT, and ASCT,
followed by two 21-day consolidation treatment cycles); a 24-month maintenance phase that 
starts after the post-ASCT consolidation disease evaluation; and a long-term follow-up phase.
All subjects will be followed in the long-term follow-up phase for at least 1 year after last dose 
of study treatment and will continue until death, withdrawal of consent for study participation, or 
the end of study definition is met. The end of study is defined as when all subjects have 
completed at least 1 year of long-term follow up, or until death or withdrawal of consent for 
study participation, whichever occurs first.
Initially, a safety run-in phase will be performed at selected study sites. In this safety run-in 
phase, a total of 8 to 16 subjects will be enrolled and assigned to receive D-RVd to assess 
potential DLTs during Cycle 1 of treatment. Subjects who are enrolled in the safety run-in phase 
will have all procedures indicated in the TIME AND EVENTS SCHEDULE performed except 
PRO assessments and MRU data collection.
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Dose-limiting toxicities are defined as:

Grade 4 neutropenia lasting more than 7 days.

Grade 4 thrombocytopenia lasting more than 7 days despite transfusion support. 

Grade 3 or higher nonhematological toxicity except: 

Grade 3 nausea, vomiting, or diarrhea that can be controlled within 48 hours with 
maximal supportive care.

Grade 3 hyperglycemia that can be controlled within 48 hours with appropriate 
supportive care.

Asymptomatic Grade 3 or higher electrolyte disturbances that can be controlled with 
repletion within 24 hours. 

Grade 3 maculopapular rash attributable to lenalidomide.

Infusion-related reactions:

Any Grade 4 IRR occurring within 48 hours of the infusion of daratumumab.

Any Grade 3 IRR occurring within 48 hours of the infusion of daratumumab that does 
not resolve with a reduced infusion rate or temporarily stopping the infusion, as well as 
administration of supportive care and symptomatic therapy such as a steroid and an 
antihistamine.
Alopecia, lymphopenia, and anemia will not be part of DLT determination.
Up-to 16 subjects (minimum 8) will be enrolled in the safety run-in phase. Subjects will be 
monitored according to stopping boundaries specified in Section 11.10, Safety Analyses. 
Subjects who experience a DLT during the safety run-in will be withdrawn from the study (based 
on investigator’s judgment and best clinical practice). If the stopping boundaries are crossed after 
8, 12, or 16 subjects, all subjects will be withdrawn from the study, and the study will be 
stopped. Unless the study is stopped due to DLTs, subjects enrolled in the safety run-in phase 
will continue in the study and follow the visit schedule and procedures described for the main 
study (except PRO assessments and MRU data collection). 
Following successful completion of the safety run-in phase, approximately 200 subjects will be 
randomly assigned to 1 of 2 treatment groups (100 per treatment group) in the main study:

D-RVd group: RVd with daratumumab 16 mg/kg IV weekly during induction treatment 
(Days 1, 8, and 15 of Cycles 1 through 4) and every 3 weeks during consolidation treatment
(Day 1 of Cycles 5 and 6), followed by every 4 or 8 weeks during maintenance treatment.
Subjects will receive pre- and postinfusion medications for each dose of daratumumab as 
described in Sections 6.1.3.1 and 6.1.3.2, respectively. 

RVd group: RVd alone as induction and consolidation treatment (Cycles 1 through 6: 
lenalidomide 25 mg orally on Days 1 through 14, bortezomib 1.3 mg/m2 subcutaneously on 
Days 1, 4, 8, and 11, and oral dexamethasone 40 mg weekly [20 mg on Days 1, 2,8, 9, 15, 
and 16]) followed by maintenance treatment with oral lenalidomide 10 mg daily on Days 1-
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21 throughout each 28-day cycle on Cycles 7 through 9. Beginning at Cycle 10, the 
lenalidomide dose will be increased to 15 mg unless there is a tolerability concern. 
Subjects will be stratified at randomization by International Staging System Stage I, II, or III 
disease (β-2 microglobulin and albumin) and creatinine clearance (CrCl [30-50 mL/min and 
>50 mL/min]). 
Additional details for daratumumab and RVd administration are provided in Section 6, Dosage 
and Administration and in the Study Drug Dosing. After 4 cycles of induction study treatment, 
subjects will undergo stem cell mobilization and then proceed to HDT and ASCT, which will be 
performed according to institutional standards (see Section 9.1.3 Induction/Consolidation Phase
for additional details). If the decision is made by the investigator not to pursue HDT and ASCT, 
subjects will be discontinued from study treatment and enter the long-term follow-up phase;
subjects who do not undergo HDT and ASCT will not receive consolidation or maintenance 
treatment on protocol.
Consolidation treatment may commence when engraftment is complete and when in the opinion 
of the investigator the subject is fit enough to tolerate subsequent systemic therapy (60-100 days 
post-ASCT). At the start of consolidation treatment, both groups will receive the same dosages 
of lenalidomide, bortezomib, and oral dexamethasone that were tolerated at the end of induction 
treatment. Subjects will be evaluated for the primary endpoint (post-ASCT consolidation sCR).  
MRD will be assessed by next-generation sequencing, regardless of treatment group, as detailed 
in the TIME AND EVENTS SCHEDULE. After the post-ASCT consolidation disease 
evaluation, subjects will enter the 24-month maintenance phase of the study. Following 
completion of the last cycle of the maintenance phase, subjects may continue lenalidomide as per 
local standard of care.
Subjects will receive study treatment through completion of the 24-month maintenance phase, or 
until confirmed disease progression, discontinue study treatment due to an unacceptable drug 
toxicity, or other reasons. Unless a subject withdraws consent for study participation, or is lost to 
follow-up, an EOT visit is to be scheduled 30 days after the last dose of all components of the 
study treatment have been discontinued, or as soon as possible before the start of next-line 
therapy. After completion of the EOT visit, subjects will enter the long-term follow-up phase of 
the study. Subjects who enter the long-term follow-up phase before disease progression will 
return to the site every 12 weeks for disease evaluation, PRO assessments, and other follow-up 
assessments (ie, other malignancies, start of next-line therapy, and survival), until confirmed 
disease progression, death, the start of a new treatment for multiple myeloma, withdrawal of 
consent for study participation, or the end of study, whichever occurs first (see TIME AND 
EVENTS SCHEDULE). After confirmed disease progression or the start of a new treatment for 
multiple myeloma, subjects will return to the site or be contacted by telephone every 12 weeks
for follow-up assessments (ie, other malignancies, next-line therapy, progressive disease (PD) on 
next-line therapy, and survival, as applicable). Following disease progression on the next-line 
therapy, subjects will only be followed for survival.
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No daratumumab dose modification (increase or decrease) will be permitted. Protocol-specified 
dose delays for daratumumab have been included in this protocol (refer to Section 6.1.4, Dose 
Modification and Dose Delays) and will be implemented as necessary. Subjects will be evaluated 
for toxicity before each dose of daratumumab is administered. Investigators will focus on 
hematologic toxicity and the occurrence of IRRs (refer to Section 6.1.3, Guidelines for 
Prevention and Management of Infusion Reactions and Section 6.1.4, Dose Modification and 
Dose Delays). Doses may be held based on the severity of and recovery from a previous toxicity.
Dose adjustments and delays of lenalidomide, bortezomib, and dexamethasone will be permitted
(refer to Sections 6.2.1, 6.3.1, and 6.4, respectively).
Disease response and progression will be based on assessments according to the IMWG
guidelines. Efficacy evaluations include: M-protein measurements (serum and urine), 
immunofixation (IFE) (serum and urine), serum FLC, serum calcium corrected for albumin, 
examination of bone marrow aspirate or biopsy, skeletal survey (assessment of lytic bone 
disease), and documentation of extramedullary plasmacytomas. Minimal residual disease in the 
bone marrow aspirate will also be assessed.
Throughout the study, subjects will be monitored closely for adverse events, laboratory 
abnormalities, and clinical response, as specified in the TIME AND EVENTS SCHEDULE. The 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE 
Version 4.03) will be used to grade toxicity throughout the study.
Blood samples for biomarker studies will be collected from all subjects. Blood samples for 
pharmacokinetic and immunogenicity assessments will only be collected from subjects in the 
D-RVd/D-R group.
To measure functional status, well-being, and symptoms, the EORTC QLQ-C30, EORTC 
QLQ-MY20, and the EQ-5D-5L instruments will be completed by subjects throughout the study. 
Medical resource utilization data will also be collected.
A Data Review Committee will review safety data after 8, 12, and 16 subjects in the safety run-
in phase complete Cycle 1 (or discontinue before the end of Cycle 1) and will use stopping 
boundaries described in Section 11.10, Safety Analyses. Refer to Section 11.13, for details. If the 
study is not stopped due to DLTs in the safety run-in phase, one interim safety analysis is 
planned for the safety run-in cohort after all subjects are treated for at least 4 cycles or 
discontinue study participation.
An independent Data Monitoring Committee (DMC) will meet periodically to review interim 
safety data during the main study. One planned interim safety analysis will occur after at least 
50 subjects are treated for at least 4 cycles and undergo stem cell mobilization (or are evaluated 
for mobilization feasibility) in the main study or have discontinued before completing 4 
cycles/stem cell mobilization/feasibility. Refer to Section 11.12, Independent Data Monitoring 
Committee for details.
A diagram of the study design is provided in Figure 3.
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Figure 3:
Schematic Overview of the Study
Note:
In the above figure it states that daratumumab is to be administered every 4 weeks during the maintenance phase. While this is the 
preferred treatment schedule, for those who do not elect to receive daratumumab every 4 weeks, daratumumab will be administered every 
8 weeks during maintenance as originally planned.
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3.2.
Study Design Rationale
3.2.1.
Study Phase/Periods, Treatment Groups
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. Additionally, randomization will be stratified 
by International Staging System Stage I, II, or III disease and by CrCl (30-50 mL/min and 
>50 mL/min) to ensure that these prognostic factors are balanced across the treatment groups.
3.2.2.
Rationale for Daratumumab Dose Selection, Infusion Rate, and 
Backbone Chemotherapy Regimen
The dose of daratumumab in this study was based on the GEN501 and MMY2002 studies, which 
demonstrated that a dose of 16 mg/kg was more clinically active, with no significant increase in 
toxicity, than 8 mg/kg when given as a single agent. Preliminary evidence from ongoing studies 
combining daratumumab with other agents has demonstrated that 16 mg/kg of daratumumab can 
be safely given in conjunction with other anti-myeloma agents. Furthermore, extensive 
experience 
with 
monoclonal 
anti-CD20 
antibodies 
such 
as 
rituximab 
in 
B-cell 
lymphoproliferative malignancies such as chronic lymphocytic leukemia, follicular lymphoma, 
and diffuse large cell lymphoma showed that combining full dose monoclonal antibodies with 
chemotherapy can greatly improve anti-tumor activity in hematologic malignancies with an 
acceptable toxicity profile.
All subjects will receive RVd treatment during Cycles 1 through 6 in the study; the rationale for 
selection of this backbone regimen is provided in Section 1.1.6, Combination Therapy: 
Daratumumab-Lenalidomide-Bortezomib-Dexamethasone. Lenalidomide will be administered 
on Days 1 through 14 in the induction and consolidation cycles. A duration of 14 days, rather 
than 21 days as per the prescribing information, was chosen based on the co-administration with
bortezomib; this schedule of lenalidomide with bortezomib and dexamethasone has been shown 
to be tolerable, safe, and effective in the treatment of patients with previously untreated multiple 
myeloma who are transplant eligible. Therefore, this study will utilize this dosing schedule for 
lenalidomide.
The daratumumab infusion rate initially chosen for this study was based on historic data obtained 
from the sponsor in clinical trials of daratumumab. Since then, the efficacy, safety, and 
tolerability of an accelerated infusion rate of daratumumab was evaluated in a study by Barr et 
al.1 In this single-center study, 28 subjects were treated with daratumumab utilizing an 
accelerated infusion rate after at least 2 prior doses of daratumumab administered as per standard 
prescribing information. The accelerated infusion was calculated to deliver 20% of the dose over 
the first 30 minutes followed by the remaining 80% over 60 minutes, resulting in an estimated 
90-minute infusion. Subjects who tolerated the infusion were allowed to continue dosing at the 
accelerated rate. Premedication regimens were allowed to be altered based on previous 
tolerability. Out of all 28 subjects treated, only 1 adverse reaction (grade 2 hypertension in a 
subject who received 10 prior infusions at standard rates) was observed. The infusion was 
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paused, and a diuretic was administered. After symptom resolution, the infusion was restarted,
and the infusion rate was subsequently increased to the accelerated rate without further 
incidence. There were no grade 3 or greater IRRs. At the 4-week follow-up, all subjects
remaining on daratumumab treatment continued at the accelerated infusion rate.
The protocol has been amended (Protocol Amendment 3) to allow subjects the option to receive 
daratumumab via accelerated infusion., This change will impact dosing from Cycle 7 onward.
Subjects who elect to receive the rapid infusion must sign a new informed consent form (ICF) 
prior to dosing. No changes are permitted to the protocol requirements with respect to pre- and 
post-infusion daratumumab medications. 
3.2.3.
Rationale for Pharmacokinetics, Immunogenicity, and Biomarker 
Evaluations
Data obtained from the current study will provide information about the pharmacokinetics of 
daratumumab by IV delivery in subjects with multiple myeloma. 
Immunogenicity to daratumumab is possible. Therefore, samples to determine the presence of 
anti-daratumumab antibodies (immunogenicity) will be collected from all subjects who receive 
daratumumab.
Biomarkers collected in this study will potentially provide information about the mechanism of 
action of daratumumab in newly diagnosed multiple myeloma, as well as information on 
potential markers of clinical response. Depth of clinical response will be measured by MRD 
using 
next-generation 
sequencing 
of 
immunoglobulin 
genes 
in 
bone 
marrow. 
Immunophenotyping may include analysis of NK cells (including activated NK cells), T cells
(cytotoxic, regulatory, memory T cells subsets) B cells, MDSC, macrophages, and dendritic 
cells, as these cells are involved in immune-mediated tumor lysis. Samples may be used to 
evaluate specific subsets of immune cells such as cytotoxic T cells, regulatory T cells, myeloid-
derived suppressor cells, and activated NK cells.  Refer to Section 9.5, Biomarkers for details of 
the biomarker analyses. 
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 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 should consult with the appropriate sponsor representative before enrolling a subject 
in the study. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
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4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
18 to 70 years of age, inclusive at study entry.
2.
considered by the investigator to be eligible for HDT and ASCT according to the 
institution’s criteria based on age, medical history, cardiac and pulmonary status, 
overall health and condition, co-morbid condition(s), physical examination, and 
laboratory studies.
3.
have documented multiple myeloma as defined by the IMWG 2014 criteria22
including:
Clonal bone marrow plasma cells ≥10%*. In addition, the subject must 
meet one of the criteria in 3a or 3b:
a.
Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, specifically (one or more of the following):
i.
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the 
upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
ii.
Renal insufficiency: CrCl <40 mL/min (measured or estimated by validated 
equations, Attachment 2) or serum creatinine >177 μmol/L (>2 mg/dL)
iii. Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a 
hemoglobin value <100 g/L
iv. Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed 
tomography (CT), or magnetic resonance imaging (MRI)**.
b.
Any one or more of the following:
i.
Clonal bone marrow plasma cell percentage** ≥60%
ii.
Involved:uninvolved serum FLC ratio*** >100
iii. >1 focal lesions on MRI studies; Each focal lesion must be 5 mm or more in 
size.
* 
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.
**
Clonality should be established by showing κ/λ-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 core biopsy, the highest value should be used.
*** These values are based on the serum Freelite assay (The Binding Site Group, 
Birmingham, UK).  The involved FLC must be ≥100 mg/L.
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4.
Measurable disease as defined by any of the following: 
i.
Serum M-protein level 1.0 g/dL or urine M-protein level 200 mg/24 hours. 
Note: 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 for 
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; or
ii.
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
iii.
Light chain multiple myeloma without measurable disease in the urine: serum 
Ig FLC 10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio.
5.
has not had prior systemic therapy for multiple myeloma. An emergency course of 
steroids (defined as no greater than 40 mg of dexamethasone, or equivalent per day for 
a maximum of 4 days (ie, a total of 160 mg) is permitted. In addition, radiation 
therapy is permitted prior to study entry, during screening, and during Cycles 1-2 of 
study treatment as needed for lytic bone disease.
6.
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 
(refer to Attachment 3).20
7.
woman of childbearing potential must have 2 negative highly sensitive serum
(-human chorionic gonadotropin [-hCG]) during screening, the first one within 
10 to 14 days prior to the first dose of any component of study treatment and the 
second within 24 hours prior to the first dose of any component of study treatment. 
8.
before randomization, a woman must be either:
a.
Not of childbearing potential defined as: 
o
postmenopausal
A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. A high follicle stimulating hormone level 
(>40 IU/L or mIU/mL in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy, however in the absence 
of 12 months of amenorrhea, a single follicle stimulating hormone
measurement is insufficient.
o
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, bilateral tubal occlusion/ligation procedures, and 
bilateral oophorectomy.
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b.
Of childbearing potential and
o
practicing 2 highly effective user-independent methods of contraception 
(failure rate of <1% per year when used consistently and correctly
Examples of highly effective user-independent methods of contraception
include:
implantable progestogen-only hormone contraception associated 
with inhibition of ovulation; intrauterine device (IUD); intrauterine 
hormone-releasing system (IUS); vasectomized partner; sexual 
abstinence (sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the 
subject.)
Typical use failure rates may differ from those when used consistently 
and correctly. Use should be consistent with local regulations regarding 
the use of contraceptive methods for subjects participating in clinical 
studies.
Hormonal contraception may be susceptible to interaction with the study 
drug, which may reduce the efficacy of the contraceptive method.
o
agrees to remain on a highly effective method for 4 weeks before the 
first dose of any component of study treatment, throughout the study
(including during dose interruptions), and for 4 weeks following 
discontinuation of lenalidomide, and if receiving daratumumab, for 
3 months after the last dose. 
Note: If the risk of pregnancy changes (eg, a woman who is not heterosexually active 
becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered. 
9.
a woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted 
reproduction during the study (including during dose interruptions), and for 4 weeks 
following discontinuation of lenalidomide, and if receiving daratumumab, for 
3 months after the last dose.
10.
due to the teratogenicity of lenalidomide and the lack of adequate reproductive 
toxicity data for daratumumab, in addition to the user independent highly effective 
method of contraception, a male or female condom with or without spermicide,
diaphragm, or cervical cap is required. Male condom and female condom should not 
be used together (due to risk of failure with friction). 
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11.
during the study (including during dose interruptions), and for 4 weeks following 
discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the 
last dose, in addition to the user independent highly effective method of contraception
(even if he has undergone a successful vasectomy), a man 

who is sexually active with a woman of childbearing potential must agree to use a 
barrier method of contraception (ie, latex or synthetic condom with spermicidal 
foam/gel/film/cream/suppository)

who is sexually active with a woman who is pregnant must use a latex or 
synthetic condom.

must agree not to donate sperm
12.
willing and able to adhere to the prohibitions and restrictions specified in this protocol 
and referenced in the ICF.
13.
must sign an ICF (or their legally acceptable representative must sign) indicating that 
he or she understands the purpose of, and procedures required for, the study and is 
willing to participate in the study.
Note:
Subjects who elect to receive daratumumab every 4 weeks instead of every 
8 weeks during the maintenance phase and/or those who elect to receive the 
rapid infusion of daratumumab during the maintenance phase must sign (or 
their legally acceptable representative must sign) a new ICF, consenting to the 
new daratumumab dosing administration(s).
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
diagnosed or treated for malignancy other than multiple myeloma, except:

Malignancy treated with curative intent and with no known active disease 
present for ≥3 years before randomization.

Adequately treated non-melanoma skin cancer, lentigo maligna or in situ 
malignancies (including but not limited to, cervical, breast) with no
evidence of disease.
2.
exhibiting clinical signs of or has a known history of meningeal or central nervous 
system involvement by multiple myeloma.
3.
known to be seropositive for human immunodeficiency virus, known to have hepatitis 
B surface antigen positivity, or known to have a history of hepatitis C.  Subjects who 
completed treatment for hepatitis C at least 6 months prior to screening and have no 
detectable circulating hepatitis C virus (HCV) at screening, may participate in the 
study. Such subjects will be required to undergo regular assessment for HCV 
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reactivation during their participation in the study.  Subjects who test positive for 
HCV at any time during these assessments will be withdrawn from the study.
4.
known chronic obstructive pulmonary disease with a forced expiratory volume in 
1 second (FEV1) <50% of predicted normal. 
Note: FEV1 testing is required for subjects suspected of having chronic obstructive 
pulmonary disease and asthma. Subjects must be excluded if FEV1 <50% of predicted 
normal.
5.
known moderate or severe persistent asthma within the past 2 years (see
Attachment 4), or currently has uncontrolled asthma of any classification. 
Note: Subjects who currently have controlled intermittent asthma or controlled mild 
persistent asthma are allowed in the study. FEV1 testing is required for subjects 
suspected of having asthma.
6.
concurrent medical condition or disease (eg, active systemic infection) that is likely to 
interfere with study procedures or results, or that in the opinion of the investigator 
would constitute a hazard for participating in this study. Specifically, any potential 
subject who is unsuitable for ASCT would be excluded from the study.
7.
clinically significant cardiac disease, including:
a.
Myocardial infarction within 6 months before Cycle 1, Day 1, or unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, 
unstable angina, congestive heart failure, New York Heart Association Class III-
IV).
b. Uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI-CTCAE] Version 4.03 Grade 2 or higher) or 
clinically significant electrocardiogram (ECG) abnormalities. 
c.
Screening 12-lead ECG showing a baseline corrected QT interval (QTc) 
>470 msec.
8.
any of the following laboratory test results during the screening phase:
a.
Absolute neutrophil count <1.0 × 109/L; no granulocyte colony stimulating factor 
(G-CSF) treatment in the past 7 days are allowed.
b. Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintain 
hemoglobin >7.5 g/dL are acceptable.
c.
Platelet count <75 × 109/L for subjects in whom <50% of bone marrow nucleated 
cells are plasma cells; otherwise platelet count <50 × 109/L; no platelet 
transfusions in the past 7 days are allowed.
d. Alanine aminotransferase (ALT) level ≥2.5 × ULN
e.
Aspartate aminotransferase (AST) level ≥2.5 × ULN
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f.
Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin 
≥2 × ULN)
g. Creatinine clearance <30 mL/min (lenalidomide dose adjustment for subjects with 
CrCl ≤50 mL/min; see Section 6.2.1, Renal Impairment); please note that the CrCl
can be either measured by 24-hour urine study, or estimated using a validated 
equation, such as a the Modification of Diet in Renal Disease (MDRD), Chronic 
Kidney Disease Epidemiology Collaboration (CKD-epi), or Cockcroft-Gault 
(Attachment 2).
h. Corrected serum calcium >14.0 mg/dL (>3.5 mmol/L) or free ionized calcium 
>6.5 mg/dL (>1.6 mmol/L); see Attachment 5.4
9.
known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human 
proteins, daratumumab or its excipients (refer to Investigator’s Brochure), or known 
sensitivity to mammalian-derived products.
10.
plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential),
Waldenström’s 
macroglobulinemia,
POEMS 
syndrome 
(polyneuropathy, 
organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), or light-
chain amyloidosis.
11.
known or suspected of not being able to comply with the study protocol (eg, because 
of alcoholism, drug dependency, or psychological disorder) or the 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 their well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
12.
contraindications to the use of lenalidomide, bortezomib, or dexamethasone per local 
prescribing information.7,25,35
13.
taken any disallowed therapies as noted in Section 8, Pre-study and Concomitant 
Therapy before the planned first dose of study drug.
14.
participated in an interventional clinical trial(s) and received an investigational drug 
(including investigational vaccines) or used an invasive investigational medical 
device within 4 weeks before Cycle 1, Day 1.
15.
pregnant or breast-feeding or planning to become pregnant while enrolled in this 
study or within 4 weeks following discontinuation of lenalidomide, and if receiving 
daratumumab, within 3 months after the last dose.
16.
plans to father a child while enrolled in this study or within 4 weeks following 
discontinuation of lenalidomide, and if receiving daratumumab, within 3 months after 
the last dose.
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17.
had major surgery within 2 weeks before Cycle 1, Day 1, or will not have fully 
recovered from surgery, or has surgery planned during the time the subject is expected 
to participate in the study or within 2 weeks after the last dose of study drug 
administration. 
Note: Subjects with planned surgical procedures to be conducted under local 
anesthesia may participate. Kyphoplasty is not considered a major surgery.
18.
has had a plasmapheresis within 28 days before randomization
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject’s clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before Cycle 1 Day 1 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, Source Documentation describes the required documentation to support 
meeting the enrollment criteria.
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:
1.
agree to follow the contraceptive requirements as noted in the inclusion criteria.
2.
agree to required serum pregnancy tests weekly during Cycle 1 and then monthly in 
subsequent cycles in women with regular menstrual cycles or every 2 weeks in women 
with irregular menstrual cycles. A serum or urine pregnancy test is also required at the 
EOT visit. Additional pregnancy tests may be required, as specified in the lenalidomide 
REMS program that can be accessed at http://www.revlimidrems.com/.
3.
because of the embryo-fetal risk of lenalidomide, all subjects must adhere to the 
lenalidomide REMS program that can be accessed at http://www.revlimidrems.com/.
4.
not donate blood during therapy and for at least 4 weeks following discontinuation of 
lenalidomide.
5.
typically, IV contrast is not used in 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.
6.
refer to Section 8, Prestudy and Concomitant Therapy for details regarding prohibited 
and restricted therapy during the study.
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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by International Staging System Stage I, 
II, or III (β-2 microglobulin and albumin) and by CrCL (30-50 mL/min and >50 mL/min). The 
interactive web response system (IWRS) will assign a unique treatment code, which will dictate 
the treatment assignment and matching study drug kit for the subject. The requestor must use his 
or her own user identification and personal identification number when contacting the IWRS and 
will then give the relevant subject details to uniquely identify the subject.
Blinding
As this is an open-label study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
In this protocol, the term “study drug” refers to daratumumab only, and “study treatment” refers 
to D-RVd or RVd. Daratumumab is to be administered as described in the Study Drug Dosing. 
Induction and consolidation cycles are 21 days in duration; there will be a maximum of 
4 induction cycles and 2 consolidation cycles. All subjects will receive RVd with or without 
daratumumab, based on random assignment, during induction and consolidation cycles. The 
D-RVd group will receive daratumumab weekly during induction and every 3 weeks during 
consolidation. At the start of the consolidation phase, both groups will receive the same dosages 
of lenalidomide, bortezomib, and oral dexamethasone that were tolerated at the end of induction 
treatment. Maintenance treatment cycles are 28 days in duration with lenalidomide given on 
Days 1-21; the D-RVd group will receive daratumumab every 4 or 8 weeks. Maintenance 
treatment will continue until disease progression or up to a maximum of 2 years. The start of a 
cycle will be the day of the first full dose of lenalidomide, depending on the treatment group and 
study phase.
At a minimum, subjects must have an absolute neutrophil count of 1 x 109/L and a platelet count 
of 50 x 109/L to begin a new cycle. Delays of up to 14 days for the start of the subsequent cycle 
are acceptable.  Any delays more than 14 days of the scheduled day will need to be discussed 
with the sponsor.  
Every effort should be made to keep subjects on the planned dosing schedule. The start of each 
cycle may occur within ±3 days during induction, ±14 days (consolidation), or ±14 days
(maintenance) of the scheduled day to accommodate the schedule of the site or subject. Every 
effort should be made to keep a subject on schedule with dosing; however, in exceptional 
circumstances dose delay may be considered.
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Subjects who need to temporarily interrupt treatment due to toxicity or discontinue treatment 
with any one component of study treatment (lenalidomide, bortezomib, dexamethasone, or 
daratumumab, as applicable depending on the study phase) may continue to receive treatment 
with the other component(s) of study treatment, as assigned.
6.1.
Daratumumab 
6.1.1.
Preparation
Infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second and subsequent 
doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation of infusion bags 
should be done on the day of the planned infusion. Daratumumab must be administered as an 
IV infusion given through a well-functioning IV catheter by using an infusion pump. The study 
drug must be filtered by using an inline filter (0.2 μM) during the infusion. Manuals with 
detailed descriptions for preparation and administration of daratumumab will be supplied to each 
pharmacy and site.
6.1.2.
Treatment Schedule and Administration
Daratumumab (16 mg/kg) will be administered as an IV infusion. Each subject’s dose will be 
calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The 
dose of daratumumab will remain constant throughout the study unless the subject’s weight 
changes more than 10% from Cycle 1 Day 1 or the most recent weight used for dose calculation.
Subject’s weight will be recorded on all daratumumab dosing days. All infusions will be planned 
as outpatient visits. Subjects will receive preinfusion medications and postinfusion medications 
as detailed in the protocol (Sections 6.1.3.1 and 6.1.3.2, respectively).
Daratumumab will be administered weekly during induction treatment in Cycles 1 to 4 (Days 1, 
8, and 15), every 3 weeks during consolidation treatment in Cycles 5 and 6 (Day 1), and every 4 
or 8 weeks during maintenance treatment in Cycle 7 and beyond for 24 months, at which time all 
study treatment will be discontinued. Subjects who signed the original ICF stating that 
daratumumab maintenance was to be administered every other month and who do not agree to 
the revised daratumumab maintenance administration every month will be permitted to receive 
daratumumab every other month. However, every effort should be taken to ensure that the 
subject understands the benefit of the monthly daratumumab maintenance schedule. The dilution 
volumes, initial infusion rates, and increment for the first, second, and subsequent doses are 
provided in Table 2. The first infusion, with a volume of 1,000 mL, takes approximately 8 hours; 
the second and subsequent infusions, with volumes of 500 mL, take approximately 4 hours. The 
maximum infusion rate for all infusions is 200 mL/hour. The sponsor may modify the infusion 
rates or the preinfusion medications prospectively based upon the information collected to date 
from this and other studies. Additional details for administration times and rates, as well as 
preinfusion medications, will be provided in the administration guidelines (study site 
investigational product and procedures manual).
Beginning at Cycle 7 Day 1 and onward, all subjects in the D-RVd arm, if clinically feasible, 
will be given the option to receive an accelerated 90-minute infusion of daratumumab.
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Table 2:
Daratumumab Infusion Rates
Dilution 
Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum 
Infusion Rate
First infusion
1000 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Second infusiona
500 mL
50 mL/hour
50 mL/hour every hour
200 mL/hour
Subsequent infusionsb
(C1D15 through C6D1)
500 mL
100 mL/hour
50 mL/hour every hour
200 mL/hour
Accelerated infusion
(beginning C7D1)
Dilution 
Volume
Initial Infusion 
Rate (first 
30 minutes)
Subsequent Infusion 
Rate (last 60 minutes)
Maximum 
Infusion Rate
500 mL
200 mL/hour
400 mL/hour
400 mL/hour
a
Modified rates should only be used if the first infusion of daratumumab was well-tolerated as defined by an 
absence of > Grade 1 infusion-related reactions during the first 3 hours.
b
Modified rates should only be used if the first 2 infusions of daratumumab were well-tolerated as defined by an 
absence of > Grade 1 infusion-related reactions during a final infusion rate of ≥100 mL/hr.
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 the 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. 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.
6.1.3.
Guidelines for Prevention and Management of Infusion-Related
Reactions
6.1.3.1.
Preinfusion Medication
The following preinfusion medications are administered, as described in the Study Drug Dosing, 
approximately 1 hour before each daratumumab infusion:
Dexamethasone 20 mg oral or IV (only if oral is not available) (an equivalent of long-acting 
corticosteroid may be substituted [see Attachment 1 for conversion table]). 
Note: During Cycles 1 to 6, when dexamethasone is taken at a total 40 mg weekly dose (ie, 
20 mg orally on Days 1, 2, 8, 9, 15, and 16), the dexamethasone 20 mg oral dose 
administered as a preinfusion medication on daratumumab infusion days (Days 1, 8, and 15) 
replaces the oral dexamethasone 20 mg dose for that day for subjects in the D-RVd group.

Acetaminophen 650 to 1,000 mg oral or IV equivalent

Diphenhydramine 25 to 50 mg, or equivalent dose of another antihistamine, either given oral 
or IV 
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
Montelukast 10 mg PO, at Cycle 1 Day 1 approximately 1 hour or less before the 
daratumumab infusion. An additional 10 mg PO can be given the day before infusion at the 
discretion of the investigator. Montelukast may be omitted for any daratumumab dose after 
the second infusion if the subject has no respiratory symptoms.
If necessary, oral preinfusion medications may be administered outside of the clinic on the day of 
the infusion, provided they are given within 3 hours prior to the infusion.
6.1.3.2.
Postinfusion Medication
For subjects with a higher risk of respiratory complications (eg, subjects who have mild asthma, 
or subjects with chronic obstructive pulmonary disease who have an FEV1 <80%), the following 
postinfusion medications should be considered:

Antihistamine (diphenhydramine or equivalent) on the first and second days after all 
infusions

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 chronic obstructive 
pulmonary disease)
If an at-risk subject experiences no major IRRs, these post-infusion measures may be stopped 
after 4 full doses of daratumumab at the investigator’s discretion.
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 no IRR has occurred, the follow-up 
telephone call 48 hours after the infusion is not required. 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. 
6.1.3.3.
Management of Infusion-Related Reactions
Subjects should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any infusion 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 bedside. Attention to staffing should be considered when multiple subjects will be 
dosed at the same time. 
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If an IRR 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 apply:

Subjects should be treated with acetaminophen, antihistamine, or corticosteroids as needed. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, and/or bronchodilators. For hypotension, 
subjects may require vasopressors.

In the event of a life-threatening IRR (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. 
Cases of severe reaction should be discussed with the sponsor’s medical monitor.
If an infusion is paused or the infusion rate is decreased, 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.
6.1.3.3.1.
Infusion-Related Reactions 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 onset, then the subject must be withdrawn from treatment.
6.1.3.3.2.
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.
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6.1.4.
Dose Modification and Dose Delays 
6.1.4.1.
Dose Modification
No daratumumab dose modification (increase or decrease) will be permitted unless the subject’s 
weight changes more than 10% from Cycle 1 Day 1 or the most recent weight used for dose 
calculation. Subject’s weight will be recorded on all daratumumab dosing days.
6.1.4.2.
Toxicity Management
ONLY if any of the following criteria are met and the event cannot be ascribed to 
lenalidomide,
bortezomib, dexamethasone, or underlying multiple myeloma, the 
daratumumab infusion must be held to allow for recovery from toxicity. The criteria for a 
dose delay are:

Grade 4 hematologic toxicity (except for Grade 4 lymphopenia), or Grade 3 or higher
thrombocytopenia with bleeding

Febrile neutropenia of any grade

Grade 4 Neutropenia with any grade infection

Grade 3 or higher non-hematologic toxicities with the following exceptions: 

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 that was present at baseline and lasts for <7 days after the 
last administration of daratumumab

Grade 3 or 4 electrolyte disturbances which can be managed with replacement therapy
If daratumumab administration does not commence within the prespecified window (Table 3) of 
the scheduled administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. See Section 6.1.4.3, Interruption or 
Missed Doses for additional information.
Table 3:
Daratumumab-Related Toxicity Management
Cycles
Frequency
Missed Dose
Dosing Resumption
1-4
Weekly (every 1 week)
>3 days
Next planned weekly dosing date
5-6
Every cycle (every 3 weeks)
>14 days
Next planned every 3 week dosing date
7 and beyond
Every 4 or 8 weeks 
>14 days
Next planned every 4 or 8 week dosing 
date
A missed dose will not be made up. Any adverse event deemed to be related to daratumumab 
that requires a dose hold of more than 28 days will result in permanent discontinuation of 
daratumumab. If a dose delay occurs, then pharmacokinetic blood samples should be collected 
on the actual day of study drug administration, not on the original scheduled administration day.
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6.1.4.3.
Interruption or Missed Doses
A daratumumab dose held for more than 3 days during induction, 14 days during consolidation, 
or 14 days during maintenance 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 who miss ≥3 consecutive planned doses of 
daratumumab for reasons other than toxicity will be withdrawn from treatment, unless, upon 
consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.
6.2.
Lenalidomide
In Cycles 1 through 6, lenalidomide will be self-administered at a dose of 25 mg orally each day 
on Days 1 through 14 of each 21-day cycle for subjects with CrCl >50 mL/min; or at the start of 
consolidation (Cycle 5 Day 1), at the same dose that was tolerated at the end of induction 
treatment. During maintenance treatment in Cycle 7 and beyond, lenalidomide 10 mg will be 
administered daily on Days 1-21 throughout each 28-day cycle. Beginning at Cycle 10, the 
lenalidomide dose will be increased to 15 mg unless there is a tolerability concern. Following 
completion of the last cycle of the 24-month maintenance phase, subjects may continue 
lenalidomide as per local standard of care. See Section 6.2.5, Renal Impairment for lenalidomide 
dose adjustments in subjects with renal impairment. 
6.2.1.
Dose Adjustments of Lenalidomide
Dose adjustments of lenalidomide will follow the approved labeling as follows:

Starting dose: 25 mg

Dose level -1: 20 mg

Dose level -2: 15 mg

Dose level -3: 10 mg

Dose level -4: 5 mg
Dose adjustments should be based on the highest grade of toxicity that is ascribed to 
lenalidomide.
6.2.2.
Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide has been associated with increased incidence of deep vein thrombosis and 
pulmonary embolism. Therefore, all subjects should be prophylactically treated with baby aspirin
(162 mg, at a minimum) by mouth daily. Subjects at increased risk of thromboembolic events 
(based on their medical history) should be treated with enoxaparin at a dose of 40 mg 
subcutaneously daily (or other low molecular heparin with equivalent dose and frequency for 
prophylaxis indication). The injection should be handled according to local practice. Vitamin K 
antagonists, or direct thrombin inhibitors are another option for deep vein thrombosis/pulmonary 
embolism prophylaxis and treatment and may be used at the discretion of the treating physician.
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6.2.3.
Thrombocytopenia
If the subject’s platelet count decreases, dose adjustments should be made according to the 
recommendations in Table 4.
Table 4:
Lenalidomide Dose Adjustment for Thrombocytopenia
Platelet Count
Recommended Course of Action
When count first falls to <30 109/L
When count returns to 30 109/L
Interrupt lenalidomide treatment, follow complete blood 
count weekly
Resume lenalidomide at dose level -1 (or at 5 mg per day 
if the subject is on maintenance therapy) 
For each subsequent drop in count to <30 109/L
When count returns to 30 109/L
Interrupt lenalidomide treatment
Resume lenalidomide at the next lower dose level once 
daily. Do not decrease dose below 5 mg once daily
6.2.4.
Neutropenia
If the subject experiences neutropenia, the investigator should consider the use of growth factors 
in the subject’s management. If the subject’s neutrophil count decreases further despite growth 
factor utilization, dose adjustments should be made according to the recommendations in
Table 5.
Table 5:
Lenalidomide Dose Adjustment for Neutropenia
Neutrophil Count
Recommended Course of Action

When count first falls to <1.0 109/L

When count returns to 1.0 109/L and neutropenia 
is the only observed toxicity

Interrupt lenalidomide treatment, start G-CSF 
treatment, follow complete blood count weekly

Resume lenalidomide at 25 mg once daily if during 
induction phase of the study. Resume lenalidomide 
at 10 mg once daily on Days 1-21 if during 
maintenance phase of the study.

When count returns to 1.0 109/L and other 
hematologic toxicity attributable to lenalidomide is 
observed

During induction therapy, resume lenalidomide at 
20 mg once daily 

If the subject is on maintenance therapy, continue 
10 mg of daily lenalidomide every 21 days to allow 
for a 7-day rest period at the end of each cycle.

For each subsequent drop in count to <1.0 109/L

When count returns to 1.0 109/L

Interrupt lenalidomide treatment

Resume lenalidomide at the next lower dose level 
once daily. Do not decrease dose below 5 mg once 
daily.
G-CSF = granulocyte colony stimulating factor
6.2.5.
Renal Impairment
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the dose of 
lenalidomide are recommended to provide appropriate drug exposure in subjects with moderate 
or severe renal impairment. Lenalidomide dose adjustment should be instituted for subjects with 
a CrCl ≤50 mL/min. The recommended doses for subjects with multiple myeloma and renal 
impairment are shown in Table 6. To be enrolled in the study, subjects must have 
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CrCl ≥30 mL/min. If during treatment a subject’s renal status changes, the dose should be 
adjusted as shown in Table 6. 
Table 6:
Lenalidomide Dose Adjustment for Renal Impairment
Category
Renal Functiona
Dose
Moderate renal impairmentb
CrCl 30-50 mL/min
10 mg every 24 hours
Severe renal impairment
CrCl <30 mL/min (not requiring dialysis)
15 mg every 48 hours
End-stage renal disease
CrCl <30 mL/min (requiring dialysis)
5 mg once daily. On dialysis days, 
administer the dose after dialysis
CrCl = creatinine clearance.
a
Estimated by creatinine clearance as calculated by the Cockcroft-Gault equation (Attachment 2).
b
For subjects with moderate renal impairment, escalate the dose to 15 mg after 2 cycles if the subject tolerates 
the 10 mg dose without dose-limiting toxicity.
6.2.6.
Other Grade 3 or 4 Adverse Events
For other Grade 3 or 4 toxicities judged by the investigator to be related to lenalidomide alone, 
treatment with lenalidomide should be interrupted and restarted at the next lower dose level once 
the toxicity has resolved to Grade 2 or less. If a Grade 3 toxicity can be controlled (eg, a Grade 3
electrolyte disturbance that can be controlled with repletion within 24 hours), the investigator 
should discuss the toxicity with the sponsor’s medical monitor before interrupting or lowering 
the lenalidomide dose. Treatment with daratumumab, bortezomib, and dexamethasone may 
continue, as applicable depending on the study phase.
6.3.
Bortezomib
The amount (in mg) of bortezomib to be administered will be determined by body surface area, 
calculated according to a standard nomogram (Attachment 6). Each subject’s dose will be 
calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The 
dose should be readjusted if weight changes >10% from the value on C1D1.The total calculated 
dose of bortezomib may be rounded to the nearest decimal point (eg, a calculated dose of 
2.47 mg can be rounded to 2.5 mg). Subjects will receive 1.3 mg/m2 bortezomib as a 
subcutaneous injection twice weekly (Days 1, 4, 8, and 11) during the 21-day induction and 
consolidation cycles (Cycles 1-6); or at the start of consolidation [Cycle 5 Day 1], at the same 
dose that was tolerated at the end of induction treatment. For subjects who experience injection-
site reactions at the subcutaneous administration site, bortezomib may be administered by IV 
injection (see study site investigational product and procedures manual and bortezomib US
prescribing information). On daratumumab infusion days, bortezomib will be administered at the 
end of the daratumumab infusion. Neither group will receive bortezomib after the first 6 cycles 
of D-RVd or RVd.
6.3.1.
Dose Adjustments of Bortezomib
Dose adjustments should be based on the highest grade of toxicity that is ascribed to bortezomib. 
Bortezomib therapy should be withheld at the onset of any Grade 3 or Grade 4 
non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed in 
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Table 7. Once the symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated 
at a 25% reduced dose per approved labelling, as follows: 

Starting dose: 1.3 mg/m2

Dose level -1: 1.0 mg/m2

Dose level -2: 0.7 mg/m2

Dose level -3: discontinue bortezomib
A dose of bortezomib may be delayed up to 48 hours. Doses that need to be withheld are skipped 
and will not be made up later in the cycle.
6.3.2.
Neurologic Toxicity
If the subject experiences peripheral neuropathy, then dose adjustments should be made 
according to the recommendations in Table 7.
Table 7:
Recommended Dose Modification for Bortezomib-related Neuropathic Pain and/or 
Peripheral Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy Signs and Symptomsa
Recommended Modification of Dose and 
Regimen
Grade 1 (asymptomatic; loss of deep tendon reflexes or 
   paresthesia) without pain or loss of function
No action
Grade 1 with pain or 
Grade 2 (moderate symptoms; limiting instrumental ADLb)
Reduce bortezomib to 1 mg/m2 or
Change bortezomib treatment schedule to 
1.3 mg/m2 once per week (ie, Day 1 and Day 8).
Grade 2 with pain or 
Grade 3 (severe symptoms; limiting self-care ADLc)
Withhold bortezomib treatment until symptoms 
of toxicity have resolved. 
When toxicity resolves, reinitiate with a reduced 
dose of bortezomib at 0.7 mg/m2 once per week
(ie, Day 1 and Day 8).
Grade 4 (life-threatening consequences; urgent intervention 
   indicated)
Discontinue bortezomib.
ADL = activities of daily living
a
Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
v4.03.
b
Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing 
money etc. 
c
Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden.
6.4.
Dexamethasone
Dexamethasone (or equivalent in accordance with local standards; see Attachment 1 for 
conversion table) will be self-administered orally at a total dose of 40 mg weekly (ie, 20 mg on 
Days 1, 2, 8, 9, 15, and 16) during induction and consolidation cycles (Cycles 1-6); or at the start 
of consolidation [Cycle 5 Day 1], at the same dose that was tolerated at the end of induction 
treatment. For subjects in the D-RVd group, the dexamethasone 20 mg oral or IV (only if oral is 
not available) dose administered as a preinfusion medication on daratumumab infusion days 
(Days 1, 8, and 15) replaces the oral dexamethasone dose for that day. Dexamethasone will be 
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administered until the subject experiences disease progression or unacceptable toxicity during 
the induction/consolidation phase.
In the maintenance phase, dexamethasone, 20 mg orally (or IV), will be administered to subjects 
in the D-R group as a preinfusion medication prior to daratumumab.
After Cycle 4, the dose of dexamethasone may be reduced at the investigator’s discretion. The 
20-mg oral dose of dexamethasone given before the infusion on the day of daratumumab 
infusions must not be decreased. When dexamethasone is reduced to 20 mg/week and is given as 
preinfusion medication, subjects may receive low-dose methylprednisolone (≤20 mg) orally (or 
equivalent in accordance with local standards) for the prevention of delayed IRRs as clinically 
indicated.
Dexamethasone Toxicity 
For management of dexamethasone toxicity see Table 8. If dexamethasone is permanently 
discontinued due to toxicity, pre- and post-infusion doses administered on the day of 
daratumumab dosing for subjects in the D-RVd group may be given at the investigators 
discretion. This table represents suggested dose modifications of dexamethasone, but physician 
discretion and clinical judgment should prevail.
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Table 8:
Dexamethasone Dose Modification Based on Toxicity
NCI-CTCAE Category
Toxicity
Dose Change
Gastrointestinal
Grade 1-2 dyspepsia, gastric, 
or duodenal ulcer, gastritis 
requiring medical 
management
Treat with H2 blockers, sucralfate, or omeprazole. If 
symptoms persist despite above measure, decrease 
dexamethasone dose by 50%.
≥Grade 3 requiring 
hospitalization or surgery
Hold dexamethasone until symptoms adequately 
controlled. Restart at 50% of current dose along with 
concurrent therapy with H2 blockers, sucralfate, or 
omeprazole. If symptoms persist despite above 
measure, discontinue dexamethasone and do not 
resume.
Acute pancreatitis
Discontinue therapeutic dose of dexamethasone and 
do not resume.
Cardiovascular
≥Grade 3 edema limiting 
function and unresponsive to 
therapy or anasarca
Diuretics as needed and decrease dexamethasone dose 
by 25%. If edema persists despite above measures, 
decrease dose to 50% of initial dose. Discontinue 
dexamethasone and do not resume if symptoms persist 
despite 50% reduction.
Neurology/
Psychiatric
≥Grade 2 interfering with 
function but not interfering 
with activities of daily living
Hold dexamethasone until symptoms adequately 
controlled. Restart at 50% of current dose. If 
symptoms persist despite above measure, discontinue 
dexamethasone and do not resume. 
Musculoskeletal
≥Grade 2 muscle weakness 
symptomatic and interfering 
with function but not 
interfering with activities of 
daily living
Decrease dexamethasone dose by 25%. If weakness 
persists despite above measures, decrease dose to 50% 
of initial dose. Discontinue dexamethasone and do not 
resume if symptoms persist despite 50% reduction.
Metabolic
≥Grade 3 hyperglycemia
Treatment with insulin or oral hypoglycemic agents as 
needed. If uncontrolled despite above measure, 
decrease dose by 25% decrements until levels are 
satisfactory.
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events
7.
TREATMENT COMPLIANCE
Study drug (daratumumab) will be administered as an IV infusion by qualified staff and the 
details of each administration will be recorded in the case report form (CRF). Additional details 
are provided in the study site investigational product and procedures manual. Subjects will be 
provided with a diary to record intake of lenalidomide and dexamethasone; sites will use 
information to complete exposure information in the CRF.
8.
PRESTUDY AND CONCOMITANT THERAPY
The following prestudy therapies given at any time before first dose of study treatment must be
recorded at screening: steroids of any dose or duration given for multiple myeloma, or radiation 
therapy for multiple myeloma.
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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, 
Prohibited Therapies. The sponsor must be notified in advance (or as soon as possible thereafter) 
of any instances in which prohibited therapies are administered.
Systemic use of the following concomitant medications will be collected in the CRF 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 next-line anticancer treatment, if earlier: growth 
factors, transfusions, anti-infective medications (antibacterials, antivirals, and antimycotics), 
steroids, anti-arrhythmic medications and other cardiac supportive therapy, anti-epileptic 
medications, centrally acting psychiatric medications, anti-histamines and other medications 
targeting post-infusion systemic reactions, and any anticancer therapy (including radiation).
During the mobilization and stem cell transplantation procedures, concomitant medications 
related to the planned procedures do not need to be reported in the eCRF. However, concomitant 
medications related to the mobilization and transplantation procedures should be documented by 
providing a copy of the medication order set.
8.1.
Recommended Therapies
8.1.1.
Bisphosphonate Therapy
For subjects who have not previously received bisphosphonates, bisphosphonates are 
recommended for all subjects with evidence of lytic destruction of bone or with osteopenia. 
Bisphosphonate therapy is recommended to be continued per treatment guidelines.17,19
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. Investigators should use the same route of bisphosphonate therapy for 
all subjects at their sites. Subjects who are currently using bisphosphonate therapy when they 
enter the study should continue the same treatment. Subjects who are not using a bisphosphonate 
at the time of randomization should start a bisphosphonate as soon as possible. In addition, 
denosumab use is also permitted in this study.
8.1.2.
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Subjects who develop 
signs or symptoms of tumor lysis syndrome, including dehydration and abnormal laboratory test 
results such as hyperkalemia, hyperuricemia, and hypocalcemia, should be managed 
appropriately according to institutional guidelines and the investigator’s medical judgment. It is 
recommended that high-risk subjects (ie, those with a high tumor burden, or high lactate 
dehydrogenase and/or high uric acid level before the start of treatment) be treated 
prophylactically in accordance with local standards (eg, rehydration; diuretics; allopurinol 
300 mg daily and medication to increase urate excretion). Subjects are to be provided 
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prophylactic therapy to manage infusion reactions during the induction, consolidation, and 
maintenance treatment as described in Section 6.1.3.1, Preinfusion Medication.
8.1.3.
Prophylaxis for Bacterial Infection
Prophylaxis for bacterial infections should be considered per institutional guidelines, especially 
for subjects with a history of recurrent bacterial infections or severe hypogammaglobulinemia.
8.1.4.
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation should be given unless contraindicated. Acceptable 
antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times a day, or 800 mg given 
orally 2 times a day or per institutional standards), famciclovir (eg, 125 mg given orally, twice a 
day or per institutional standards), or valacyclovir (eg, 500 mg given orally, twice a day or per 
institutional standards), initiated within 1 week after the start of study treatment and continued at 
least through Cycle 6.
8.1.5.
Prophylaxis for Pneumonia
Prophylaxis for pneumonia is recommended during the first 2 cycles of study treatment. 
Antibacterial therapy with quinolones (or alternative if contraindicated) should be administered 
as per institutional guidelines.
8.1.6.
Therapy for Pneumocystis Carinii
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional 
guidelines.
8.1.7.
Prevention of Steroid Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are
permitted per institutional guidelines, for example proton pump inhibitors (omeprazole or 
equivalent) or sucralfate, or H2 blockers (ranitidine or equivalent).
8.2.
Permitted Therapies
In addition, subjects are to receive full supportive care. The following medications and 
supportive therapies are examples of support therapies that may be used at any time during the 
study:

Antiviral medications should be considered per institutional guidelines.

Colony stimulating factors, erythropoietin, and transfusion of platelets and RBCs. If 
erythropoietin is given, then this should be given according to the US prescribing 
information for lenalidomide and epoetin alfa, as there is an increased risk of thrombosis 
with lenalidomide.

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.
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
Intravenous immunoglobulin (IVIG) may be considered for subjects with recurrent infection 
related to hypogammaglobulinemia. 

Prophylactic antiemetics, with the exception of corticosteroids

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.
8.3.
Prohibited Therapies
Concomitant administration of any other antineoplastic therapy for the intention of treating 
multiple myeloma is prohibited, including medications that target CD38, as well as medications 
used for other indications that have anti-myeloma properties (for example, interferon). 
Continuation of study drug and components of the RVd regimen during or after emergency
orthopedic surgery or radiotherapy because of subject benefit may only occur in the absence of 
disease progression and after consultation with and approval 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 
within the first 2 cycles of treatment and the absence of evidence of disease progression is to be 
reviewed and approved by the sponsor.
During Cycle 1 of the safety run-in, the prophylactic use of hematopoietic growth factors is 
prohibited.
Concomitant participation in an interventional clinical trial(s) or use of investigational agent(s)
as well as medical devices 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 IRRs as described in 
Section 6.1.3.3, Management of Infusion-Related Reactions) should be avoided. Nonsteroidal 
anti-inflammatory agents should be avoided to prevent myeloma-related kidney disease. 
Typically, IV contrast is not used in 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.
Concomitant administration of the strong cytochrome P450 (CYP) 3A4 inhibitors 
(eg, ketoconazole, ritonavir) and inducers should be avoided and is not recommended with 
the use of bortezomib. If a strong CYP3A4 inhibitor must be given in combination with 
bortezomib, monitor subjects for signs of bortezomib toxicity and consider a bortezomib 
dose reduction. 
For
an 
ongoing 
list 
of 
CYP3A 
inhibitors 
and 
inducers, 
see 
http://medicine.iupui.edu/clinpharm/ddis/main-table/.
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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 study 
procedures and assessments applicable to this study.
Study assessments will be performed only after written informed consent is obtained. At each
visit, study assessments should be completed before the administration of any treatment. All 
PRO assessments should be conducted/completed before any tests, procedures, or other 
consultations to prevent influencing subject perceptions.
Throughout the study, 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. 
Due to the potential of birth defects or embryo-fetal death associated with the use of 
lenalidomide, investigators and subjects must adhere to the lenalidomide REMS program 
throughout the study; details are available at http://www.revlimidrems.com/.
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.
Medical resource utilization data will be collected. Refer to Section 9.7, Medical Resource 
Utilization for details.
The total blood volume for the study is approximately 700 mL. This includes laboratory 
assessments for safety, efficacy, pharmacokinetics/immunogenicity, and biomarkers. 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. Subjects 
who elect to receive daratumumab every 4 weeks during maintenance and/or the rapid infusion 
of daratumumab must sign an additional ICF prior to dosing. 
The screening phase begins when the ICF is signed. During the screening phase, eligibility 
criteria will be reviewed and a complete clinical evaluation will be performed. Screening 
procedures will be performed within 28 days before randomization; however, results of tests 
such as skeletal survey, radiologic tests (eg, MRI) to document baseline size of known or 
suspected extramedullary plasmacytomas; or chest X-rays) performed up to 6 weeks (42 days) 
before randomization may be used if these tests have been performed as part of routine follow-up 
for the subject’s disease. 
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A negative highly sensitive serum (-hCG) pregnancy test for women of childbearing potential 
must be documented within 10 to 14 days before the first dose and again within 24 hours before 
the first dose for Cycle 1 Day 1.
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 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.
9.1.3.
Induction/Consolidation Phase
Induction Treatment
Subjects who meet the entry criteria will be randomly assigned within 72 hours before the first 
dose on Cycle 1 Day 1 to receive either D-RVd or RVd alone. Subjects will receive four 21-day 
treatment cycles of induction treatment as detailed in Section 6, Dosage and Administration. 
Subjects who have confirmed disease progression will discontinue study treatment, have an EOT 
visit, and enter the long-term follow-up phase. Subjects may also discontinue study treatment 
due to occurrence of unacceptable toxicity or other reasons outlined in Section 10.2, 
Discontinuation of Study Treatment/Withdrawal From the Study.
Stem Cell Mobilization, High-Dose Chemotherapy, and Autologous Stem Cell 
Transplantation
After completion of Cycle 4 of induction treatment, subjects will undergo stem cell mobilization 
with G-CSF, with or without plerixafor. G-CSF and plerixafor should be administered according 
to institutional standards of dose and schedule. Use of cyclophosphamide is only allowed if 
G-CSF with or without plerixafor is not successful. Stem cell collection should be performed and 
stem cells frozen according to institutional standards. Subjects will then proceed to HDT and 
ASCT. 
Melphalan 200 mg/m2 should be used as the conditioning regimen which can either be given on a 
single day or divided into 2 days depending on local practice. A dose adjustment of melphalan 
(for renal failure or other co-morbidity) can also be considered per investigator discretion. 
Treatment with prophylactic antibiotics, G-CSF, and other supportive care, and laboratory testing 
during and in the post-ASCT phase should be per institutional standards. 
An assessment of the efficiency of harvesting will be recorded in the CRF (see Section 9.8, 
Safety Evaluations). During the mobilization and stem cell transplantation procedures, adverse 
events related to the planned procedures do not need to be reported, however any toxicity related 
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to daratumumab, lenalidomide, bortezomib, or dexamethasone exposure should continue to be 
reported. 
If the decision is made by the investigator not to pursue HDT and ASCT, subjects will be 
discontinued from study treatment, have an EOT visit, and then enter the long-term follow-up 
phase. Subjects who do not undergo HDT and ASCT will not receive consolidation or 
maintenance treatment on protocol.
Consolidation Treatment
Based upon initial randomization and as detailed in Section 6, Dosage and Administration an 
additional two 21-day cycles of either D-RVd or RVd will be given as consolidation treatment 
starting approximately 60 to 100 days after ASCT, when the subject has recovered sufficiently 
and engraftment is complete. 
Subjects will be evaluated for the primary endpoint (post-ASCT consolidation sCR).  MRD will 
be assessed by next-generation sequencing, regardless of treatment group, as detailed in the 
TIME AND EVENTS SCHEDULE. The post-ASCT consolidation disease evaluation should be 
performed the day after completion of C6D21 (+7-day window).
After the post-ASCT consolidation disease evaluation for the primary endpoint, subjects will 
enter the maintenance phase of the study based upon initial randomization.
Subjects who have confirmed disease progression will discontinue study treatment, have an EOT 
visit, and enter the long-term follow-up phase. Subjects may also discontinue study treatment 
due to occurrence of unacceptable toxicity or other reasons outlined in Section 10.2, 
Discontinuation of Study Treatment/Withdrawal From the Study.
9.1.4.
Maintenance Phase
The 24-month maintenance phase starts after assessment of the primary endpoint (post-ASCT 
consolidation disease evaluation for sCR). The timing of start of maintenance is at the discretion 
of the investigator, however, it should start within the 14 days following post-ASCT 
consolidation disease evaluation.
If Cycle 7 Day 1 is started within the 14 days following the post-ASCT consolidation disease 
evaluation, Cycle 7 Day 1 collection of MRU data and disease evaluations do not need to be 
repeated; other procedures will be performed as indicated in the TIME AND EVENTS 
SCHEDULE. Subjects will have study visits every 4 to 8 weeks in the D-R group dependent on 
when daratumumab is administered and every 8 weeks in the lenalidomide group. Subjects who 
signed the original ICF stating that daratumumab maintenance was to be administered every 
other month and who do not agree to the revised daratumumab maintenance administration every 
month will be permitted to receive daratumumab every other month. However, every effort 
should be taken to ensure that the subject understands the benefit of the monthly daratumumab 
maintenance schedule. Treatment will continue until disease progression, occurrence of 
unacceptable toxicity, or other reasons outlined in Section 10.2, Discontinuation of Study 
Treatment/Withdrawal From the Study. At the end of the maintenance phase or at the time of 
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treatment discontinuation, all subjects will have an EOT visit and then enter the long-term 
follow-up phase.
Following completion of the last cycle of the maintenance phase, subjects may continue 
lenalidomide as per local standard of care. The day of the EOT visit will be based on the last 
dose of study treatment in the maintenance phase. 
9.1.5.
End-of-Treatment
Subjects will receive study treatment through completion of the 24-month maintenance phase, or 
until confirmed disease progression, discontinuation of study treatment due to an unacceptable 
drug toxicity,
or other reasons outlined in Section 10.2, Discontinuation of Study 
Treatment/Withdrawal From the Study. Unless a subject withdraws consent for study 
participation, or is lost to follow-up, an EOT visit is to be scheduled 30 days (±7 days) after the 
last dose of all components of the study treatment have been discontinued, or as soon as possible 
before the start of next-line therapy. After completion of the EOT visit, subjects will enter the 
long-term follow up phase of the study.
9.1.6.
Long-Term Follow-Up Phase
All subjects will be followed in the long-term follow-up phase until at least 1 year after last dose 
of study treatment and will continue until death, withdrawal of consent for study participation, or 
the end of study definition is met. The end of study is defined as when all subjects have 
completed at least 1 year of long-term follow-up, or until death or withdrawal of consent for 
study participation, whichever occurs first. 
Subjects who enter the long-term follow-up phase before disease progression will return to the 
site every 12 weeks for disease evaluation, PRO assessments, and other follow-up assessments 
(ie, other malignancies, start of next-line therapy, and survival) until confirmed disease 
progression, death, the start of a new treatment for multiple myeloma, withdrawal of consent for 
study participation, or the end of study, whichever occurs first (see TIME AND EVENTS 
SCHEDULE). After confirmed disease progression or the start of a new treatment for multiple 
myeloma, subjects will return to the site or be contacted by telephone every 12 weeks for follow-
up assessments (ie, other malignancies, next-line therapy, PD on next-line therapy, and survival, 
as applicable) until death, withdrawal of consent for study participation, or the end of study, 
whichever occurs first. Following disease progression on the next-line therapy, subjects will only 
be followed for survival.
If the information on other malignancies, next-line therapy, PD on next-line therapy, and survival 
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 on the CRF.
Investigators may recontact the subject to obtain long-term follow-up information regarding the 
subject’s safety or survival status as noted in the ICF (refer to Section 16.2.3, Informed Consent).
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Subjects will be instructed that study drug (ie, daratumumab) will not be made available to them 
after they have completed/discontinued study drug and that they should return to their primary 
physician to determine standard of care.
9.2.
Efficacy Evaluations
Disease response and progression will be based on assessments according to the IMWG
Guidelines23 as defined in Section 9.2.1, Response Categories. Daratumumab detection on serum 
IFE has been demonstrated in subjects treated with 16 mg/kg and may interfere with the 
traditional IMWG criteria of negative serum IFE for CR or sCR. To mitigate this interference, 
the sponsor has developed a reflex assay that utilizes anti-idiotype antibody to bind 
daratumumab and confirm its interference on IFE (see laboratory manual). For all subjects in the 
D-RVd/D-R group with VGPR, a positive serum IFE, and a negative M-protein by SPEP, reflex 
IFE testing will be performed to confirm the presence of daratumumab on IFE. In addition, 
subjects who have an SPEP of ≤0.2 g/dL and IgG kappa myeloma, reflex testing will also be 
performed to determine whether the para-protein identified on SPEP/IFE is monoclonal 
daratumumab or the subject’s endogenous myeloma protein.
9.2.1.
Response Categories
Disease evaluations must be performed during the induction, consolidation phase and every 8 
weeks during the maintenance phase according to the TIME AND EVENTS SCHEDULE. Note 
that an additional disease evaluation occurs on Day 21 of Cycle 4 and the day after Day 21 of 
Cycle 6 (with a 7-day window) to assess end of Cycle 4 and end of Cycle 6 response, 
respectively. 
Disease evaluations will be performed by central and local laboratories (unless otherwise
specified) according to the TIME AND EVENTS SCHEDULE until disease progression. This 
study will use the IMWG consensus recommendations for multiple myeloma treatment response 
criteria presented in Table 9.14,22 For quantitative Ig, M-protein, and IFE measurements in serum 
and 24-hour urine, the investigator will use results provided by the central laboratory. Subjects 
with positive serum IFE and confirmed daratumumab IFE interference, that meet all other 
clinical criteria for CR or sCR, will be considered CR/sCR. 
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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 flow 
cytometry
Complete response 
(CR)b
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)b
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 FLC assay is also not 
measurable, ≥50% reduction in bone marrow PCs is required in place of M-protein, 
provided baseline bone marrow PC 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 PD
Progressive disease 
(PD)c
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 PC 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 or 2.8 mmol/L) 
that can be attributed solely to the PC proliferative disorder
Relapse from CR 

Any one or more of the following: Reappearance of serum or urine M-protein by 
immunofixation or electrophoresis. Development of ≥5% plasma cells in the bone 
marrow. Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone 
lesion, or hypercalcemia) 
FLC = free light chain; IMWG = International Myeloma Working Group; M-protein = monoclonal paraprotein; 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 documentation of 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.
Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 1 repeat investigation. Clinical 
judgment should prevail; however, repeat assessments after 1 to 3 weeks can be used as a general guideline.
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.
b
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.
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Table 9:
International Uniform Response Criteria Consensus Recommendations
c
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. 
Clinical Relapse
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria15,22 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; >2.875 mM/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.
Disease progression must be consistently documented across clinical study sites using the criteria 
in Table 9. Disease progression based on 1 of the laboratory tests alone must be confirmed by at
least 1 repeat investigation. Clinical judgment should prevail; however, repeat assessments after 
1 to 3 weeks can be used as a general guideline.
It is important that instances of disease progression be reported to the sponsor as soon as 
possible. Diagnosis and documentation of disease progression will be faxed within 24 hours to 
the sponsor (see Contact Information provided in the Investigator File). The medical monitor will 
review the form to confirm that the IMWG criteria for disease progression have been met. If the 
medical monitor agrees that disease progression has occurred, then a confirmation fax or email 
will be returned to the investigator, and the subject will be withdrawn from study treatment. If 
the medical monitor considers that the IMWG criteria for disease progression have not been met, 
then the medical monitor will contact the investigator to discuss the subject.
For continuation of treatment, the IMWG response will be determined and recorded 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 FLC assay test results will be analyzed by the central laboratory for the assessment of 
sCR, according to the most recently published IMWG criteria.14 Additionally, the absence of 
clonal plasma cells by immunohistochemistry, immunofluorescence or flow cytometry will be 
analyzed at the local laboratory as required for sCR. Morphology (aspirate and biopsy) will also 
be assessed at the local laboratory for clinical staging. For subjects who discontinue study 
treatment before disease progression, disease evaluations should continue to be performed as 
described in 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, 
or the end of study, whichever occurs first. Disease evaluations scheduled for treatment days 
should be collected before any study treatment is administered.
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9.2.2.
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples will be collected for serum quantitative Igs, serum and urine 
M-protein measurements, serum and urine IFE measurements, and serum FLC assay on Day 1
(24-hour urine samples can be completed or started on Day 1 and returned at the next visit), of 
Cycles 1 to 6, Day 21 of Cycle 4, post-ASCT consolidation disease evaluation, and EOT visit. 
During the maintenance phase, blood and 24-hour urine samples will be collected from all 
subjects for serum quantitative Igs and serum and urine M-protein measurements according to 
the TIME AND EVENTS SCHEDULE and for serum and urine IFE measurements and serum 
FLC assay whenever CR or sCR is suspected or maintained. For FLC-only subjects, without 
measurable disease in the serum or urine, blood and 24-hour urine samples for serum and urine 
IFE measurements and serum FLC assay will be collected according to the TIME AND 
EVENTS SCHEDULE. All samples will be sent to and analyzed by a central laboratory. Only 1 
serum and one 24-hour urine sample per time point as specified in the TIME AND EVENTS 
SCHEDULE are required by the central laboratory to perform the following tests:

Serum quantitative Igs

All subjects: IgG, IgA, IgM

For subjects with IgE or IgD myeloma: IgE or IgD

Serum M-protein quantitation by electrophoresis and serum IFE

If daratumumab interference is suspected based on SPEP and IFE results, additional 
reflex IFE testing will be performed

Serum FLC assay 

24-hour urine M-protein quantitation by electrophoresis (UPEP)

Urine IFE 
Blood and 24-hour urine samples will be collected until the development of confirmed disease 
progression. Disease progression based on 1 of the laboratory tests alone must be confirmed by 
at least 1 repeat investigation. Clinical judgment should prevail; however, repeat assessments 
after 1 to 3 weeks can be used as a general guideline. Disease evaluations will continue beyond 
relapse from CR until disease progression is confirmed. 
For subjects in the D-RVd/D-R group with VGPR and suspected daratumumab interference (see 
Section 9.2, Efficacy Evaluations), reflex serum IFE using the anti-idiotype monoclonal antibody 
will be used to confirm daratumumab migration on the IFE. Subjects that meet all other IMWG 
criteria for CR, and whose positive IFE is confirmed to be daratumumab, will be considered 
complete responders.
9.2.3.
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected and 
analyzed by the local laboratory until the development of confirmed disease progression. 
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 
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response criteria in Table 9). 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”). The formula for adjustment is presented in Attachment 5.
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.
9.2.4.
β2-microglobulin
A blood sample for β2-microglobulin will be collected at screening and will be analyzed by the 
central laboratory to determine the International Staging System stage.
9.2.5.
Bone Marrow Examination
Clinical staging of the bone marrow aspirate or biopsy will be performed and a portion of the 
bone marrow aspirate will be used to assess MRD and plasma clonality at the time points 
described in Table 10. 
During the bone marrow aspirate procedure, the first aspirate sample that is drawn will be sent to 
the central laboratory to determine MRD. The second aspirate sample will be sent to the local 
laboratory to determine plasma cell clonality. Additional bone marrow aspirate samples may be 
taken and used for local laboratory testing. Refer to the TIME AND EVENTS SCHEDULE for 
the time points of bone marrow aspirate collection.
9.2.6.
Minimal Residual Disease Assessment
At the time the original protocol was written, MRD assessment was a relatively new tool in the 
assessment of subjects with multiple myeloma. Some investigators have shown that MRD 
assessment is predictive of overall outcome in patients with myeloma.18,24 and several studies 
have demonstrated that MRD status is correlated with PFS and OS.16 In the present study, MRD 
will be assessed in bone marrow aspirate whenever a bone marrow sample is obtained as 
described below and in the TIME AND EVENTS SCHEDULE.
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Table 10:
Bone Marrow Testing Requirements
Study Time Point
Sample to be Collected
Local Laboratory 
Testing
Central Laboratory 
Testing
Screening
Bone marrow biopsy 
and aspirate
Cytogenetics
(FISH)a
PC clonality assay
(immunohistochemistry 
or immunofluorescence, 
or flow cytometry)
Morphology
(aspirate and biopsy)
MRD aspirateb
At the following times:
At first evidence of suspected CR or sCR 
(including subjects with VGPR or better)
After induction and before stem cell 
collection
Post-ASCT consolidation disease evaluation 
(+7-day window after Cycle 6 Day 21)
At 12 and 24 months (+/-3 weeks) during 
maintenance phase
Bone marrow aspirate
(The collection of an 
additional biopsy 
specimen is optional 
based on the site’s 
preference for PC 
clonality testing)
PC clonality assay
Morphology 
(aspirate)
MRD aspirate
ASCT = autologous stem cell transplantation; CR = complete response; FISH = fluorescence in situ hybridization; MRD = minimal 
residual disease; PC = plasma cell; sCR = stringent complete response; and VGPR = very good partial response.
a:
FISH testing to include del(1p), gain of 1q, del(17p), t(4;14), t(14;16), and t(14;20).
b:
May also be used to investigate markers of response, resistance and progression: a portion of the bone marrow aspirates (at least 
2 mL) 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 28 days prior to randomization, then diagnostic tissue such as non-decalcified bone marrow 
clot sections or bone marrow aspirate smears can be utilized for MRD assessment (characterization of MRD clone). 
9.2.7.
Assessment of Lytic Bone 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 during the screening phase. 
During the induction/consolidation and maintenance treatment phases and before disease 
progression is confirmed, x-rays should be performed whenever clinically indicated based on 
symptoms, to document response or progression. Magnetic resonance imaging and/or low dose 
CT-scan studies are acceptable methods for evaluation of bone disease and may be included at 
the discretion of the investigator; (see the disease response criteria in Table 9: International 
Uniform Response Criteria Consensus Recommendations). If an alternative imaging modality 
(MRI, CT) was used at screening in addition to the complete skeletal survey, then both methods 
must be used to document disease status. These tests must be performed at the same time.
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 imaging studies, depending on the symptoms that the subject experiences. If the 
diagnosis of disease progression is obvious by radiographic investigations, then no repeat 
confirmatory x-rays are necessary. In instances where changes may be more subtle, a repeat 
x-ray may be needed in 1 to 3 weeks.
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9.2.8.
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 IV 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. Assessment of measurable sites of extramedullary disease will be performed and 
evaluated locally for subjects with a history of plasmacytomas or as clinically indicated during 
treatment until development of confirmed CR or confirmed disease progression. If assessment 
can only be performed radiologically, then evaluation of extramedullary plasmacytomas must be 
performed according to the TIME AND EVENTS SCHEDULE. For every subject, the 
methodology used for evaluation of each disease site should be consistent across all visits. 
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: International Uniform 
Response Criteria Consensus Recommendations). 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.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations 
For all subjects who receive daratumumab (D-RVd during induction/consolidation and/or D-R 
during maintenance), blood samples will be collected according to the TIME AND EVENTS 
SCHEDULE to determine serum concentration of daratumumab as well as immunogenicity 
(anti-daratumumab antibodies). 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 
anti-daratumumab antibodies analysis [when appropriate], and 1 aliquot as a backup). Samples 
collected for determining serum concentrations of daratumumab and anti-daratumumab 
antibodies in this study may be retained to address questions about drug characteristics that may 
arise at a later time point. Genetic analyses will not be performed on these samples, and subject 
confidentiality will be maintained. 
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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. 
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
anti-daratumumab antibodies using validated immunoassay methods by or under the supervision 
of the sponsor’s bioanalytical facility. 
9.3.3.
Pharmacokinetic Parameters
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained 
from all subjects in the D-RVd and D-R groups. Pharmacokinetic endpoints include:

Minimum observed concentration (Cmin)

Maximum observed concentration (Cmax)
If sufficient data are available, then other pharmacokinetic parameters may be calculated. 
9.3.4.
Immunogenicity Assessments
Venous blood samples drawn from all subjects who receive daratumumab (D-RVd during 
induction/consolidation and/or D-R during maintenance) will be assessed for the generation of 
anti-daratumumab antibodies (immunogenicity), according to the TIME AND EVENTS 
SCHEDULE. Subjects who discontinue treatment will also be asked to return for 
immunogenicity evaluation during the long-term follow-up phase. 
All samples collected for immunogenicity analysis will also be evaluated for daratumumab 
serum concentration to ensure appropriate interpretation of immunogenicity data. At each time 
point, immunogenicity and serum daratumumab concentration analyses will be 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. 
Serum samples will be screened for antibodies binding to daratumumab and serum titer will also 
be determined from confirmed positive samples using validated assay methods by or under the 
supervision of the sponsor. Other immunogenicity analyses (eg, assessment of neutralizing 
capabilities) may be performed to further characterize the immune responses that are generated. 
A blood sample should be drawn, if possible, for determination of anti-daratumumab antibodies, 
at 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 
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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.
9.5.
Biomarkers 
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 TIME 
AND EVENTS SCHEDULE.
Biomarker evaluations will focus on the assessment of MRD. Minimal residual disease 
negativity is being evaluated in the field as a potential surrogate for PFS and OS. Minimal 
residual disease will be evaluated in subjects who achieve CR or sCR (including subjects with 
VGPR or better and suspected daratumumab interference) using next-generation sequencing 
which utilizes multiple myeloma cell DNA from bone marrow aspirates.9 If this methodology is 
unavailable, or determined to be scientifically inferior, then alternative methods for MRD 
assessment may be utilized. Baseline bone marrow aspirates will be used to define myeloma 
clones and samples collected as specified in the TIME AND EVENTS SCHEDULE will 
evaluate the depth of MRD. Baseline bone marrow aspirate samples will be subjected to DNA 
and RNA sequencing to establish the myeloma clone for MRD monitoring. In cases where 
daratumumab is suspected of interfering with IFE and preventing clinical CR calls, subjects with 
VGPR may also be evaluated for MRD. 
In addition to evaluating MRD, a whole blood sample will be collected from subjects, as outlined 
in the TIME AND EVENTS SCHEDULE, for processing to plasma and PBMCs and monitoring 
changes 
in 
immune 
cell 
subpopulations. 
The 
immune 
system-related 
parameters 
(immunophenotyping) to be analyzed may include the determination of the frequency and 
activity of immune effector cells including T cells (cytotoxic, regulatory, memory T cells 
subsets), B cells, NK cells (including activated NK cells), myeloid derived suppressor cells, 
macrophages, and dendritic cells, as these cells are involved in immune-mediated tumor lysis. 
The initial values of all these parameters and the relative changes during therapy will be 
correlated with the quality and the duration of CR. For these immune monitoring studies, flow 
cytometry and/or CyTOF may be performed. These immune profiles will be analyzed for 
associations with clinical data (quality of response, MRD status and depth, PFS, OS) as well as 
with multiple myeloma sequencing data. In addition to immunophenotyping, gene expression 
profiling of peripheral blood mononuclear cells for immune specific signatures, and T-cell 
receptor sequencing to examine clonal T-cell expansion may be examined to determine whether 
a specific immune signature or T-cell response may be associated with D-RVd response.
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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, EORTC QLQ-MY20, and the EQ-5D-5L 
instruments will be used. These 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. 
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 
multiple myeloma patients.36,37 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.
The EORTC QLQ-MY20 is a disease-specific validated instrument, which measures the 
symptom burden of multiple myeloma. The module contains 20 questions that measures 
4 myeloma-specific PRO domains: disease symptoms, side effects of treatment, future 
perspective, and body image. Three of the QLQ-MY20 domains are multi-item scales (disease 
symptoms, side effects of treatment, future perspective), while the body image scale contains a 
single-item that addresses physical attractiveness. Similar to the QLQ-C30, QLQ-MY20 domain 
scores are transformed to a 0 to 100 scale. A higher score on the disease symptoms and side 
effects of treatment scales represents a high level of symptom burden, and, in contrast, a higher 
score for future perspective and body image represents a more positive outcome.
An example of the EORTC QLQ-C30 and EORTC QLQ-MY20 is provided in Attachment 7.
The EQ-5D-5L is a standardized instrument for use as a 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).10 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. An example of the EQ-5D-5L is provided in Attachment 8.
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9.7.
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all subjects throughout the study at each 
time point as indicated in the TIME AND EVENTS SCHEDULE. Protocol-mandated 
procedures, tests, and encounters are excluded. The data collected may be used to conduct 
exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit)

Number and character of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications)
9.8.
Safety Evaluations
Safety will be measured by adverse events, laboratory test results, pregnancy tests, ECGs, vital 
sign measurements, physical examination findings, and ECOG performance status. Any 
clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF. During the mobilization and stem cell transplantation procedures, adverse 
events related to the planned procedures do not need to be reported, however any toxicity related
to daratumumab, lenalidomide, bortezomib, or dexamethasone exposure should continue to be 
reported. 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, IRRs/allergic reactions, hemolysis, and thrombocytopenia will be closely 
monitored. As a biologic agent, immunogenicity will also 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 DMC are provided in Section 11.12, Independent Data 
Monitoring Committee. Details regarding the Safety Run-in Data Review Committee are
provided in Section 11.13. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the TIME AND EVENTS SCHEDULE.
9.8.1.
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) for the duration of the study (ie, from the time a signed and dated informed 
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consent if 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.
9.8.2.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the CRF. The laboratory reports must 
be filed with the source documents.
At a minimum the following tests will be performed by the local laboratory, unless otherwise 
noted:

Hematology Panel
-hemoglobin
-RBC count
-white blood cell (WBC) count with absolute 
counts for neutrophils and 
lymphocytes
-platelet count

Serum Chemistry Panel
-sodium
-total bilirubin
-potassium
-creatinine and CrCla
-alkaline phosphatase
- BUN
-glucose
-calcium and albumin-adjusted calciumb
-aspartate aminotransferase (AST)
- albumin
-alanine aminotransferase (ALT)
-lactic acid dehydrogenase (screening only; sample to be sent to central laboratory)
a
Creatinine clearance can be either measured by 24-hour urine study, or estimated using a validated 
equation, such as the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease 
Epidemiology Collaboration (CKD-epi), or Cockcroft-Gault (Attachment 2).
b
These parameters will be part of the efficacy evaluations as specified in Section 9.2.3, Serum Calcium 
Corrected for Albumin.

Pregnancy testing

Cytogenetics (FISH)

PC Clonality (immunohistochemistry, immunofluorescence or flow cytometry)

Morphology of bone marrow aspirate or biopsy
9.8.3.
Pregnancy Testing (for women of childbearing potential only) 
Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Birth 
defects have been observed in preclinical studies of lenalidomide similar to thalidomide in 
humans. Therefore, strict monitoring for pregnancy must be conducted during screening,
throughout the study, and at the EOT visit as specified in the TIME AND EVENTS 
SCHEDULE. Highly sensitive serum (-hCG) pregnancy tests are required during screening and 
throughout the study; either a serum (-hCG) or urine pregnancy test may be performed at the 
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EOT visit. All pregnancy testing will be performed locally. Subjects (women of childbearing 
potential and men who are sexually active with a woman of childbearing potential) must adhere 
to the lenalidomide REMS program that can be accessed at http://www.revlimidrems.com/.
9.8.4.
Daratumumab Interference With Indirect Antiglobulin Test Results 
Blood Type, Rh, and IAT should be done before the first dose of daratumumab. Subject RBC 
phenotyping (standard or extended) is an alternative option to the IAT test, if locally required.  
Either method must be completed prior to first daratumumab infusion.
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 
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 an identification wallet card for the study 
that includes the blood profile (ABO, Rh, and IAT or phenotyping) 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 with IAT by treating reagent RBCs with dithiothreitol (DTT).6
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping prior to 
daratumumab administration) 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.
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 
Investigator’s Brochure for daratumumab.
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9.8.5.
Stem Cell Harvest
The following information will be recorded for each subject: target CD34 dose prior to 
collection, agents used for mobilization, total number of CD34+ cells collected, number of days 
required to collect stem cells, and hematopoietic engraftment information. During the 
mobilization and stem cell transplantation procedures, adverse events related to the planned 
procedures do not need to be reported, however any toxicity related to daratumumab, 
lenalidomide, bortezomib, or dexamethasone exposure should continue to be reported. 
Stem cell mobilization will be performed with G-CSF, with or without plerixafor. G-CSF and 
plerixafor should be administered according to institutional standards of dose and schedule. Use 
of cyclophosphamide is only allowed if G-CSF with or without plerixafor is not successful. Stem 
cell collection should be performed and stem cells frozen according to institutional standards. 
Subjects will then proceed to HDT and ASCT. 
9.8.6.
FEV1 Test
Subjects with known or suspected chronic obstructive pulmonary disease and asthma must have 
an FEV1 test during screening. Refer to Section 6.1.3.2, Postinfusion Medication for details on 
subjects with higher risk of respiratory complications.
9.8.7.
Electrocardiogram and Vital Signs
Electrocardiograms will be performed as specified in the TIME AND EVENTS SCHEDULE. 
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 (temperature, pulse/heart rate, respiratory rate, blood pressure) will be measured in 
the sitting position and recorded as specified in the TIME AND EVENTS SCHEDULE. It is 
recommended that blood pressure and pulse/heart rate measurements be preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).
9.8.8.
Physical Examination and ECOG Performance Status
Physical examinations will be performed on the day of the study treatment and ECOG 
performance status will be assessed as specified in the TIME AND EVENTS SCHEDULE. 
ECOG performance status (Attachment 3) will be used to evaluate the impact of the disease 
status on the activities of daily living.
9.9.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the CRF or laboratory 
requisition form. 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.
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Refer to the TIME AND EVENTS SCHEDULE for the timing and frequency of all sample 
collections.
Further 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, DISCONTINUATION OF STUDY TREATMENT, 
AND WITHDRAWAL FROMTHE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has died 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. 
10.2.
Discontinuation of Study Treatment/Withdrawal From the Study
Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if they have to discontinue 
treatment before the end of the treatment regimen.
A subject’s study treatment must be discontinued if:

The investigator believes that for safety or tolerability 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

Subjects with a history of HCV who completed treatment at least 6 months prior to 
screening, but who do not agree to undergo regular assessment for HCV reactivation during 
their participation in the study.

The subject experiences unacceptable toxicity, including IRRs as described in 
Section 6.1.3.3,
Management of Infusion-Related Reactions. For subjects whose 
daratumumab treatment is discontinued because of a daratumumab-related infusion reaction, 
they may continue to receive lenalidomide, bortezomib, and dexamethasone (as applicable 
depending on study phase). For subjects whose lenalidomide is discontinued because of a 
lenalidomide-related toxicity (eg, deep vein thrombosis), bortezomib and daratumumab 
treatment may be continued (as applicable depending on study phase). For subjects whose 
bortezomib is discontinued because of a bortezomib-related toxicity (eg, peripheral 
neuropathy), lenalidomide and daratumumab treatment may be continued.
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
The subject’s daratumumab dose is held for more than 28 days or if ≥3 consecutive planned 
doses are missed for reasons other than toxicity 

The subject experiences disease progression. Relapse from CR is not considered as disease 
progression.
If a subject discontinues study treatment for any reason before the end of the 
induction/consolidation phase or maintenance phase, EOT assessments should be obtained and 
posttreatment long-term follow-up scheduled assessments should be continued.
The primary reason for discontinuation of study treatment is to be recorded in the CRF. For 
subjects who discontinue study treatment due to disease progression, sites will complete a 
disease progression form and fax the form to the sponsor’s medical monitor. 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.
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

Death

Sponsor terminates the study

Subjects with a history of HCV who completed treatment at least 6 months prior to 
screening but who test positive for HCV at any time during the regular assessments 

The study investigator, for any reason, stops the subject’s participation in the study
If a subject withdraws from the study before the end of the induction/consolidation phase or 
maintenance phase, EOT assessments should be obtained.
If a subject is 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 before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
10.3.
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional Future Research). 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.
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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.
The primary analysis will be performed after all randomized subjects have completed the post-
ASCT consolidation disease evaluation or have been discontinued from study treatment by this 
time point. A second analysis will be performed after all randomized subjects complete the 
maintenance phase or have been discontinued from study treatment by this time point. A final 
data cutoff and analysis, to update secondary endpoints and safety, will occur at the end of study 
when all subjects have completed at least 1 year of long-term follow up, or until death or 
withdrawal of consent for study participation, whichever occurs first. 
All data, including efficacy and safety, from subjects enrolled in the safety run-in phase during 
the study will be summarized and presented separately from the randomized portion of the study 
(main study) using similar methods. 
11.1.
Subject Information
Analysis of primary and secondary efficacy variables will be based on the response-evaluable 
population, which includes all randomized subjects who have measurable disease, receive at 
least 1 dose of study treatment, and have at least 1 efficacy evaluation assessment.
All safety analyses will be based on the safety analysis set, which includes all randomized 
subjects who receive at least 1 dose of study treatment.
11.2.
Sample Size Determination
Historical data suggest that the post-consolidation sCR rate is approximately 35% for RVd
therapy. To detect an absolute 15% increase in post-consolidation sCR rate with 80% power 
using a 1-sided likelihood ratio test at the 10% significance level, 200 subjects need to be 
randomized with a 1:1 randomization ratio, assuming a 5% non-evaluable rate.
11.3.
Efficacy Analyses
Response to study treatment and progressive disease will be evaluated by a validated computer 
algorithm to calculate IMWG response. Rate of sCR achieved after post-ASCT consolidation 
will be tabulated. Treatment comparison will be made using the Cochran-Mantel-Haenszel test. 
The difference in post-ASCT consolidation sCR rate and its 2-sided 95% confidence interval will 
be provided. Other binary endpoints, including overall CR, sCR, ORR, VGPR, or better rate 
following induction, ASCT, post-ASCT consolidation, maintenance, and MRD-negative rate 
after consolidation, will be analyzed similarly. 
Time-to-event efficacy endpoints, such as duration of CR, sCR, TTP, PFS, OS, and time to next-
line anti-myeloma treatment, will be descriptively summarized using the Kaplan-Meier method. 
Except for duration of CR and sCR, treatment comparisons will be made via a log-rank test, and 
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treatment effects, measured by hazard ratios, will be estimated via a Cox regression model with 
treatment as the sole explanatory variable in the model. 
11.4.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population, 
defined as subjects who have received at least 1 dose of daratumumab and have at least 
1 postinfusion 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. 
Cmin is defined as the concentration observed immediately before infusion and Cmax is defined as 
the concentration observed at the end of infusion, as presented in the summary of serum 
concentration by sampling time point.
If sufficient data are available, then population pharmacokinetic
analysis of serum 
concentration-time data of daratumumab may be performed and may include data from other 
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.
11.5.
Immunogenicity Analyses
The incidence of anti-daratumumab antibodies (immunogenicity) will be summarized for all 
subjects who receive a dose of daratumumab and have appropriate samples for detection of 
anti-daratumumab antibodies. In addition, subjects who are positive for antibodies to 
daratumumab will be listed. 
11.6.
Pharmacokinetic/Pharmacodynamic Analyses 
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. Details and 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 and to monitor subjects for MRD. Analyses will be stratified by clinical covariates 
using the appropriate statistical methods (eg, parametric or non-parametric, univariate or 
multivariate, analysis of variance [ANOVA], 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 following treatment 
with daratumumab. 
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Any biomarker measurements will be listed, tabulated, and where appropriate, plotted. As this is 
an open-label study with an active control treatment, statistical analyses will be done to aid in the 
understanding of the results. 
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.
11.8.
Medical Resource Utilization Analyses
Medical resource utilization will be descriptively summarized by treatment group. Additional 
analyses may be conducted; details and results of any additional analyses will be presented in a 
separate report.
11.9.
Patient-Reported Outcomes
EORTC QLQ-C30 and QLQ-MY20 domain scores and EQ-5D-5L scores will be descriptively 
summarized by treatment group at each time point as indicated in the TIME AND EVENTS 
SCHEDULE.
11.10. Safety Analyses
During the safety run-in phase for D-RVd, DLTs in Cycle 1 will be monitored in cohorts of 
4 subjects, after first 8 subjects have completed Cycle 1 or discontinued due to DLT, using the 
Bayesian approach of Thall, Simon, Estey31,32 as extended by Thall and Sung.33 The prior 
probability of DLT in Cycle 1 for the D-RVd regimen is modeled by beta distribution 
(Beta(0.25, 0.75)). This distribution has the same mean as the maximum acceptable DLT in 
Cycle 1 of 0.25, and an Effective Sample Size of 1. The decision criteria applied will be to stop if 
Prob{p(DLT) >0.25| data}>0.95; ie, the posterior probability of the unknown DLT rate being 
>0.25 given the observed data is more than 0.95.
Subjects will be monitored according to the following stopping boundaries for DLT.
Stop the study if there are this many toxicities total:
Number of Subjects 
(in complete cohorts of 4)
Number of Toxicities
8
≥5
12
≥6
16
≥8
Adverse Events
The verbatim terms used in the CRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse 
events are adverse events with onset during the induction/consolidation or maintenance treatment 
phase or that are a consequence of a pre-existing condition that has worsened since baseline. All 
reported adverse events 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 
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treatment group. In addition, comparisons between treatment groups will be provided if 
appropriate.
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. These will be provided using the same formats as those used for 
adverse events.
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 posttreatment cross-tabulations (with classes for 
below, within, and above normal ranges). Worst toxicity grade during treatment will be 
presented, according to NCI-CTCAE (version 4.03). 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.
Stem Cell Harvest
Descriptive statistics of the number of planned ASCTs, agents used for mobilization, total 
number of CD34+ cells collected, number of days required to collect stem cells, and 
hematopoietic engraftment information will be summarized by treatment group.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point. The percentage of subjects with values beyond clinically important limits will be 
summarized.
Electrocardiogram data will be summarized by vital signs parameters (temperature, pulse/heart 
rate and blood pressure (systolic and diastolic). Descriptive statistics will be calculated at 
baseline and for observed values and changes from baseline at each scheduled time point. 
Frequency tabulations of the abnormalities will be made.
11.11. Interim Analysis
If the study is not stopped due to DLTs in the safety run-in phase, one interim safety analysis is 
planned for the safety run-in cohort after all subjects are treated for at least 4 cycles or 
discontinue study participation.
One interim safety analysis is planned for the main study. The interim safety analysis will occur 
after at least 50 subjects are treated for at least 4 cycles and undergo stem cell mobilization (or 
are evaluated for mobilization feasibility) in the main study.
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An independent Data Monitoring Committee (DMC) as described in Section 11.12, Independent 
DMC will be established to review the interim results in the main study.
11.12. Independent Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in the main study. The committee will meet 
periodically during the main study to review interim safety data and will also perform the 
predetermined interim safety analysis in the main study as detailed in Section 11.11, Interim 
Analysis. After the review, the DMC will make recommendations regarding the continuation of 
the main study. The details will be provided in a separate DMC charter.
The DMC will consist of at least 2 medical experts in the relevant therapeutic area and at least 
1 statistician. The DMC responsibilities, authorities, and procedures will be documented in its 
charter.
11.13. Safety Run-in Data Review Committee
A Safety Run-in Data Review Committee will be established to review safety data after 8, 12, 
and 16 subjects in the safety run-in phase complete Cycle 1 (or discontinue before the end of 
Cycle 1) and will use stopping boundaries described in Section 11.10, Safety Analyses. The 
Safety Run-in Data Review Committee will consist of the sponsor’s medical monitor, a sponsor 
physician who is not involved in the study, a sponsor statistician who is not involved in the 
study, and a medical safety representative.
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]).
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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).
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 any component of 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 in the Investigator’s Brochure. For 
lenalidomide, bortezomib, and dexamethasone with a marketing authorization, the expectedness 
of an adverse event will be determined by whether or not it is listed in the respective prescribing 
information.7,25,35
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, Attribution Definitions.
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12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
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 4.03. Any adverse event or serious adverse event not listed in the 
NCI-CTCAE Version 4.03 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).
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12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational 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)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the CRF.
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 any 
component of the study treatment, until the subject withdraws consent for study participation or 
is lost to follow-up, or until the subject starts next-line anticancer therapy, whichever occurs first. 
The only exceptions are for subjects who have withdrawn informed consent for study 
participation or for subjects who have received additional treatment with therapeutic intent for 
multiple myeloma within 30 days after the last administration of any component of the study 
treatment. For subjects who have received additional 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 any component of the study treatment
must be reported (unless the subject has been withdrawn from the study). Serious adverse events, 
including those spontaneously reported to the investigator within 30 days after the last dose of 
any component of the study treatment and those that are considered related to daratumumab 
within the long-term follow-up phase, must be reported using the Serious 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.
During the mobilization and stem cell transplantation procedures, adverse events related to the 
planned procedures do not need to be reported, however any toxicity related to daratumumab, 
lenalidomide, bortezomib, or dexamethasone exposure should continue to be reported.
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, Adverse Event Definitions and Classifications).
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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. 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.
All adverse events, regardless of seriousness, severity, or presumed relationship to any 
component of the study treatment, must be recorded using medical terminology in the source 
document and the CRF. 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 "upper respiratory infection"). Investigators must record in the 
CRF 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). The 
investigator (or sponsor where required) must report SUSARs 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 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

Subject’s blood type
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 has not experienced a significant medical event but is hospitalized overnight 
only for observation following infusion of daratumumab, then the hospitalization should not 
be reported as a serious adverse 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 CRF). 
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 be promptly withdrawn from the study and discontinue 
further study treatment. The subject should be referred to a physician experienced in teratology 
for evaluation and advice. Investigators should follow the local label for guidance on subject 
education and ensure that all subjects adhere to the lenalidomide REMS program that can be 
accessed at http://www.revlimidrems.com/.
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Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required. 
12.4.
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 in 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 (ie, daratumumab in 
this study) 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 as a liquid vial. It will be manufactured and provided under the responsibility of the
sponsor. Refer to the Investigator’s Brochure for a list of excipients.
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14.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL. 
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
Daratumumab product must be stored in the original carton in a refrigerator at controlled 
temperatures ranging from 2°C to 8°C. Daratumumab must not be utilized after the expiry date 
printed on the label. The daratumumab 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.
Refer to the study site investigational product and procedures manual for additional guidance on 
study drug preparation, handling, and storage.
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 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. Returned study drug must not be dispensed again, even to 
the same subject. 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.
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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator’s Brochure for daratumumab

Study site investigational product and procedures manual

Laboratory manual

NCI-CTCAE Version 4.03

PRO questionnaires (electronic or paper, as appropriate) 

Electronic Data Capture (eDC) Manual

Sample ICF

Subject diaries
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Based on the potential IRRs associated with administration of daratumumab, guidelines for 
prevention and management of IRRs are provided (see Section 6.1.3). 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. No bleeding 
events were observed. Anemia was also reported in Study GEN501. Free hemoglobin was mildly 
elevated, but other parameters did not support hemolysis. Routine safety laboratory measurement 
of RBCs and platelets will be closely monitored in this study.
All subjects will be receiving RVd for multiple myeloma in this study. Refer to Section 1.1.6, 
Combination Therapy: Daratumumab-Lenalidomide-Bortezomib-Dexamethasone regarding the 
use of daratumumab in combination with RVd in newly diagnosed patients with multiple 
myeloma who are eligible for ASCT.
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 to be collected is considered to be acceptable for subjects participating in 
a cancer clinical study and reasonable (eg, less than the standard blood donation [500 mL over 
60 days]3) over the time frame of the study.
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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, unless required locally), 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).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. 
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, which includes permission to obtain information about 
his or her survival status. It also denotes that the subject agrees to allow his or her study 
physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations and subsequent disease-related treatments, if needed. 
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.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
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.
Note that per Protocol Amendments 2 and 3, subjects who elect to receive daratumumab every 
4 weeks instead of every 8 weeks during the maintenance phase and/or who elect to receive the 
rapid infusion of daratumumab, must sign a new ICF prior to the change in daratumumab 
administration.
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.
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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-
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 DNA, pharmacodynamics, biomarker, and 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 Use of Research Samples.
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/IEC (where required) only needs to be notified.
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 listed in the Contact Information page(s), which will be provided as a separate
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document). 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 CRF 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 Prestudy 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
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)
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
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. In cases where the subject is not randomized into the study, the date seen and 
date of birth 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 documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care, must be available for the 
following: 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 drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Subject-completed scales and assessments designated by the sponsor (EORTC QLQ-C30,
EORTC QLQ-MY20, and EQ-5D-5L) will be recorded directly into an electronic device and will 
be considered source data.
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:
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
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 prepared and provided by the sponsor for each subject in electronic format. 
All data relating to the study must be recorded in CRF. All CRF entries, corrections, and 
alterations must be made by the investigator or authorized study-site personnel. The investigator 
must verify that all data entries in the CRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor. 
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any 
such worksheets will become part of the subject’s source documents. Data must be entered into 
CRF in English. The CRF must be completed 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. 
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after 
the initial entry into the CRF, this can be done either of the following ways:

Investigator and 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).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
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, and direct 
transmission of clinical laboratory data from a central laboratory and electronic PRO data from 
the vendor into the sponsor’s data base. Written instructions will be provided for collection, 
handling, storage, and shipment of samples. 
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Guidelines for CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review CRF 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 CRF 
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.
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 CRF with the source documents (eg, 
hospital/clinic/physician’s office medical records). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the 
CRF 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. 
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Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review 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 documents 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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed once all subjects have completed at least 1 year of long-term 
follow up, or until death or withdrawal of consent for study participation, whichever occurs first. 
The final data from the study site will be sent to the sponsor (or designee) after completion of the 
final subject visit 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
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. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
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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 data from all study sites that participated in the study as per protocol. 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. 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.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors 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 
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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 12 months of the availability of the final data (tables, 
listings, graphs), 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 Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Barr H, Dempsey J, Waller A, et al. Ninety-minute daratumumab infusion is safe in multiple myeloma. 
Leukemia. 2018;epub. 
2.
Basch E, Prestrud AA, Hesketh PJ, et al. American society of clinical oncology guideline for antiemetics in 
oncology: update. J Clin Oncol. 2011;29:4189-4198.
3.
Blood facts and statistics. American Red Cross Web site. http://www.redcrossblood.org/learn-about-
blood/blood-facts-and-statistics#donation-process. Accessed October 26, 2015.
4.
Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd ed. Philadelphia; WB Saunders, 1998.
5.
Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the 
treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 
2011; 117: 6063–6073. 
6.
Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood 
compatibility testing. Transfusion. 2015;55:1545-1554.
7.
Dexamethasone prescribing information. Drugs.com Web Site. 
http://www.drugs.com/pro/dexamethasone.html. Accessed September 3, 2015.
8.
Dimopoulos MA, Richardson PG, Schlag R, et al. VMP (bortezomib, melphalan, and prednisone) is active and 
well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, 
and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 
2009;27(38):6086-6093.
9.
Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in 
acute lymphoblastic leukemia. Blood. 2012;120(26):5173-5180. 
10.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of 
the EQ-5D (EQ-5D-5L). Qual Lif Res. 2011;20:1727-1736.
11.
Kapoor P, Kumar SK, Dispenzieri A, et al. Importance of achieving stringent complete response after 
autologous stem-cell transplantation in multiple myeloma. J Clin Oncol. 2013;31(36):4529-4535.
12.
Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J 
Hematol Oncol. 2009;2:36.
13.
Krejcik J, Casneuf, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell 
expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-394.
14.
Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response 
and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328-346.
15.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple 
myeloma. Leukemia. 2009;23:3-9.
16.
Martinez-Lopez, J, Lahuerta, JJ, Pepin, F, et al. Prognostic Value Of Deep Sequencing Approach For Minimal 
Residual Disease (MRD) Detection In Multiple Myeloma Patients. Blood 2013;122:1848.
17.
Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Annals Oncol. 2013;00:1–5.
18.
Munshi N, Anderson, K. Minimal residual disease in multiple myeloma. JCO. 2013;31:2523-2526.
19.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines): Multiple Myeloma, version 2.2014. Fort Washington, PA: National Comprehensive Cancer 
Network; 2013.
20.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5(6):649-655.
21.
Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-1060.
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22.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for 
the diagnosis of multiple myeloma. Lancet Oncol 2014;15:e538-548.
23.
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.
24.
Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow 
cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. 
J Clin Oncol. 2013;31(20):2540-2547.
25.
Revlimid® (lenalidomide) prescribing information. Celgene Corporation; Summit NJ, USA. February 2015.
26.
Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy 
in patients with newly diagnosed multiple myeloma. Blood. 2010;116(5):679-686.
27.
Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, 
bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide 
maintenance in patients with multiple myeloma: a Phase II study by the Intergroupe Francophone du Myélome. 
J Clin Oncol. 2014;32(25):2712-2717.
28.
Sonneveld P, Goldschmidt H, Rosiñol 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(26):3279-3287.
29.
Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell 
adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008 Aug 
15;112(4):1329-1337.
30.
Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC 5013, IMiD3) augments anti CD40 
SGN 40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005 Dec 
15;65(24):11712-11720.
31.
Thall PF, Simon R, Estey EH. Bayesian sequential monitoring designs for single-arm clinical trials with 
multiple outcomes. Stat Med. 1995;14:357-379.
32.
Thall PF, Simon R, Estey EH. New statistical strategy for monitoring safety and efficacy in single-arm clinical 
trials. J Clin Oncol. 1996;14:296-303.
33.
Thall PF, Sung HG. Some extensions and applications of a Bayesian strategy for monitoring multiple outcomes 
in clinical trials. Stat Med. 1998;17:1563-1580.
34.
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. 2011b;1 e41.
35.
Velcade® (bortezomib) prescribing information. Millennium Pharmaceuticals, Inc. Cambridge MA, USA; 
2014.
36.
Wisloff F, Erika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Br J 
Hematol. 1996;92:604-613.
37.
Wisloff F, Hjorth M. The Nordic Myeloma Study Group. Health-related quality of life assessed before and 
during chemotherapy predicts for survival in multiple myeloma. Br J Hematol. 1997;97:29-37.
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ATTACHMENTS
Attachment 1:
Conversion Table for Glucocorticoid Dose
Generic Name
Oral or Intravenous
Dose (mg)
Dexamethasone
0.75
Hydrocortisone
20
Methylprednisolone
4
Prednisolone
5
Prednisone
5
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Attachment 2:
Calculated Creatinine Clearance
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault 
formula:
CrCl =
(140 - age [in years]) x weight (kg)
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, µmol/L), use 
the following formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory 
& Diagnostic Tests, 2004):
•
serum creatinine (µmol/L) divided by 88.4 = serum creatinine (mg/dL).
Modification of Diet in Renal Disease (MDRD)
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
Alternatively, creatinine clearance may be calculated or measured according to the MDRD 
(Levey 2006) or the CKD-EPI (Levey 2009). 
For online calculators, please go to https://www.kidney.org/professionals/KDOQI/gfr_calculator.
References:
Levey AS, Coresh J, Greene T, et al.  Using standard serum creatinine values in the modification of diet 
in renal disease study equation for estimating glomerular filtration rate.  Ann Intern Med. 2006;145:247-
254.
Levey AS, Stevens LA, Scmid CH, et al.  A new equation for estimating glomerular filtration rate.  Ann 
Intern Med. 2009;150:604-612.
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Attachment 3:
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 selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
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Attachment 4:
Guideline for Asthma Eligibility Criteria
Components of
Severity
Classification of Asthma 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
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
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.
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 
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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Attachment 5:
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 CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd ed. Philadelphia; WB 
Saunders, 1998.
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Attachment 6:
Standard Nomogram for Calculation of Body Surface Area
The body surface area (BSA) should be calculated using the standard calculation given below. However, 
the DuBois Formula can be used as an alternative to calculate BSA.
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Attachment 7:
EORTC QLQ-C30 and EORTC QLQ-MY20
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Attachment 8:
EQ-5D-5L
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Attachment 9:
Protocol Amendments 1 and 2
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
4 April 2016
Amendment 1
24 May 2017
Amendment 2
5 Feb 2018
Amendment 2 (5 Feb 2018)
The major reasons for this amendment are to revise the daratumumab dosing schedule during the Maintenance 
Phase (based on new information), to update background information, and to revise the instructions for various 
study procedures as needed, for clarity or improved patient safety.
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Section(s)
Description of Change(s)
Rationale:  Daratumumab administration is being changed from every 8 weeks to every 4 weeks during the 
Maintenance phase based on pharmacokinetic results from Study SMM2001 in smoldering multiple myeloma 
showing that dosing every 8 weeks is insufficient to maintain target daratumumab saturation. To align with this new 
finding and to improve clarity, the Time and Events Schedule was revised to have separate schedules for each 
treatment group (Daratumumab-RVd/D-R and RVd/lenalidomide). Changes to the Time and Events Schedule for D-
RVd (eg, in response and disease evaluations, laboratory tests, etc) reflect the new dosing regimen during the 
Maintenance Phase. 
The RVd/lenalidomide Time and Events Schedule has all of the relevant changes that the D-RVd/D-R Time and 
Events Schedule has; for consistency, the footnote identifiers were kept the same in both Schedules, resulting in 
some being left blank in the RVd Time and Events Schedule.
D-RVd Time and Events 
Schedule, Study Drug 
Dosing Schedule, and 
throughout protocol as 
appropriate
To reflect every 4 week (q4w) dosing for the D-R group during the Maintenance 
Phase, ECOG performance status, physical examinations, weight and vital signs, 
hematology and serum chemistry tests, and MRU evaluations now to be done on 
Day 1 of each cycle. Medications to be given prior to daratumumab infusions 
during the Maintenance phase are also reflected in the Study Drug Dosing 
Schedule. 
Rationale:  Text regarding daratumumab informed consent for the new maintenance dosing schedule was added. 
Study Drug Dosing 
Schedule; 
Section 6.1.2 Treatment 
Schedule and 
Administration; 2nd
paragraph; Section 9.1.4 
Maintenance Phase; 2nd
paragraph
Subjects who signed the original ICF stating that daratumumab maintenance 
was to be administered every other month and who do not agree to the 
revised daratumumab maintenance administration every month will be 
permitted to receive daratumumab every other month. However, every effort 
should be taken to ensure that the subject understands the benefit of the 
monthly daratumumab maintenance schedule.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
139
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale: In order for subjects to receive the correct, weight-based daratumumab dose, a requirement to check 
subject weight on all daratumumab dosing days was added. Similarly, a requirement to check and adjust weight was
made for bortezomib dosing.
Section 6.1.2 Treatment 
Schedule and 
Administration, 1st
paragraph, new 3rd
sentence (and Time and 
Events Schedule)
Section 6.3, Bortezomib 
(and Time and Events 
Schedule)
… The dose of daratumumab will remain constant throughout the study unless the 
subject’s weight changes more than 10% from Cycle 1 Day 1…. Subject’s weight 
will be recorded on all daratumumab dosing days…
The amount (in mg) of bortezomib to be administered will be determined by body 
surface area, calculated according to a standard nomogram (Attachment 6). Each 
subject’s dose will be calculated based on the subject’s weight at Cycle 1 
Day 1 rounded to the nearest kilogram. The dose should be readjusted if 
weight changes >10% from value on C1D1.The total calculated dose…
Rationale:  For both groups, the window for the start of each cycle during consolidation was changed from 7 days 
to 14 days to be consistent with dose delays during the consolidation phase specified in Table 3 (Daratumumab-
Related Toxicity Management).
Throughout protocol as 
appropriate
The start of each cycle may occur within… ±714 days (consolidation)…
Rationale:  Several clarifications were made to both groups’ Time and Events Schedules (for laboratory 
assessments and PROs), as listed below.
(Both) Time and Events 
Schedules:
Laboratory assessments
PRO Assessments and 
MRU
For D1 of Cycles 1-6, the following 2 central laboratory kits must be 
completed: assessment kit and disease evaluation kit.
The PRO assessments should be performed before any other study procedures 
scheduled for the same day. The initial set up of the PRO device and 
administration of the first questionnaire for each subject are to be completed 
on C1D1 (and subsequent D1 visits) before any study-specific procedures are 
performed. 
(Under Cycles 5-6) C5 only (added for PROs)
Rationale: In both Time and Events Schedules, clarification was made for the extramedullary plasmacytoma row.  
Under Consolidation
(Cycles 5-6)
C5 only
Rationale:  Additional instructions for Montelukast dosing were added.
Study Drug Dosing 
Schedule, 
Daratumumab; 
Section 6.1.3.1 
Preinfusion Medication
Montelukast 10 mg/day PO, day before and the day of infusion; may be omitted 
after the second infusion if the subject has no respiratory symptoms. Montelukast 
10 mg/day PO, at C1D1 approximately 1 hour or less before the 
daratumumab infusion. An additional 10 mg PO can be given the day before 
infusion at the discretion of the investigator. May be omitted for any 
daratumumab dose after the second infusion if the subject has no respiratory 
symptoms.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
140
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  In Section 1 (Introduction), the background information for daratumumab was brought up to date.
Paragraph 1, revised 
from 2nd sentence 
through the end of the 
paragraph and 
corresponding update to 
reference list
Paragraph 2, last 
sentence added
Section 1.1.2, text for 
nonclinical, and clinical 
efficacy and 
pharmacokinetic results 
and Table 1 (safety 
information) were 
updated to reflect the 
most recent data.
Daratumumab can induce complement dependent cytotoxicity, antibody dependent 
cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, direct 
apoptosis after cross-linking, and can modulate CD38 enzymatic activity. CD38 is 
highly expressed on myeloma cells, but is expressed at relatively low levels on 
normal lymphoid and myeloid cells and in some tissues of non-hematopoietic 
origin, making it a relevant target for the treatment of multiple myeloma. The 
mechanisms of action of daratumumab comprise immune-mediated effects, 
including complement-dependent cytotoxicity, antibody-dependent cell-
mediated cytotoxicity, antibody-dependent cellular phagocytosis, and 
apoptosis by means of cross-linking. Moreover, daratumumab also induces 
immunomodulatory effects via several different pathways that contribute to 
killing CD38+ immune cells that modulate T cell activity, namely myeloid-
derived suppressor cells (MDSC) and regulatory T (TReg), and B (BReg) cells 
(Krejcik 2016).12 Daratumumab’s converging mechanisms of actions are 
hypothesized to lead synergistically to the deep responses observed in patients 
with multiple myeloma.
In June 2017, the US FDA approved daratumumab in combination with 
pomalidomide and dexamethasone for the treatment of patients with 
multiple myeloma who have received at least 2 prior therapies including 
lenalidomide and a proteasome inhibitor.
12.
Krejcik J, Casneuf, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell 
expansion, and skews T-cell repertoire in multiple myeloma. BLOOD. 2016;128:384-394.
(Refer to current body of the protocol for the most up to date information)
Rationale:  Since RVd is no longer the standard of care for multiple myeloma, text was revised accordingly.
General change made 
throughout the protocol 
as appropriate
RVd (standard of care)
Rationale:  The language pertaining to lenalidomide use after the maintenance phase was clarified.
General change made 
throughout the protocol 
as appropriate
Following completion of the last cycle of the maintenance phase, subjects will
may continue lenalidomide as per local standard of care.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
141
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  Clarifications were made to text summarizing the study design.
Section 3.1 (Overview of 
Study Design)
5th paragraph, 2nd
sentence
4th to last paragraph, last 
sentence
2nd to last paragraph, 2nd
sentence (Note, a similar 
change was made in the 
synopsis)
Figure 3 was revised for 
clarity, and to show the 
new q4Wk 
daratumumab dosing 
during the Maintenance 
Phase. The increased 
dose of lenalidomide 
beginning at Cycle 10 
applies to both treatment 
groups.
Subjects who experience a DLT during the safety run-in will be withdrawn from 
the study (based on investigator’s judgment and best clinical practice).
Secondary endpoints include overall CR and sCR rate, ORR, VGPR, duration of 
response, negative MRD rate, time to response, TTP, PFS, OS, safety and 
tolerability, PROs, stem cell yield after mobilization, and time to engraftment after 
ASCT.
…One planned interim safety analysis will occur after at least 50 subjects are 
treated for at least 4 cycles and undergo stem cell mobilization (or are evaluated 
for mobilization feasibility) in the main study or have discontinued before 
completing 4 cycles / stem cell mobilization / feasibility. Refer to Section 11.12, 
Independent Data Monitoring Committee for details.
Daratumumab: 16 mg/kg IV every 4 weeksevery 8 weeks (on day 1 of odd cycles (ie, 7, 9, 11, etc))
Lenalidomide: 10 mg PO on Days 1-21.  
Beginning at Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a 
tolerability concern
   
Rationale:  Text for concomitant medications to be recorded during mobilization and stem cell transplantation were 
clarified.
Time and Events 
Schedules (both), row 
for Concomitant 
Medications; Section 8, 
Prestudy and 
Concomitant Therapy, 
4th paragraph
During the mobilization and stem cell transplantation procedures, 
concomitant medications related to the planned procedures do not need to be 
reported in the eCRF. However, concomitant medications related to the 
mobilization and transplantation procedures should be documented by 
providing a copy of the medication order set.
Rationale:  Text regarding dexamethasone administration for the lenalidomide group was deleted to align with 
evolving standard of care for maintenance therapy.
Synopsis, Dosage and 
Administration; 
Section 3.1, Overview of 
Study Design; and 
Section 6.4, 
Dexamethasone
To prevent administration of dexamethasone from being a confounding factor, 
subjects in the lenalidomide group will also have dexamethasone 20 mg 
administered orally on Day 1 of odd cycles.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
142
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  Text describing the analysis of immune cells was clarified.
Section 3.2.3 (Rationale 
for Pharmacokinetics, 
Immunogenicity, and 
Biomarker Evaluations) 
3rd paragraph, 3rd
sentence
Immunophenotyping may include analysis of NK cells (including activated NK 
cells), T cells (cytotoxic, regulatory, memory T cells subsets), B cells, MDSC, 
macrophages, and dendritic cells, as these cells are involved in immune-
mediated tumor lysis. Samples may be used to evaluate specific subsets of 
immune cells….
Rationale:  Several entry criteria were clarified in Sections 4.1 (Inclusion Criteria) and 4.2 (Exclusion Criteria, as 
well as the Time and Events Schedule).
Inclusion criterion No. 1
Exclusion criterion No. 
1 2nd bullet
Exclusion criterion No. 
4, under the “Note:”. 
A similar clarification 
regarding asthma was 
made in Section 9.8.6 
FEV1 Testing
Exclusion criterion No. 
5, under the “Note:”
1. 18 to 70 years of age, inclusive at study entry.
      1.
diagnosed or treated for malignancy other than multiple myeloma, except:

Malignancy treated with curative intent and with no known active disease 
present for ≥3 years before randomization.

Adequately treated non-melanoma skin cancer, lentigo maligna or in situ 
malignancies (including but not limited to cervical, breast) with no evidence 
of disease.
4. Note: FEV1 testing is required for subjects suspected of having chronic 
obstructive pulmonary disease and asthma. Subjects must be excluded if FEV1 
<50% of predicted normal.
5. Note: Subjects who currently have controlled intermittent asthma or controlled 
mild persistent asthma are allowed in the study. FEV1 testing is required for 
subjects suspected of having asthma.
Rationale:  A requirement to increase the lenalidomide dose as of Cycle 10 was added, as it was not clearly stated 
previously.  
Section 6.2 
Lenalidomide,  new 2nd 
sentence; Figure 3; and 
Study Drug Dosing 
Schedule
During maintenance treatment in Cycle 7 and beyond, lenalidomide 10 mg will be 
administered daily on Days 1-21 throughout each 28-day cycle. Beginning at 
Cycle 10, the lenalidomide dose will be increased to 15 mg unless there is a 
tolerability concern. Following completion …
Rationale:  The instructions for prophylactic treatment with aspirin were clarified.
Section 6.2.2 Deep Vein 
Thrombosis and 
Pulmonary Edema, 2nd
sentence revised
Therefore, all subjects should be prophylactically treated with baby aspirin (162 
mg, at a minimum) by mouth daily.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
143
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  Text regarding participation in another interventional clinical trial was clarified.
Section 8.3 Prohibited 
Therapies, 3rd paragraph, 
1st sentence revised
Concomitant administration of investigational agents is prohibited. Concomitant 
participation in an interventional clinical trial(s) or use of investigational 
agent(s) as well as medical devices is prohibited.
Rationale:  Text for disease evaluations was updated. 
Section 9.2.1 Response 
Categories, 1st paragraph 
revised; and Time and 
Events Schedule
Disease evaluations must be performed every 21 days during the induction (±3 
days)/ consolidation (±7 days) phase and every 8 weeks (±14 days) during the 
maintenance phase. Disease evaluations must be performed according to the 
TIME AND EVENTS SCHEDULE. Note that an additional disease 
evaluation occurs on Day 21 of Cycle 4 and the day after Day 21 of Cycle 6 
(with a 7-day window) to assess end of Cycle 4 and end of Cycle 6 response, 
respectively.
Rationale:  Details describing assessment of response were clarified. 
Section 9.2.1, Response 
Categories: Table 9, 1st
paragraph under 
abbreviation definitions; 
and text following 
Table 9
1st paragraph under 
Table 9, new 2nd
sentence
3rd paragraph under 
Table 9, revised 1st
sentence
All response categories … require documentation of no known evidence of 
progressive or new bone lesions if radiographic studies were performed.
Disease progression based on 1 of the laboratory tests alone must be confirmed by 
at least 1 repeat investigation. Clinical judgment should prevail; however, 
repeat assessments after 1 to 3 weeks can be used as a general guideline.
Disease progression must be consistently documented across clinical study sites 
using the criteria in Table 9. Disease progression based on 1 of the laboratory 
tests alone must be confirmed by at least 1 repeat investigation. Clinical 
judgment should prevail; however, repeat assessments after 1 to 3 weeks can 
be used as a general guideline.
For continuation of treatment, the IMWG response will be determined and 
recorded on an ongoing basis by the investigator.
Rationale:  Text describing the timing of screening procedures was corrected.
Section 9.1.2 Screening 
Phase, 1st paragraph 3rd
sentence
Screening procedures will be performed within 28 days before Cycle 1 Day 1
randomization; however, results of tests such as skeletal survey, radiologic tests 
(eg, MRI) to document baseline size of known or suspected extramedullary 
plasmacytomas; or chest X-rays) performed up to 6 weeks (42 days) before Cycle 
1 Day 1randomization may be used….
Rationale: Timing for the post-ASCT consolidation disease evaluation was clarified.
Section 9.1.3, 
Induction/Consolidation 
Phase; Consolidation 
Treatment, sentence 
added to 2nd paragraph
The post-ASCT consolidation disease evaluation should be performed the day 
after completion of C6D21 (+7-day window).
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
144
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  Timing for the start of the maintenance phase was clarified.
Section 9.1.4, 
Maintenance Phase; 
sentence added to 1st
paragraph
The timing of start of maintenance is at the discretion of the investigator, 
however, it should start within the 14 days following post-ASCT consolidation 
disease evaluation.
Rationale:  Table 10 (Section 9.2.6, Minimal Residual Disease Assessment) was reformatted and revised for 
clarity, with corresponding changes to the TIME AND EVENTS SCHEDULE.
Table 10 Bone Marrow 
Testing Requirements, 
Text for when to collect 
samples for local or 
central laboratory 
testing.
At the following times:

At first evidence of suspected CR or sCR (including subjects with VGPR or better)

After induction and before stem cell collection

Post-ASCT consolidation disease evaluation (+7-day window after Cycle 6 Day 21)

At 12 and 24 months (+/-3 weeks) during maintenance phase
Rationale:  Additional detail was provided for the description of biomarkers to be evaluated.
Section 9.5 Biomarkers, 
2nd paragraph, new 2nd to 
last sentence
Section 9.5 Biomarkers, 
3rd paragraph, revised 1st
sentence
…will evaluate the depth of MRD. Baseline bone marrow aspirate samples will 
be subjected to DNA and RNA sequencing to establish the myeloma clone for 
MRD monitoring. In cases where daratumumab is suspected of interfering with 
IFE and preventing clinical CR calls, subjects with VGPR may also be evaluated 
for MRD.
In addition to evaluating MRD, a whole blood sample will be collected from 
subjects, as outlined in the TIME AND EVENTS SCHEDULE, for processing 
to plasma and PBMCs and monitoring changes in immune cell 
subpopulations.
Rationale:  Text was clarified for neutrophil counts; text pertaining to local laboratory testing was corrected or 
clarified.
Section 9.8.2 Clinical 
Laboratory Tests
Hematology panel
Text under serum 
chemistry panel

White blood cell (WBC) count with absolute counts for neutrophils and…

Hepatitis C viral load testing – for reactivation of HCV for any subjects who had 
prior, treated hepatitis C and no detectable circulating HCV at study entry

Pregnancy testing

Cytogenetics (FISH)

PC Clonality (immunohistochemistry, immunofluorescence or flow cytometry)

Morphology of bone marrow aspirate or biopsy
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
145
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  Instructions for stem call harvest and mobilization were added as they were not mentioned in the 
previous version of the protocol.
Section 9.8.5 Stem Cell 
Harvest, 1st paragraph 
revised and new 2nd
paragraph
The following information will be recorded for each subject: target CD34 dose 
prior to collection, agents used for mobilization, total number of CD34+ cells 
collected, number of days required to collect stem cells, and hematopoietic 
engraftment information. During the mobilization and stem cell transplantation 
procedures, adverse events related to the planned procedures do not need to 
be reported, however any toxicity related to daratumumab, lenalidomide, 
bortezomib, or dexamethasone exposure should continue to be reported. 
Stem cell mobilization will be performed with G-CSF, with or without 
plerixafor. G-CSF and plerixafor should be administered according to 
institutional standards of dose and schedule. Use of cyclophosphamide is only 
allowed if G-CSF with or without plerixafor is not successful. Stem cell 
collection should be performed and stem cells frozen according to 
institutional standards. Subjects will then proceed to HDT and ASCT.
Rationale:  Text for the timing of physical examinations was added for clarity.
Section 9.8.8 Physical 
Examination…, 1st
paragraph
Physical examinations will be performed on the day of the study treatment and 
ECOG performance status will…
Rationale:  Text pertaining to a daratumumab dose delay was clarified.
Section 10.2, 
Discontinuation of Study 
Treatment/Withdrawal 
from the Study, 8th bullet
The subject’s daratumumab dose is held for more than 28 days during induction or 
consolidation cycles or if ≥3 consecutive planned doses are missed for reasons 
other than toxicity;
Rationale:  The ECG assessment was clarified to show is only needed at C5 (not C5 and C6).
(Both) Time and Events 
Schedules
(Under Cycles 5-6) X C5 only
Rationale: The diary review at Day 15 in Cycles 5 and 6 was deleted as its prior inclusion was a typographical 
error.
Study Drug Dosing 
Schedule
D15 (under Cycle5-6)
Rationale:  Clarification was made regarding vital signs.
Footnote o of the D-RVd 
Time and Events 
Schedule.
Day 15 vital signs are required only for subjects in D-RVd arm.
Rationale:  The requirement for the local laboratories to be used for hematology testing was added.
Footnote s of (both) 
Time and Events 
Schedules
On-site or accredited local laboratory must be used for hematology laboratory 
assessments.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
146
Approved, Date: 10 January 2019
Applicable Section(s)
Description of Change(s)
Rationale:  The timing for randomization was clarified.
Footnote x, (both) Time 
and Events Schedules
Randomization may will be performed up to 72 hours before the first dose of study 
treatment on C1D1.
Rationale: The instructions for aspirate and biopsy samples were clarified and the bone marrow aspirate amount 
required was decreased.
Footnote cc, (both) Time 
and Events Schedules; 
and Table 10 footnote b.
A fresh aspirate and biopsy are preferred at screening; if not available, obtain non-
decalcified clot sections (block or slides) or aspirate smear or clot slides. 
At all visits, during the bone marrow aspirate procedure, the first aspirate sample 
that is drawn will be sent to the central laboratory to determine MRD. All bone 
marrow aspirates to be sent to the central laboratory should be at least 5 2 mL.
Amendment Int-1 (24 May 2017)
This amendment is considered 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 overall reasons for the amendment are to revise lenalidomide 
dosing, to update background information, and to clarify several instructions for study procedures or entry 
criteria.
Edits and additions to original text are noted in bold, and deletions are noted in strikeout.
Applicable Section(s)
Description of Change(s)
Rationale: Lenalidomide dosing was changed to be on days 1-21 of each 28-day cycle (in both treatment 
groups); and to allow the dose to be increased at Cycle 10. Since both continuous and non-continuous dosing has 
been found to be efficacious in recent Phase 3 maintenance studies, the non-continuous dosing is being called for 
as it may be better tolerated, may lessen the risk of neutropenia in the daratumumab arm, and may lessen the risk 
of secondary malignancies.
Synopsis, Overview of 
Study Design; Dosage 
and Administration; 
Time and Events 
Schedule - Study Drug 
Dosing
3.1, Overview of Study 
Design; 6, Dosage and 
Administration; 6.2, 
Lenalidomide 
….maintenance treatment with daratumumab every 8 weeks plus oral lenalidomide … 
on days 1-21 throughout each 28-day cycle. Beginning at Cycle 10, the lenalidomide 
dose will be increased to 15 mg unless there is a tolerability concern.
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
147
Approved, Date: 10 January 2019
Rationale:    An interim analysis was added to review the data for subjects who participate in the safety run-in 
phase. 
Synopsis, Overview of 
Study Design; 3.1, 
Overview of Study 
Design; 11.11. Interim 
Analysis
If the study is not stopped due to DLTs in the safety run-in phase, one interim 
safety analysis is planned for the safety run-in cohort after all subjects are treated 
for at least 4 cycles or discontinue study participation.
Rationale:    A correction was made to the Synopsis text describing the patients.
Synopsis, Subject
Population
Potential subjects will not be eligible if they have been diagnosed or treated for 
malignancy other than multiple myeloma (with exception of malignancies treated with 
curative intent and no known disease for ≥53 years….
Rationale:  A detail regarding timing of bortezomib dosing was removed for the bortezomib dosing as it is not 
required.
Time and Events 
Schedule – Study Drug 
Dosing; 6.3.1, Dose 
Adjustments of 
Bortezomib
Dose may be delayed up to 48 hours; however, subsequent doses must be adjusted as all 
bortezomib doses must be at least 72 hours apart.
Rationale:  Clarifications were made to the Time and Events Schedule.
Time and Events 
Schedule
(C4 only) was added to the column heading for Day 21 (for Induction Cycles 1-4).
Medical history was clarified by adding footnote j: Including Surgery or procedure 
planned prior to entry into the study
The neurological examination was clarified by adding footnote m: General 
neurological exam focused on sensory peripheral neuropathy
Pulmonary function test changed to Spirometry (FEV1) and footnote l was edited as 
below: 
Pulmonary function testing (spirometry) is required only for subjects with 
chronic obstructive pulmonary disease or asthma. FEV1 should be measured.
Only subjects with known or suspected chronic obstructive pulmonary disease must 
have FEV1 measured.
PK sampling for daratumumab recipients was clarified in footnote u: If the sampling 
falls on a dosing day, On a daratumumab dosing day
NCT02874742


JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
148
Approved, Date: 10 January 2019
Rationale:  Brief text regarding approval dates for daratumumab was added to the Introduction (Section 1), for 
information.
Rationale: The background information for ongoing trials with daratumumab (Section 1.1.2.2.3) was updated 
with data through 30 June 2016. Text was updated based on the last version of the IB; safety data is summarized 
in a table rather than in text (Table 1: Safety Findings in Ongoing Daratumumab Clinical Trials Through 30 June 
2016).
Rationale: The timing of the primary endpoint was clarified. 
Synopsis and 3.1, Overview of 
Study Design; 9.1.3, 
Induction/Consolidation Phase; 
9.1.4, Maintenance Phase
Subjects will be evaluated for the primary endpoint (post-ASCT 
consolidation sCR).  MRD will be assessed by next-generation 
sequencing, regardless of treatment group, as detailed in the  sCR (+7 
day window after Cycle 6, Day 21; primary endpoint,  approximately 100 
to 150 days post-ASCT and MRD by next-generation sequencing,
regardless of treatment group, as detailed in the TIME AND EVENTS 
SCHEDULE.
Rationale: The inclusion criterion (#3) for diagnosis of multiple myeloma was edited to match the 2015 IMWG 
criteria, in order to have the most current criteria, and one error was corrected (see below). For clarity, inclusion 
criterion #3 was edited and split into 2 separate criteria (#3 and #4), resulting in renumbering of the inclusion 
criteria.
4.1, Inclusion criterion 3a.iii 
Anemia: hemoglobin value of >200 g/L below the lower limit of normal, 
or a hemoglobin value <1000 g/L
Rationale: The exclusion criterion regarding malignancy was clarified.
4.2, Exclusion criterion #1; 
Synopsis, Subject Population

Adequately treated non-melanoma skin cancer, lentigo maligna 
or in situ malignancies (eg, cervical, breast) with no evidence 
of disease.

Adequately treated carcinoma in situ (eg, cervical, breast) with 
no evidence of disease
Rationale: The exclusion criterion related to QT interval on electrocardiogram was clarified. 
4.2, Exclusion criterion #7c
Screening 12-lead ECG showing a baseline corrected QT interval as 
corrected by Fridericia’s formula (QTcF) >470 msec.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY2004 Amendment 3
149
Approved, Date: 10 January 2019
Rationale:   
The exclusion criterion for human immunodeficiency virus and hepatitis 
was clarified, and assessments for hepatitis C reactivation were added. 
4.2, Exclusion Criteria, #3; 
Treatment and Events Schedule, 
new row for HCV viral load; and 
footnote w
9.8.2, Clinical Laboratory Tests
10.2, Discontinuation of Study 
Treatment
10.2, Withdrawal from the Study
Known to be seropositive for human immunodeficiency virus, known to 
have hepatitis B surface antigen positivity, or known to have a history of 
hepatitis C. Subjects who completed treatment for hepatitis C at least 
6 months prior to screening and have no detectable circulating 
hepatitis C virus (HCV) at screening, may participate in the study. 
Such subjects will be required to undergo regular assessment for 
HCV reactivation during their participation in the study.  Subjects 
who test positive for HCV at any time during these assessments will 
be withdrawn from the study.
[To be checked every 3 months through 6 months after last 
daratumumab administration and every 4 months during 
Maintenance Phase]
Subjects who completed treatment for hepatitis C at least 6 months 
prior to screening and have no detectable circulating hepatitis C 
virus (HCV) at screening, may participate in the study. Such subjects 
will be required to undergo regular assessment for HCV reactivation, 
as shown and will be withdrawn from the study if they test positive at 
any time during the study. 
Hepatitis C viral load testing – for reactivation of HCV for any 
subjects who had prior, treated hepatitis C and no detectable 
circulating HCV at study entry
Subjects with a history of HCV who completed treatment at least 6 
months prior to screening, but who do not agree to undergo regular 
assessment for HCV reactivation during their participation in the 
study.
Subjects with a history of HCV who completed treatment at least 6 
months prior to screening but who test positive for HCV at any time 
during the regular assessments.
Rationale: For patient safety, instructions were added for minimum neutrophil and platelet counts considered 
acceptable for a new cycle to be administered. 
6, Dosage and Administration
At a minimum, subjects must have an absolute neutrophil count of 1 
x 109/L and a platelet count of 50 x 109/L to begin a new cycle. Delays 
of up to 14 days for the start of the subsequent cycle are acceptable. 
Any delays more than 14 days of the scheduled day will need to be 
discussed with the sponsor.
Rationale: For patient safety, instructions were added for prophylaxis for deep vein thrombosis or pulmonary 
embolism while taking lenalidomide.
6.2.2, Deep Vein Thrombosis and 
Pulmonary Embolism
Therefore, all subjects should be prophylactically treated with baby 
aspirin (162 mg) by mouth daily. 
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Rationale: Positron emission tomography (PET)/computed tomography (CT) fusion studies were removed for 
assessing lytic bone disease and extramedullary plasmacytomas since this method is unlikely to be used.
9.2.7, Assessment of Lytic Bone 
Disease
9.2.8, Documentation of 
Extramedullary Plasmacytomas
Magnetic resonance imaging and/or low dose CT-scan, and/or PET/CT 
fusion studies are acceptable methods for evaluation of bone disease…. If 
an alternative imaging modality (MRI, CT, or PET/CT) was used at 
screening….
Positron emission tomography scan or ultrasound tests are not acceptable 
to document the size of extramedullary plasmacytomas. However, 
PET/CT fusion studies are acceptable.
Rationale: A clarification was added for safety run-in dosing.
8.3, Prohibited Therapies
During Cycle 1 of the safety run-in, the prophylactic use of 
hematopoietic growth factors is prohibited.
Rationale:  A correction was made regarding timing of the start of the screening phase.
9.1.2, Screening Phase
The screening phase begins when the first screening assessment is 
conductedICF is signed. 
Rationale: The timing of Day 1 sample for myeloma protein was clarified.
9.2.2, Myeloma Protein 
Measurement in Serum and Urine
Blood and 24-hour urine samples will be collected for serum quantitative 
Igs, serum and urine M-protein measurements, serum and urine IFE 
measurements, and serum FLC assay on Day 1 (the 24-hour urine 
samples can be completed or started on Day 1 and returned at the 
next visit)….
Rationale: Prophylaxis for pneumonia language was softened as it may not be necessary for all patients.
8.1.5, Prophylaxis for Pneumonia
Prophylaxis for pneumonia is required recommended during the first 2 
cycles of study treatment.
Rationale:  Minimal residual disease (MRD) will no longer be assessed from whole blood samples. It will only 
be assessed from bone marrow biopsies. Whole blood assessment has been determined not to be comparable to 
assessment from aspirate, and is not a substitute for aspirate in MRD testing via NGS (the intended platform for 
all of our trials).
Synopsis, Efficacy Evaluations and 
Biomarker Evaluations; Time and 
Events Schedule; 3.1, Overview of 
Study Design; 3.2, Study Design 
Rationale; 9.2.5, Bone Marrow 
Examination; 9.2.6, Minimal 
Residual Disease Assessment; 9.5, 
Biomarkers
Only bone marrow aspirates are now mentioned for measurement of 
Minimal Residual Disease; mention of samples from whole blood have 
been deleted.
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Rationale: The details for assessing minimal residual disease were clarified. 
9.2.6, Minimal residual disease 
assessment, Table 10
Bone marrow aspirate for CR:
For response confirmation, additional bone marrow aspirates (or both) will be 
performed locally to confirm CR or sCRfor all subjects with suspected or 
maintained CR or sCR (including subjects with VGPR or better and 
suspected daratumumab interference):
o
After induction and before stem cell collection
o
Post-ASCT consolidation disease evaluation (+7 day window after 
Cycle 6 Day 21)  
o
At 12 and 24 months (3 weeks) during maintenance phase
Bone marrow aspirate for MRD:
After induction and before stem cell collection: subjects with CR or sCR 
(including subjects with VGPR or better and suspected daratumumab 
interference)To confirm CR or sCR at any time (including subjects 
with VGPR or better and suspected daratumumab interference)
Rationale: Membership on the planned Safety Run-in Data Review Committee was corrected and the Data 
Safety Monitoring Board is now referred to as the Data Monitoring Committee, per Sponsor conventions.
Synopsis and 3.1, Overview of 
Study Design; 9.8, Safety 
Evaluations; 11.11, Interim 
Analysis; 11.12, Independent Data 
Monitoring Committee; 11.13, 
Safety Run-in Data Review 
Committee
The Safety Run-in Data Review Committee will consist of the sponsor’s 
medical monitor, the principal investigators, a sponsor physician who is 
not involved in the study, a sponsor statistician who is not involved in the 
study, and a medical safety representative.
Rationale: Minor updates to the required laboratory tests were made.
Time and Events, Serum chemistry 
footnote t; 9.8.2, Clinical Laboratory 
Tests
At a minimum the following tests will be performed by the local 
laboratory, unless otherwise noted:….
Uric acid changed to BUN, and Phosphate deleted
Rationale: Dosing for acetaminophen was clarified.
Time and Events – Drug Dosing; 
6.1.3.1, Preinfusion Medication
Acetaminophen 650 to 1,000 mg oral or IV equivalent
Rationale:  No IWRS manual is being provided to investigators and this was corrected. 
Section 15, Study-specific Materials

IWRS Manual
Rationale: The classifications of asthma severity in Attachment 4 have been corrected.
Rationale:  The DuBois formula for body surface area (BSA) calculation is an acceptable alternative to the 
Mostellar formula and language was added to allow use of both formulas.
Attachment 6                                            The body surface area (BSA) should be calculated using the standard
                                                                  calculation given below. However, the DuBois Formula can be used     
                                                                  as an alternative to calculate BSA.
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INVESTIGATOR AGREEMENT
LAST PAGE
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SAP_001.pdf: 
1
Approved Date: 27 February 2019
Janssen Research & Development 
Statistical Analysis Plan
Phase 2, Randomized, Open-Label Study Comparing Daratumumab, Lenalidomide, 
Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and 
Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma Eligible for 
High-Dose Chemotherapy and Autologous Stem Cell Transplantation
Protocol 54767414MMY2004; Phase 2
JNJ-54767414  (daratumumab)
Author: Huiling Pei
Date: 24 September 2018
Status:
Approved
Date:
27 February 2019
Prepared by:
Janssen Research & Development
Document No.:
EDMS-ERI-181425339
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
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Approved Date: 27 February 2019
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)                         
                                                                 
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
ABBREVIATIONS ........................................................................................................................................ 5
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.1.1.
Primary Objective ......................................................................................................................... 7
1.1.2.
Secondary Objectives................................................................................................................... 7
1.1.3.
Exploratory Objective.................................................................................................................... 8
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 10
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 11
2.1.
Visit Windows................................................................................................................................. 11
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 11
2.3.
Analysis Sets.................................................................................................................................. 11
2.4.
Definition of Subgroups.................................................................................................................. 12
2.5.
Study Day and Relative Day .......................................................................................................... 13
2.6.
Baseline Measurement .................................................................................................................. 14
2.7.
Treatment Phases.......................................................................................................................... 14
2.8.
Unique Laboratory Value ............................................................................................................... 14
2.9.
Imputation of Missing/Partial Dates ............................................................................................... 15
2.9.1.
Missing/Partial Adverse Event Onset Date................................................................................. 15
2.9.2.
Missing/Partial Adverse Event End Date.................................................................................... 16
2.9.3.
Partial Multiple Myeloma Diagnosis Date................................................................................... 16
2.9.4.
Partial Concomitant Medication Start/End Date ......................................................................... 16
2.9.5.
Partial Subsequent Antimyeloma Therapy Start Date ................................................................ 17
2.10.
General Analysis Method............................................................................................................... 17
3.
INTERIM ANALYSIS AND DATA REVIEW/MONITORING COMMITTEES .................................... 18
3.1.
Safety Run-in Data Review Committee (DRC) .............................................................................. 18
3.2.
Interim Analysis.............................................................................................................................. 18
3.3.
Independent Data Monitoring Committee (DMC) .......................................................................... 18
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 18
4.2.
Disposition Information................................................................................................................... 19
4.3.
Extent of Exposure......................................................................................................................... 19
4.4.
Protocol Deviations ........................................................................................................................ 20
4.5.
Prior, Concomitant Medications and Subsequent Therapies......................................................... 20
4.6.
Autologous Stem Cell Transplantation (ASCT) ............................................................................. 21
5.
EFFICACY ......................................................................................................................................... 22
5.1.
Analysis Specifications................................................................................................................... 22
5.1.1.
Level of Significance................................................................................................................... 22
5.1.2.
Data Handling Rules................................................................................................................... 22
5.2.
Primary Efficacy Endpoint.............................................................................................................. 22
5.2.1.
Definition..................................................................................................................................... 22
5.2.2.
Analysis Methods........................................................................................................................ 22
5.2.3.
Sensitivity Analysis ..................................................................................................................... 23
5.3.
Secondary Efficacy Endpoints ....................................................................................................... 23
5.3.1.
Response Rate and Overall Response Rate (ORR) .................................................................. 23
5.3.1.1.
Definition.................................................................................................................................. 23
5.3.1.2.
Analysis Methods .................................................................................................................... 24
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5.3.2.
Duration of sCR, CR and Duration of Response (DOR) ............................................................ 24
5.3.2.1.
Definition.................................................................................................................................. 24
5.3.2.2.
Analysis Methods .................................................................................................................... 24
5.3.3.
Time to Response....................................................................................................................... 25
5.3.3.1.
Definitions................................................................................................................................ 25
5.3.3.2.
Analysis Methods .................................................................................................................... 25
5.3.4.
Progression-Free Survival .......................................................................................................... 25
5.3.4.1.
Definition.................................................................................................................................. 25
5.3.4.2.
Analysis Methods .................................................................................................................... 26
5.3.5.
Time to Disease Progression (TTP) ........................................................................................... 27
5.3.5.1.
Definition.................................................................................................................................. 27
5.3.5.2.
Analysis Methods .................................................................................................................... 27
5.3.6.
Overall Survival (OS).................................................................................................................. 27
5.3.6.1.
Definition.................................................................................................................................. 27
5.3.6.2.
Analysis Methods .................................................................................................................... 28
5.3.7.
Progression-free Survival on Next Line of Therapy (PFS2) ....................................................... 28
5.3.7.1.
Definition.................................................................................................................................. 28
5.3.7.2.
Analysis Methods .................................................................................................................... 29
5.4.
Functional Status and Well-being .................................................................................................. 29
5.4.1.
Definition..................................................................................................................................... 29
5.4.2.
Analysis Methods........................................................................................................................ 30
5.5.
Subgroup Analyses........................................................................................................................ 31
6.
SAFETY............................................................................................................................................. 31
6.1.
Adverse Events .............................................................................................................................. 31
6.1.1.
Overview of TEAEs..................................................................................................................... 32
6.1.2.
All TEAEs.................................................................................................................................... 32
6.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 32
6.1.4.
Study Treatment-Related TEAEs ............................................................................................... 32
6.1.5.
Serious Adverse Events (SAEs) ................................................................................................. 32
6.1.6.
TEAEs Leading to Discontinuation of Any Study Treatment ...................................................... 33
6.1.7.
TEAEs Leading to Cycle Delays or Dose Modifications............................................................. 33
6.2.
Deaths............................................................................................................................................ 33
6.3.
Adverse Events of Clinical Interest ................................................................................................ 33

Second primary malignancies......................................................................................................... 34
6.4.
Clinical Laboratory Tests................................................................................................................ 35
6.5.
Vital Signs and Physical Examination............................................................................................ 35
6.6.
12-lead Electrocardiogram (ECG).................................................................................................. 35
6.7.
ECOG Performance Status............................................................................................................ 36
7.
PHARMACOKINETICS/IMMUNOGENICITY.................................................................................... 36
7.1.
Pharmacokinetics........................................................................................................................... 36
7.1.1.
Pharmacokinetic Parameters ..................................................................................................... 36
7.1.2.
Analysis Methods........................................................................................................................ 36
7.2.
Immunogenicity.............................................................................................................................. 37
7.2.1.
Sampling Timepoints .................................................................................................................. 37
7.2.2.
Analysis Methods........................................................................................................................ 37
7.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 37
8.
BIOMARKER..................................................................................................................................... 37
8.1.
Minimal Residual Disease (MRD) .................................................................................................. 37
8.1.1.
Definition..................................................................................................................................... 38
8.1.2.
Analysis Methods........................................................................................................................ 38
9.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 38
10.
REFERENCES................................................................................................................................... 39
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase 
ANC
absolute neutrophil count 
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
BUN
blood urea nitrogen
C
cycle
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response
CrCl
creatinine clearance
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
D-R
daratumumab-lenalidomide
DRC
Data Review Committee
D-RVd
daratumumab-lenalidomide-bortezomib-dexamethasone
DOR
duration of response
ECG
electrocardiogram
ECOG
European cooperative oncology group
eCRF
electronic case report form
FISH
fluorescence in situ hybridization
HDT
high-dose chemotherapy
IFE
immunofixation
Ig
immunoglobulin
IMWG
international multiple 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
MM
multiple myeloma
MRD
minimal residual disease
MRU
medical resource utilization
NCI CTC
national cancer institute common terminology criteria
NCI-CTCAE
national cancer institute common terminology criteria for adverse events
NE
not evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
RBC
red blood cell
RVd
lenalidomide-bortezomib-dexamethasone
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
sCR
stringent complete response
SD
stable disease
SMQ
standardized MedDRA queries 
SOC
system organ class
SRI
safety run-in subjects
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TEAE
treatment-emergent adverse event
TTP
time to disease progression
TTR
time to response
VGPR 
very good partial response
WHO
World Health Organization
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the planned analysis for study protocol 54767414MMY2004: comparing 
Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) versus Lenalidomide, 
Bortezomib, and Dexamethasone (RVd) in subjects with newly diagnosed multiple myeloma 
eligible for high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT).
1.1.
Trial Objectives
1.1.1.
Primary Objective
The primary objective is to determine if the addition of daratumumab to RVd will increase the 
proportion of subjects achieving stringent complete response (sCR), as defined by the IMWG 
criteria, by the time of completion of post-ASCT consolidation treatment, compared with RVd 
alone.
1.1.2.
Secondary Objectives
The secondary objectives are:

To evaluate CR and sCR rate following induction, ASCT, post-ASCT consolidation, and 
maintenance treatment

To evaluate overall response rate and rate of VGPR or better following induction, ASCT, 
post-ASCT consolidation, and maintenance treatment

To evaluate duration of and time to sCR and time to CR

To evaluate time to VGPR or better

To evaluate time to PR or better

To assess negative MRD rate following induction, post-ASCT consolidation, and 
maintenance treatment

To evaluate clinical outcomes including:

Time to progression

Progression-free survival

Overall survival (OS)

Duration of response

To assess the safety and tolerability of D-RVd 
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
To assess the pharmacokinetics of daratumumab 

To assess the immunogenicity of daratumumab 

To evaluate patient-reported outcomes (PROs)

To evaluate stem cell yield after mobilization 

To assess time to absolute neutrophil count (ANC) recovery, defined as the date of the first 
of 3 consecutive laboratory values (obtained on different days) where the ANC is >0.5 x 
109/L

To assess time to platelet count recovery, defined as the date of the first of 3 consecutive 
laboratory values (obtained on different days) where the platelet count is >20 x 109/L and at 
least 7 days after the most recent prior platelet transfusion

To evaluate the tolerability of daratumumab when administered as a rapid infusion
during maintenance treatment (ie, an accelerated infusion rate whereby 20% of the
daratumumab dose is administered over 30 minutes and the remaining 80% is administered 
over 60 minutes for a total dose administration time 90 minutes)
1.1.3.
Exploratory Objective
The exploratory objectives are:

To evaluate PFS on next-line therapy (PFS2)

To evaluate the clinical efficacy of D-RVd in high-risk cytogenetic subgroups currently 
defined as del(17p), t(4;14), t(14;16) 

To explore immune modulatory effects of D-RVd as compared with RVd through immune 
profiling (NK, T, and B cells) and T-cell receptor sequencing 

To collect medical resource utilization (MRU) data that may be used in future economic 
modeling (the construction and reporting of the economic model will be conducted 
separately from this study)

To evaluate serum concentrations and potential immunogenicity of daratumumab with
respect
to infusion-related reactions (IRRs) in the setting of rapid infusion during 
maintenance.
1.2.
Trial Design
This is a multicenter, randomized, open-label, active-controlled, Phase 2 study in subjects with 
newly diagnosed multiple myeloma eligible for HDT and ASCT. Initially, there will be a safety 
run-in phase in up-to-16 subjects to assess potential dose-limiting toxicities (DLTs) that may be 
associated with the addition of daratumumab to the RVd regimen. The main study consists of 4 
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phases: a 28-day screening phase; an induction/consolidation phase (which is inclusive of four 
21-day induction treatment cycles followed by stem cell mobilization, HDT, and ASCT, 
followed by two 21-day consolidation treatment cycles); a 24-month maintenance phase that 
starts after the post-ASCT consolidation disease evaluation; and a long-term follow-up phase. 
All subjects will be followed in the long-term follow-up phase for at least 1 year after last dose 
of study treatment and will continue until death, withdrawal of consent for study participation, or 
the end of study definition is met. The end of study is defined as when all subjects have 
completed at least 1 year of long-term follow up, or until death or withdrawal of consent for 
study participation, whichever occurs first.
Initially, a safety run-in phase will be performed at selected study sites. In this safety run-in 
phase, a total of 8 to 16 subjects will be enrolled and assigned to receive D-RVd to assess 
potential DLTs during Cycle 1 of treatment. Subjects who experience a DLT during the safety 
run-in will be withdrawn from the study (based on investigator’s judgment and best clinical 
practice). If the stopping boundaries are crossed after 8, 12, or 16 subjects, all subjects will be 
withdrawn from the study, and the study will be stopped. Unless the study is stopped due to 
DLTs, subjects enrolled in the safety run-in phase will continue in the study and follow the visit 
schedule and procedures described for the main study (except PRO assessments and MRU data 
collection). 
Following successful completion of the safety run-in phase, approximately 200 subjects will be 
randomly assigned to 1 of 2 treatment groups (100 per treatment group) in the main study:

D-RVd group: RVd with daratumumab 16 mg/kg IV weekly during induction treatment 
(Days 1, 8, and 15 of Cycles 1 through 4) and every 3 weeks during consolidation treatment 
(Day 1 of Cycles 5 and 6), followed by every 4 or 8 weeks during maintenance treatment 

RVd group: RVd alone as induction and consolidation treatment (Cycles 1 through 6: 
lenalidomide 25 mg orally on Days 1 through 14, bortezomib 1.3 mg/m2 subcutaneously on 
Days 1, 4, 8, and 11, and oral dexamethasone 40 mg weekly [20 mg on Days 1, 2, 8, 9, 15, 
and 16]) followed by maintenance treatment with oral lenalidomide 10 mg on Days 1-21 
throughout each 28-day cycle from Cycles 7 to 9. Beginning at Cycle 10, the lenalidomide 
dose will be increased to 15 mg unless there is a tolerability concern. 
Subjects will be stratified at randomization by International Staging System (ISS) Stage I, II, or 
III disease (β-2 microglobulin and albumin) and creatinine clearance (CrCl [30-50 mL/min and 
>50 mL/min]). 
Disease response and progression will be based on assessments according to the IMWG 
guidelines. Efficacy evaluations include: M-protein measurements (serum and urine), 
immunofixation (IFE) (serum and urine), serum FLC, serum calcium corrected for albumin, 
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JNJ-54767414  (daratumumab)                         
                                                                 
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examination of bone marrow aspirate or biopsy, skeletal survey (assessment of lytic bone 
disease), and documentation of extramedullary plasmacytomas. Minimal residual disease in the 
bone marrow aspirate will also be assessed.
Throughout the study, subjects will be monitored closely for adverse events, laboratory 
abnormalities, and clinical response, as specified in the study protocol. The National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 4.03) will be 
used to grade toxicity throughout the study.
Blood samples for biomarker studies will be collected from all subjects. Blood samples for 
pharmacokinetic and immunogenicity assessments will only be collected from subjects in the 
D-RVd/D-R group.
To measure functional status, well-being, and symptoms, the EORTC QLQ-C30, EORTC 
QLQ-MY20, and the EQ-5D-5L instruments will be completed by subjects throughout the study. 
Medical resource utilization data will also be collected.
A Data Review Committee will review safety data after 8, 12, and 16 subjects in the safety run-
in phase complete Cycle 1 (or discontinue before the end of Cycle 1) and will use stopping 
boundaries to determine whether to stop or continue the trial. If the study is not stopped due to 
DLTs in the safety run-in phase, one interim safety analysis is planned for the safety run-in 
cohort after all subjects are treated for at least 4 cycles or discontinue study participation.
An independent Data Monitoring Committee (DMC) will meet periodically to review interim 
safety data during the main study. One planned interim safety analysis will occur after at least 
50 subjects are treated for at least 4 cycles and undergo stem cell mobilization (or are evaluated 
for mobilization feasibility) in the main study or have discontinued before completing 4 
cycles/stem cell mobilization/feasibility. Details will be included in the DMC Charter. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that D-RVd will improve the sCR rate by the end of 
post-ASCT consolidation treatment compared with RVd alone.
1.4.
Sample Size Justification
Historical data suggest that the post-consolidation sCR rate is approximately 35% for RVd 
therapy. To detect an absolute 15% increase in post-consolidation sCR rate with 80% power 
using a 1-sided likelihood ratio test at the 10% significance level, 200 subjects need to be 
randomized with a 1:1 randomization ratio, assuming a 5% non-evaluable rate.
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JNJ-54767414  (daratumumab)                         
                                                                 
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1.5.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be randomly assigned to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by ISS stage I, II, or III, and by CrCL (30-
50 mL/min and >50 mL/min). The interactive web response system (IWRS) will assign a unique 
treatment code, which will dictate the treatment assignment and matching study drug kit for the 
subject. 
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 with the exception of Cycle 
4. For the last cycle, the end date is defined as the end of treatment visit date, or the
earlier o f the last study treatment date plus 30 days or t h e  f i r s t  subsequent anti-
myeloma therapy start date 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.
2.2.
Pooling Algorithm for Analysis Centers
Data from participating centers in the study will be pooled together for analyses purpose.
2.3.
Analysis Sets
The following analysis sets are defined.

Safety run-in (SRI) analysis set: is defined as all subjects enrolled to safety run-in treatments.   

Intent-to-treat analysis set (ITT): is defined as all randomized and SRI subjects. Analyses of 
demographics, baseline characteristic and time-to-event variables (e.g., PFS and OS) will be 
based on this analysis set.

Safety analysis set: is defined as all randomized and SRI subjects who received at least 1 
dose (partial or complete) of study treatment (Daratumumab, Lenalidomide, Bortezomib or
Dexamethasone). This analysis set will be used for all safety analyses. The safety 
analysis grouping will be according to treatment actually received.
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Response-evaluable set: is defined as all randomized and SRI 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 1 administration of study treatment and have at 
least 1 post-baseline disease assessment. Measurable disease is defined as follows: 

Immunoglobulin G (IgG) myeloma: serum monoclonal paraprotein (M-protein) level 
≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or

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 
Ig free light chain (FLC) level ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC 
ratio
Analyses of the primary endpoint of sCR response and any secondary response-related 
endpoints such as ORR, time to response, and duration of response will be based on this 
analysis set. 

Pharmacokinetics-evaluable: defined as all subjects assigned to D-RVd 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 analysis set.

Immune response-evaluable: defined as subjects assigned to D-RVd who have at least 1
immunogenicity sample obtained after their first daratumumab administration.

Cytogenetic evaluable: defined as subjects who meet one of the following cytogenetic risk 
categories based on FISH: 

Standard risk: subjects that are negative for del(17p), t(4;14) and t(14;16)

High risk: subjects that are positive for any of del(17p), t(4;14) and t(14;16) 
2.4.
Definition of Subgroups  
If deemed necessary, the following subgroup analyses may be performed for the primary
endpoint, selected secondary efficacy endpoints or safety endpoints, depending on the number of 
subjects in each subgroup as shown in Table 1. Given that SRI only has 16 subjects, subgroup 
analyses will not be performed for the group.
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JNJ-54767414  (daratumumab)                         
                                                                 
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Table 1: Subgroup Definition
Subgroup 
Definition 
Sex 
Male, Female 
Age 
<65 years, ≥65 years
Type of MM 
IgG, Non-IgG 
ECOG performance score 
0, ≥1 
ISS Stagea
I, II, III
Baseline creatinine clearancea
CrCl [30-50 mL/min or >50 mL/min]
Cytogenetics
high risk vs. standard risk according 
to FISH
a IWRS data is used
Additionally, if deemed necessary, patients who have consolidation therapy with HDT/ASCT 
after 4 cycles of induction therapy are considered as a separate ASCT subgroup for analysis 
purpose.  
Subgroup analysis may be performed for subjects who had 4-week daratumumab dosing vs. 
those who had 8-week daratumumab dosing during maintenance period if deemed necessary.
2.5.
Study Day and Relative Day
Study treatment refers to Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (D-
RVd) and Lenalidomide, Bortezomib and Dexamethasone (RVd). Study drug refers to 
Daratumumab.  
Study treatment dosing date is the date on which a subject receives study treatment (partial or 
complete) and will be recorded in the study treatment administration dataset.
The first study treatment date is defined as the earliest date of non-zero dose of the following 
administration: Daratumumab, Lenalidomide, Bortezomib or Dexamethasone. The last study 
treatment date is defined as the latest date of non-zero dose of all the study treatment 
administrations. 
Study Day 1 or Day 1 refers to the start of the first study treatment administration date. All 
efficacy and safety assessments at all visits will be assigned a day relative to this date.
Study day or relative day for a visit is defined as:

(Visit date) - (date of Study Day 1) + 1, if visit date is ≥date of Study Day 1

(Visit date) - (date of Study Day 1), 
if visit date < date of Study Day 1
A subject is considered as treated in a cycle if he/she receives any nonzero dose of 
Daratumumab, Lenalidomide, Bortezomib or Dexamethasone in that cycle.
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JNJ-54767414  (daratumumab)                         
                                                                 
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2.6.
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).
2.7.
Treatment Phases
The study consists of 4 treatment phases: induction (Cycles 1 to 4), ASCT, consolidation (Cycles 
5-6), and maintenance (Cycles 7-32). Definition of treatment phases are as follows:
o
Induction (Cycles 1 to 4): start of induction is the first dose date of study treatment. 
The end of induction is 1 day before PBSC apheresis if subject had ASCT. If subject
discontinued the study early before ASCT, the end of induction is the end of Cycle 4 
visit date if available; or the latest of treatment discontinuation date, the last dose date
and the last non-follow-up visit date
o
ASCT: start of ASCT is the PBSC apheresis date. The end of ASCT is 1 day before 
C5D1 date if subject took Cycle 5 treatment. If subject discontinued the study early 
during ASCT, the end of ASCT is the latest of the last ASCT date, treatment 
discontinuation date and the last non-follow-up visit date
o
Consolidation (Cycles 5-6): start date of consolidation is C5D1 date. End date of 
consolidation is the post-ASCT disease evaluation date or 1 day before C7D1. If 
subject discontinued early before post-ASCT disease evaluation or C7D1, the end of 
consolidation is the latest of treatment discontinuation date, the last dose date and the 
last non-follow-up visit date  
o
Maintenance (Cycles 7-32): start date of maintenance is C7D1 date. End of 
maintenance is the later of the last dose date and the last non-follow-up visit date. If 
subject discontinued the treatment earlier, end of maintenance is the latest of 
treatment discontinuation date, the last dose date and the last non-follow-up visit date  
o
Follow-up phase: the follow-up phase starts 1 day after the end-of-treatment visit to 
the trial completion/discontinuation date.
When the start date of a phase is not available, the end date of that phase should be set to 
missing.
2.8.
Unique Laboratory Value
In general, in instances when there are multiple records at a given visit date for laboratory
parameters associated with disease assessment, the following rules will be applied to select the 
unique laboratory value for analysis: 
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JNJ-54767414  (daratumumab)                         
                                                                 
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a) When there are multiple records from both central and local labs, central lab value 
always takes precedence over local lab value
b) When there are multiple records from central lab for a treatment phase, select the latest 
value as the unique lab value within the treatment phase
c) When there are multiple records from local lab for a treatment phase, select the latest 
lab value as the unique lab value within the treatment phase.
For local lab data regarding disease-related efficacy assessment such as SPEP, UPEP, kappa, 
lambda, kappa/lambda ratio, serum calcium, albumin and etc., only qualitative data will be used 
for analysis.  Due to different local lab has different reference ranges, quantitative data from 
local labs will not be used for analysis.  
2.9.
Imputation of Missing/Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purpose, missing or partial dates in adverse event (AE 
onset date; AE end date), multiple myeloma diagnosis date, and concomitant therapies (start 
date; end date) will be imputed.
Additional imputation rules will be specified in the data presentation specification (DPS).    
2.9.1.
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 is imputed. If the imputed start date is later 
than end date, the day-component of the AE end date (possibly imputed) is imputed

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 or no components of the onset date are 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

If the onset year is different from the year of first study treatment, the 1st of January is 
imputed
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JNJ-54767414  (daratumumab)                         
                                                                 
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
If the onset date is completely missing, the earlier one of the date of the 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.
2.9.2.
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 year of the end date is missing, no imputation will be applied

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.
No imputation will be done for partial or missing AE end time.
2.9.3.
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 as the 15th day of the month, and pick the earliest day of 
the imputed date, the date of data collection, and the date of randomization for randomized 
subjects and the first dose date of study treatment for SRI subjects.

If both the day and month are missing, set to January 1 and pick the earliest day of the 
imputed date, date of data collection, and the date of randomization for randomized subjects 
and the first dose date of study treatment for SRI subjects.

If year is missing, no imputation will be applied.
2.9.4.
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 study 
treatment date, further adjust the imputed start date to make the day prior to the first dose 
date of study treatment.
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JNJ-54767414  (daratumumab)                         
                                                                 
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
If the medication was taken after study start, and the imputed start date is prior to the first 
dose date of study treatment, further adjust the imputed start date as the first dose date. Also 
adjust the imputed medication end date so that it is on or after the first dose date of study 
treatment.
2.9.5.
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 of study treatment, the earlier of the last dosing date and the day-component
of the stop date of subsequent antimyeloma therapy is used for imputation.

If the start month and year are not the same as the month and year of last dosing date of 
study treatment, the first day of the month is imputed.
No imputation will be applied for missing or partial subsequent antimyeloma therapy end
date.
2.10.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation (SD), median and range (maximum and minimum). Categorical variables will 
be summarized using frequency and percentage.  For time-to-event variables including PFS, OS, 
etc., Kaplan-Meier method will be used for descriptive summaries, and Kaplan-Meier plots.
Summary tabulations for subject disposition, duration of follow-up time and baseline 
characteristics will be presented side-by-side by the randomized treatment groups (RVd, D-
RVd), safety run-in treatment (D-RVd), all D-RVd combined from randomized D-RVd and 
safety run-in, and grand total from the randomized and the safety run-in subjects.
For each efficacy parameter, separate summary tabulations will be presented with one by the 
randomized treatment groups (RVd, D-RVd), and another one by randomized D-RVd, safety 
run-in D-RVd and all D-RVd. 
Safety parameters including AEs will be presented side-by-side by the randomized treatment 
groups (RVd, D-RVd), safety run-in treatment (D-RVd), and all D-RVd.  
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JNJ-54767414  (daratumumab)                         
                                                                 
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3.
INTERIM ANALYSIS AND DATA REVIEW/MONITORING COMMITTEES
3.1.
Safety Run-in Data Review Committee (DRC)
A Safety Run-in DRC will be established to review safety data after 8, 12, and 16 subjects in the 
safety run-in phase complete Cycle 1 (or discontinue before the end of Cycle 1) and will use 
stopping boundaries described in study protocol. The Safety Run-in DRC will consist of the 
sponsor’s medical monitor, a sponsor physician who is not involved in the study, a sponsor 
statistician who is not involved in the study, and a medical safety representative.
3.2.
Interim Analysis
There is no interim efficacy analysis planned for this study. However, interim safety analyses are 
planned to monitor data at an ongoing basis to ensure the continuing safety of the study subjects. 
If the study is not stopped due to DLTs in the safety run-in phase, one interim safety analysis is 
planned for the safety run-in cohort after all subjects are treated for at least 4 cycles or 
discontinue study participation.
One interim safety analysis is planned for the main study. The interim safety analysis will occur 
after at least 50 subjects are treated for at least 4 cycles and undergo stem cell mobilization (or 
are evaluated for mobilization feasibility) in the main study. Subsequent interim safety analysis 
will occur every 6 months afterwards. Details on the interim safety analysis can be found in its 
SAP.
3.3.
Independent Data Monitoring Committee (DMC)
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
continuing safety of the subjects enrolled in the main study. The committee will meet 
periodically during the main study to review interim safety data. The DMC will make 
recommendations regarding the continuation of the main study. The details will be provided in a 
separate DMC charter.
The DMC will consist of at least 2 external medical experts in the relevant therapeutic area and 
at least 1 external statistician. The DMC responsibilities, authorities, and procedures will be 
documented in its charter.
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
The following parameters will be summarized using ITT analysis set. No statistical comparison
among treatment groups is planned.
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Demographic and baseline characteristic variables: age (continuous), age category (<65
years, and ≥65 years), sex, ethnicity, race, weight (kg), height (cm), body surface area 
(BSA) (m2), and ECOG performance status (0, 1, 2, >2) 

Baseline disease characteristics: type of myeloma (IgA, IgD, IgE, IgG, IgM, light chain, 
biclonal, serum free light chain only), ISS staging (I, II, III) collected from eCRF not 
IWRS, type of measurable disease (serum, urine, FLC, NE), cytogenetics profile 
(del(17p), t(4;14), t(14;16)), time since initial diagnosis of MM (days), number of lytic 
bone lesions (None, 1-3, 4-10, more than 10), presence of diffuse myeloma-related 
osteopenia (Yes, No), number extramedullary plasmacytomas (0, ≥1), bone marrow 
biopsy/aspirate % plasma cells (<10, 10 – 59, ≥60), and bone marrow biopsy/aspirate 
cellularity (hypocellular, normocellular, hypercellular, indeterminate)

Medical history collected at baseline or screening visit will be summarized by system-
organ class and preferred term 

A summary of stratification factors (ISS staging, creatinine clearance (CrCl [30-50 
mL/min or >50 mL/min])) used in the randomization based on IWRS will be provided to 
evaluate whether or not randomization process was appropriately executed in the study.
These IWRS captured stratification factors in randomization will be included in the 
stratified Cochran-Mantel-Haenszel (CMH) test, log-rank test and stratified Cox’s
regression models.

Baseline vital signs: pulse, systolic blood pressure, and diastolic blood pressure

Baseline ECG overall interpretation: normal, abnormal and clinically significant, or
abnormal and not clinically significant.
4.2.
Disposition Information
The number and percentage of subjects who enrolled and discontinued study treatment will be 
summarized using the ITT analysis set, together with reasons of discontinuation reported on 
eCRF by different treatment phases (induction, ASCT, consolidation and maintenance) and 
overall. The number of subjects who discontinued from study and the reported reasons on eCRF 
will be presented similarly.  
4.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized based on the safety analysis set
including the following:
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JNJ-54767414  (daratumumab)                         
                                                                 
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
The number and percentage of subjects treated within each cycle

Maximum number of treatment cycles received by treatment phases (induction, 
consolidation and maintenance)

Total number of treatment cycles received 

Duration of study treatment, defined as the number of months from the date of the first 
administration of study treatment to the date of the last dose

The duration of Daratumumab infusion (hours) for first infusion, second infusion, and 
subsequent infusions

Total number of Daratumumab infusions per cycle by treatment phases (induction, 
consolidation and maintenance)

Total dose administered overall and by treatment cycle for Daratumumab (mg/kg), 
Lenalidomide (mg), Bortezomib (mg/m2), or Dexamethasone (mg)

Dose intensity for each treatment, which is calculated as the sum of total doses (mg/kg, or 
mg/m2, or mg) received in all cycles divided by the number of treatment cycles

Relative dose intensity (%), which is defined as the ratio of the total actually received dose 
and total planned dose. Total planned dose is calculated as the sum of planned dose level 
over the number of recorded infusions or dose administrations (zero & non-zero dosing 
records included. For each dose administration, the planned dose is 16 mg/kg for 
Daratumumab, 1.3 mg/m2 for Bortezomib, and 20 mg for Dexamethasone. The 
lenalidomide planned dose is 25 mg for Cycles 1 to 6, and 10 mg for Cycles 7 to 9. From 
Cycle 10 on, the planned dose is 15 mg per administration.

Number of subjects with cycle delay, dose skipped (not administered), adjusted, stopped
and interrupted for Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone as
well as the respective reasons.
4.4.
Protocol Deviations
The incidence of major protocol deviations will be summarized based on the ITT analysis set. A 
listing of all major protocol deviations will be provided.
4.5.
Prior, Concomitant Medications and Subsequent Therapies
Prior medications are the medications or therapies administered before the first dose of study 
treatment, or prior is marked as “Yes” on eCRF page. Concomitant medications are therapies
recorded throughout the study with start date on or after the first dose date of study treatments 
until 30 days following completion of the last dose of study treatments. Prior and concomitant 
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JNJ-54767414  (daratumumab)                         
                                                                 
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medications will be summarized by World Health Organization (WHO) drug therapeutic class, 
pharmacologic class, and generic name based on ITT analysis set.  
With the study population of newly diagnosed subjects with multiple myeloma, pre-study 
therapies are limited to prior systemic use of corticosteroids and radiation therapy for multiple 
myeloma. If any, a listing of all prior systemic use of corticosteroids, and prior radiotherapy will 
be provided for the ITT analysis set.
Pre- and post-infusion medications will be summarized separately.  This will be provided using 
the ITT analysis set.
The total number of subjects who received subsequent antimyeloma therapy will be reported
for
ITT analysis set. 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.
4.6.
Autologous Stem Cell Transplantation (ASCT)
The number (%) of subjects who undergone stem cell mobilization and who undergone 
transplant will be summarized. Stem cell yield (106 CD34 cells/kg), the number of CD34+ cells 
transplanted (106/kg), days to engraftment for neutrophils (0.5x109/L) and days to engraftment 
for platelets (20x109/L) will be summarized by mean, standard deviation, median, minimum and 
maximum based on ITT analysis set. 
Days to engraftment for neutrophils were assessed by investigators as the time to absolute 
neutrophil count (ANC) recovery, defined as the date of the first of 3 consecutive laboratory 
values (obtained on different days) where the ANC is >0.5x109/L.
Days to engraftment for platelets were assessed by investigators as the time to platelet count 
recovery, defined as the date of the first of 3 consecutive laboratory values (obtained on different 
days) where the platelet count is >20 x 109/L and at least 7 days after the most recent prior 
platelet transfusion.
When subjects’ neutrophils or platelets did not drop below the specified threshold, some 
investigators have captured engraftment days as 0. As such, 0 engraftment day will not be 
included in the summary of data. 
The ASCT related information will be listed. 
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JNJ-54767414  (daratumumab)                         
                                                                 
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5.
EFFICACY
The primary analysis will be performed after all randomized subjects have completed the post-
ASCT consolidation disease evaluation or have been discontinued from study treatment by this 
time point. A second analysis will be performed after all randomized subjects complete the 
maintenance phase or have been discontinued from study treatment by this time point. A final 
data cut-off and analysis, to update secondary endpoints and safety, will occur at the end of study 
when all subjects have completed at least 1 year of long-term follow up, or until death or 
withdrawal of consent for study participation, whichever occurs first.
Response to study treatment and progressive disease will be evaluated by a validated computer 
algorithm to calculate IMWG response. As a sensitivity analysis, investigator assessments of 
response and disease progression using the IMWG response criteria will also be performed.
All response related efficacy analyses including time to response and duration of response will 
be based on the response-evaluable analysis set, and time to events including PFS, time to 
disease progression (TTP), PFS2, and OS will be based on the ITT analysis set.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
The primary hypothesis will be tested at 1-sided 10% significant level. All the secondary and 
exploratory analysis are to be tested at a 2-sided 5% significance level.  
5.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
5.2.
Primary Efficacy Endpoint
5.2.1.
Definition
The primary endpoint is the proportion of subjects achieving a sCR by the end of post-ASCT 
consolidation treatment, as determined by the validated computer algorithm using the IMWG 
criteria.
5.2.2.
Analysis Methods 
The number and percentage of subjects with sCR as the best response achieved by the end of 
post-ASCT consolidation treatment will be tabulated based on the response-evaluable analysis 
set. The proportion of sCR response will be compared between the two randomized treatment 
groups using the stratified CMH test. A Mantel-Haenszel odds ratio, along with its 2-sided 95% 
confidence interval and the p-value from the CMH chi-square test will be reported. 
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JNJ-54767414  (daratumumab)                         
                                                                 
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Stratification factors used in the analysis include ISS Stage (I, II, or III), and creatinine 
clearance (CrCl [30-50 mL/min or >50 mL/min]) from IWRS at randomization. 
5.2.3.
Sensitivity Analysis  
As a sensitivity analysis, a landmark sCR analysis will be performed for the post-consolidation 
sCR rate defined as the percentage of response-evaluable subjects who achieved or maintained 
sCR status within 30 days of post-ASCT consolidation disease evaluation visit. The sCR status 
is assessed using the computerized algorithm according to IMWG response criteria, and must be 
achieved prior to start of subsequent therapies. Subjects must not die or progress by post-ASCT 
consolidation disease evaluation visit. The same stratified CMH chi-square test as the primary 
analysis will be implemented for the sensitive analysis and comparison will be made between 
the two randomized treatment groups. 
For subjects entered maintenance phase but with missing post-ASCT consolidation disease 
evaluation visit, the date of the visit will be imputed by the median date from the end of Cycle 6 
to the post-ASCT consolidation disease evaluation visit among the subjects with none missing 
post-ASCT consolidation disease evaluation visit date.
In addition, sCR rate will be summarized for D-RVd treated subjects by randomized and safety 
run-in subjects. 
5.3.
Secondary Efficacy Endpoints
5.3.1.
Response Rate and Overall Response Rate (ORR)
5.3.1.1.
Definition
Best response:
The proportion of subjects achieving a complete response (CR), very good partial response 
(VGPR), partial response (PR) or stable disease (SD) as best response by the end of post-ASCT 
consolidation treatment will be determined by the validated computer algorithm using the 
IMWG criteria, respectively. 
ORR is defined as the proportion of subjects who achieve PR or better response (i.e., PR, VGPR, 
CR or sCR), according to IMWG response criteria. The proportion of subjects achieving sCR or 
CR, and the proportion of subjects achieving VGPR or better (i.e., VGPR, CR or sCR) will be 
determined by the validated computer algorithm using the IMWG criteria.
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JNJ-54767414  (daratumumab)                         
                                                                 
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The proportion of subjects achieving sCR/CR/VGPR/PR/SD response as best response, CR or 
better, VGPR or better and ORR will also be determined for the following timepoints in addition 
to post-ASCT consolidation treatment:

At the end of induction prior to ASCT

At the end of ASCT prior to consolidation 

At the end of maintenance therapy.  
5.3.1.2.
Analysis Methods
The number and percentage of subjects with each response of sCR/CR/VGPR/PR/SD, CR or 
better, VGPR or better, and ORR as best response at the end of each treatment phase will be 
summarized along with its corresponding 95% CI based on the response-evaluable analysis set. 
The proportion of subjects with sCR, CR or better, VGPR or better, and ORR will be compared 
between the two randomized treatment groups using the stratified CMH test. A Mantel-Haenszel 
odds ratio, along with its 2-sided 95% confidence interval and the p-value from the CMH chi-
squared test will be reported. Stratification factors used in the analysis include ISS Stage (I, II or 
III), and creatinine clearance (CrCl [30-50 mL/min or >50 mL/min]) from IWRS at 
randomization.
A sensitivity analysis of each response category, in which disease response is based on 
investigator assessment according to the IMWG response criteria, will be performed in a similar 
manner.
5.3.2.
Duration of sCR, CR and Duration of Response (DOR)
5.3.2.1.
Definition
Duration of response is defined for subjects with a confirmed response (PR or better) as the 
duration from the date of initial documentation of a response (PR or better) according to the 
IMWG criteria to the date of first documented evidence of progressive disease according to the 
IMWG criteria or death due to progressive disease.  Responders without disease progression
will be censored at the censoring timepoint as defined in Section 5.3.5 for time to progression 
(TTP).  
Duration of sCR and duration of CR are defined similarly as the DOR with the response 
targeting on sCR and CR, respectively.
5.3.2.2.
Analysis Methods
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.  
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JNJ-54767414  (daratumumab)                         
                                                                 
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Kaplan-Meier estimates will be generated and Kaplan-Meier curves for the duration of response
will be produced. No formal statistical comparison of DOR between the 2 randomized 
treatment groups is planned.
Duration of sCR and duration of CR will be analyzed similarly as DOR.
A sensitivity analysis of DOR, duration of sCR and duration of CR, in which disease response 
and progression are based on investigator assessment according to the IMWG response criteria, 
will be performed in a similar manner.
5.3.3.
Time to Response 
5.3.3.1.
Definitions
Time to response of sCR is defined as the time from the date of the first dose of study 
treatment for SRI subjects, and the date of randomization for randomized subjects, to the 
date of the a c h i e v i n g  s C R  based on the computerized algorithm, which was confirmed by 
a repeated measurement as required by the IMWG criteria. Subjects without sCR will be
censored at the censoring date for TTP as defined in Section 5.3.5.
Time to response of CR or better, VGPR or better, and PR or better are defined similarly as 
specified above. 
5.3.3.2.
Analysis Methods
Kaplan-Meier method will be used to estimate the cumulative distribution function of
response over time for subjects with response of sCR, CR or better, VGPR or better, and PR or 
better based on the response-evaluable analysis set. Median time to response with 95% CI will
be tabulated.  Kaplan-Meier estimates and curves for each response variable will be provided.  
In addition, descriptive statistics (n, mean,
standard deviation, median, range) will be
provided to summarize time to sCR, CR or better, VGPR or better, and PR or better response.
A sensitivity analysis of time to response based on investigator assessment according to the 
IMWG criteria will be performed.
5.3.4.
Progression-Free Survival
5.3.4.1.
Definition
PFS is defined as the duration from the date of the first dose of study treatment for SRI 
subjects and the date of randomization for the randomized subjects to the date of first 
documented evidence of progressive disease based on the computerized algorithm according to
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JNJ-54767414  (daratumumab)                         
                                                                 
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the IMWG response criteria or death due to any cause, whichever occurs first throughout the 
entire study. 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 before withdrawal of consent to
study. 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 clinical cut-off date for analysis will be censored at the last disease assessment. Subjects
without any post-baseline disease assessment will be censored at the first dose date of study 
treatment for SRI subjects and at the randomization date for randomized subjects.
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 and in the 
absence of PD
Date of death
PFS event
No post-baseline disease assessment
First dose date for SRI subjects and 
randomization date for randomized subjects
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
5.3.4.2.
Analysis Methods
Kaplan-Meier method will be used to estimate the distribution of PFS based on ITT analysis 
set. The estimated median PFS with 95% CI will be provided. The number and percentage
of subjects who had a PFS event or were censored will be reported. In addition, PFS rates
with 95% CI will be estimated by 12-month interval through Kaplan-Meier method.
Kaplan-Meier PFS curves will also be generated.
The comparison between the two randomized treatment groups of the distribution of overall PFS 
will be based on a stratified log-rank test for the ITT analysis set. The p-value from a stratified 
log-rank test will be reported. Hazard ratio and its 95% confidence interval will be estimated 
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JNJ-54767414  (daratumumab)                         
                                                                 
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based on a stratified Cox’s regression model with treatment as the sole explanatory variable. 
Stratification factors used in the analyses include ISS Stage (I, II or III), and creatinine clearance 
(CrCl [30-50 mL/min or >50 mL/min]) from IWRS at randomization.
Reasons for PFS censoring will be summarized for ITT analysis set.
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
above.
5.3.5.
Time to Disease Progression (TTP)
5.3.5.1.
Definition
TTP is defined as the time from the date of the first dose of study treatment for SRI subjects 
and the date of randomization for the randomized subjects to the date of first documented
evidence of confirmed progressive disease, as defined in the IMWG response criteria, or 
death due to progressive disease, 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 clinical cut-off date
for analysis will be censored at the last disease assessment.
Subjects without any post-
baseline disease assessment will be censored at the date of the first dose of study treatment for 
SRI subjects and the date of randomization for the randomized subjects. The TTP definition is 
similar to PFS except that death not due to progressive disease will be censored.
5.3.5.2.
Analysis Methods
Similar statistical methods will be applied to TTP as described for the PFS analysis.  
A sensitivity analysis of TTP, in which progressive disease is based on investigator
assessment according to the IMWG response criteria, will be performed in a similar manner.
5.3.6.
Overall Survival (OS)
5.3.6.1.
Definition
Overall survival (OS) is measured from the date of the first dose of study treatment for SRI 
subjects, and the date of randomization for the randomized subjects, 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 clinical 
cut-off date for the analysis will be censored at the last known date of being alive. The date of 
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JNJ-54767414  (daratumumab)                         
                                                                 
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last known alive will be determined by the maximum collection/assessment date from among 
selected data domains within the clinical database.
5.3.6.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of OS for each treatment
group for the ITT analysis set. 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. 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 primary analysis, the distribution of
OS for the 2 randomized 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.
5.3.7.
Progression-free Survival on Next Line of Therapy (PFS2) 
5.3.7.1.
Definition
Progression-free survival on next line of therapy (PFS2) is defined as the time from the date of 
the first dose of study treatment for SRI subjects, or date of randomization for the randomized 
subjects, to the progression on the next line of therapy or death due to any cause, whichever
comes first. Any deaths are considered as PFS2 events regardless if the death occurs before 2nd
line of subsequent therapy or not. The disease progression on the next line of therapy will be
based on investigator judgment.
Subjects who start next line of therapy without disease progression on study treatment will be 
censored at the last disease assessment before starting next line of therapy.
For those subjects who start next line of therapy after progression on study treatment, are still 
alive and not yet progressed on next line of therapy, they will be censored on the last date of 
follow-up. 
Subjects without any post-baseline follow-up will be censored at the first dose date of study 
treatment for SRI subjects, and at the date of randomization for randomized subjects.
Otherwise, subject will be censored at the minimum of 2nd line of next therapy start date minus 1 
and last date of follow-up for subjects who had subsequent anticancer therapy, or censored at the 
last date of follow-up for subjects who did not have subsequent anticancer therapy.
Determination of dates of PFS2 and dates for censoring is summarized in Table 3 as follows.
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JNJ-54767414  (daratumumab)                         
                                                                 
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Table 3:
PFS2 Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No post-baseline disease assessment 
First dose date of study treatment for SRI 
subjects and the date of randomization for 
randomized subjects
Censored
Alive and no disease progression on 
study treatment 
Date of last disease assessment prior to start of 
1st line on next therapy 
Censored
Disease progression on study 
treatment and progress on the 1st line 
of next therapy or any death 
Minimum of earliest date that indicates 
progression on the 1st line of next therapy and 
date of death
PFS2 event
Other
Minimum of start date of 2nd line of next 
therapy minus 1 and last date of follow-up
Censored
5.3.7.2.
Analysis Methods
PFS2 will be analyzed based on ITT analysis set similarly to PFS.
5.4.
Functional Status and Well-being
5.4.1.
Definition
Functional status and well-being will be assessed using three PRO measures, EQ-5D-5L, 
EORTC QLQ-C30, and EORTC QLQ-MY20. The PROs will be scored based on the instrument 
developer guidelines.
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.
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 
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JNJ-54767414  (daratumumab)                         
                                                                 
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100 according to the algorithm in EORTC QLQ-C30 scoring manual, version 3.0 (Fayers et
al, 2001). A higher score represents a higher ("better") level of functioning, or a higher
("worse") level of symptoms.
The EORTC Myeloma Module EORTC QLQ-MY20 is meant for use among a wide range of
patients with multiple myeloma, varying in disease stage and treatment modality. The myeloma
module incorporates a single item scale to assess body image, and three multi-item scales 
assessing disease symptoms, side effects of treatment and future perspective. The raw and 
standardized scores for symptom, side effects, future perspective and body image single item
scale will be calculated as described in the scoring manual.
5.4.2.
Analysis Methods
Compliance rates for completion of EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-MY20 at
each scheduled time point will be generated based on number of expected.
Key PRO endpoints

EQ-5D-5L VAS and utility score

EORTC QLQ-C30 global health status/quality of life subscales as follows

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

EORTC QLQ-MY20 body image, disease symptoms, side effects of treatment and future 
perspective
The change from baseline at each scheduled time point will be summarized descriptively (n,
mean, standard deviation, range, median, range) by treatment groups. 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 randomized treatment groups. 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 
standard deviation away from the mean score at baseline combining both randomized treatment 
groups. 
Time to improvement will be summarized by using descriptive statistics such as mean, standard 
deviation, median and range.
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JNJ-54767414  (daratumumab)                         
                                                                 
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For randomized subjects, time to worsening will be estimated using Kaplan-Meier methods. The 
hazard ratio for D-RVd relative to RVd and its associated 95% confidence interval (CI) will be 
calculated based on the stratified Cox proportional hazards model by the stratification factors 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.
5.5.
Subgroup Analyses
Subgroup analyses of the primary and selected secondary efficacy endpoints will be performed 
based on subgroups defined in Section 2.4 if deemed necessary.  
Descriptive summaries and forest plot for the computer algorithm assessed response rates will 
be provided for the subgroups specified in Section 2.4.  The subgroup analyses will be 
performed if there is adequate number of subjects in each subgroup.
6.
SAFETY
Safety evaluation will include adverse events (AEs), death, clinical laboratory tests (hematology 
and serum chemistry), vital signs, 12-lead ECG, physical exam findings, and ECOG performance 
status. 
Safety analyses will be performed based on the safety analysis set.  AEs will be summarized with 
4 groups displayed side by side. The 4 groups are randomized D-RVd, randomized RVd, safety 
run-in D-RVd, and All D-RVd. 12-lead ECG and ECOG performance status will be summarized 
by randomized D-RVd, randomized RVd, and safety run-in D-RVd.
6.1.
Adverse Events
AEs will be monitored throughout the study. All 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 electronic case report forms (eCRF) 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 of subject summarization in 
reporting the incidence of the AE, a subject is counted once if one or more events were recorded.   
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs), which are
defined as any AE that occurs after the first administration of study treatment (e.g., 
Daratumumab, Lenalidomide, Bortezomib, or Dexamethasone) through 30 days after the last 
study treatment administration or the day prior to start of subsequent therapy, whichever is 
earlier, or any AE that is considered related to study treatment (very likely, probably, or possibly
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JNJ-54767414  (daratumumab)                         
                                                                 
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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 related to study treatment by the investigator. 
The incidence of TEAEs will be summarized overall, by MedDRA system organ class (SOC) 
and preferred term, by maximum toxicity grade, and by relationship to study treatment 
administration. 
6.1.1.
Overview of TEAEs
An overview of TEAEs will be provided and will include the number and percentage (incidence) 
of subjects with any AEs, subjects with any toxicity grade 3 or higher AEs, subjects with any 
treatment-related AEs, subjects with any toxicity grade 3 or higher treatment-related AEs,
subjects with any SAEs, subjects with any treatment-related SAEs, subjects with any AEs 
leading to study treatment discontinuation, subjects with any treatment-related AEs leading to 
study treatment discontinuation, and subjects with any AEs with outcome of death
6.1.2.
  All TEAEs

Incidence of TEAEs by SOC, preferred term, and maximum toxicity grade (1-2 and 3-4)

Incidence of most common (at least 20%) TEAEs by SOC, and preferred term 
6.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity grade of 3-4 TEAEs, by SOC, preferred term and maximum toxicity 
grade

Incidence of most common (at least 10%) TEAEs with toxicity grade of 3-4, by SOC, 
and preferred term
6.1.4.
Study Treatment-Related TEAEs

Incidence of treatment-related TEAEs by SOC, preferred term and maximum toxicity 
grade (1-2 and 3-4)

Incidence of treatment-related TEAEs by SOC, preferred term and relationship

Incidence of treatment-related TEAEs with grade of 3-4 by SOC, preferred term and 
relationship

Incidence of TEAEs related to daratumumab by SOC, preferred term and maximum 
toxicity grade (1-2 and 3-4)
6.1.5.
Serious Adverse Events (SAEs)

Incidence of treatment-emergent SAEs, by SOC and preferred term
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Incidence of most common (at least 5%) treatment-emergent SAEs, by SOC and 
preferred term

Incidence of treatment-emergent SAEs related to study treatments by SOC, preferred 
term, and relationship

Incidence of treatment-emergent SAEs related to daratumumab by SOC and preferred 
term
6.1.6.
TEAEs Leading to Discontinuation of Any Study Treatment

Incidence of TEAEs leading to any study treatment discontinuation (Daratumumab, 
Lenalidomide, Bortezomib, or Dexamethasone) by SOC, preferred term and 
maximum toxicity grade (1-2, 3-4)

List of subjects who discontinued any study treatment due to AEs including subject 
ID, preferred term/verbatim term, study day of onset, toxicity grade, relationship to 
study treatment, action taken and outcome 
6.1.7.
TEAEs Leading to Cycle Delays or Dose Modifications

Incidence of TEAEs leading to any treatment cycle delays or dose modifications of at 
least one of the study treatments (Daratumumab, Lenalidomide, Bortezomib, or
Dexamethasone) by SOC, preferred term and maximum toxicity grade (1-2, 3-4) 
where dose modifications include dose skipping (not administered) or dose 
adjustment or dose stopped 
6.2.
Deaths

Incidence of subjects who died due to TEAEs by SOC,  preferred term

List of subjects whose primary cause of death is at least one AE during the study 
6.3.
Adverse Events of Clinical Interest

Infusion-related reaction (IRR)
o
Incidence of infusion-related reactions (IRRs) reported with Daratumumab by 
SOC, preferred term and maximum toxicity grade during all cycles
o
Incidence of IRRs reported with Daratumumab by SOC, preferred term and 
maximum toxicity grade during Cycle 1
o
Incidence of IRRs reported with Daratumumab by SOC, preferred term and 
event onset time
o
List of subjects with IRRs reported with Daratumumab including subject ID, 
MedDRA preferred term/verbatim, study day of event, toxicity grade, 
relationship to study treatment, action taken with study treatment and outcome
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Infections and infestations 
refer to adverse events with SOC of infections and infestations
o
Incidence of infections and infestations TEAEs with grade 3-4 by SOC, 
preferred term and maximum toxicity

Peripheral neuropathies (PNs)
refer to adverse events with high level term (HLT) of peripheral neuropathies NEC
o
Incidence of PNs by MedDRA high level term and preferred term, and 
maximum toxicity

Hemorrhage events
refer to the adverse events defined by Standardized MedDRA Queries (SMQ) with
the first subcategory SMQ of hemorrhage terms (exclude laboratory terms)
o
Incidence of hemorrhage by MedDRA high level term and preferred term, and 
maximum toxicity

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 
tumor necrosis, tumor lysis syndrome, or tumor necrosis)
o
TLS events will be listed

Second primary malignancies
o
Summary of second primary malignancies
o
List of subjects who reported second primary malignancies during the study
along with diagnosis, study day of diagnosis, recurrence of a prior existing
malignancy (yes, no) and pathology diagnosis (biopsy, aspirate, etc.)
information at time a second primary malignancy observed, cumulative study 
treatment exposure, the treatment for second primary malignancy and the 
outcome information 

TEAEs by subgroups:
The following summaries based on subgroups specified in Section Error! Reference 
source not found. will be provided if deemed necessary:

Overview of TEAEs

All TEAEs
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JNJ-54767414  (daratumumab)                         
                                                                 
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
Toxicity Grade 3 or 4 TEAEs

SAEs.
6.4.
Clinical Laboratory Tests
The evaluation of clinical safety laboratory tests will focus on the following selected laboratory 
analytes:
Hematology:
- hemoglobin
- white blood cell (WBC) count with absolute neutrophils and lymphocytes
- red blood cell (RBC) count 
- platelet count
Chemistry: 
- sodium
- total bilirubin
- potassium
- alkaline phosphatase
- creatinine and creatinine clearance (CrCl)
- calcium and albumin-adjusted calcium
- glucose 
- albumin
- aspartate aminotransferase (AST)
- blood urea nitrogen (BUN)
- alanine aminotransferase (ALT)
- lactic acid dehydrogenase (LDH)
Since safety laboratory tests for the trial is provided by local labs, they are reported according to 
each local lab normal ranges. A listing of subjects with any laboratory results outside the 
reference ranges (any grade 3 and above laboratory results) will be provided. 
6.5.
Vital Signs and Physical Examination
Baseline vital signs (systolic and diastolic blood pressure, heart rate, and temperature) values will 
be summarized. Similar analyses will be performed for weight at Day 1 of each treatment cycle. 
Post baseline physical examination findings were collected as AEs, and therefore will not be 
summarized.
6.6.
12-lead Electrocardiogram (ECG)
The number and percentage of subjects with normal or abnormal 12-lead ECG results will be 
summarized by scheduled study visits.    
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JNJ-54767414  (daratumumab)                         
                                                                 
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6.7.
ECOG Performance Status
Frequencies of ECOG performance status (0, 1, 2, >2) over time will be summarized. In addition, 
shift from baseline to worst score during treatment may be provided.
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMIC
Unless specified otherwise, descriptive statistics (e.g., number of observations, mean, SD,
median, and range) will be used to summarize pharmacokinetics and pharmacodynamics data
at protocol specified timepoints. In addition, coefficient variation and geometric mean will be
provided in the pharmacokinetic concentration summary.
7.1.
Pharmacokinetics
7.1.1.
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.  
7.1.2.
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 (± standard deviation) daratumumab serum peak and trough
concentrations over time will be provided.
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.
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JNJ-54767414  (daratumumab)                         
                                                                 
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7.2.
Immunogenicity
7.2.1.
Sampling Timepoints
Samples to assess the generation of antibodies to daratumumab (immunogenicity) will be
obtained from all subjects treated with D-RVd at predose of Cycles 1, 4, 5 and at post-
treatment Weeks 4 and 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.
7.2.2.
Analysis Methods
The incidence of antibodies to daratumumab (immunogenicity) will be summarized for all
subjects who receive at least one 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 be provided.  
7.3.
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.
8.
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.
8.1.
Minimal Residual Disease (MRD)
Bone marrow aspirates will be collected at baseline from all patients, as well as during 
treatment period in those subjects who attain or suspect to have a CR/sCR (including subjects 
with VGPR or better and suspected daratumumab interference) at 4 timepoints: at the end of 
induction prior to ASCT, at post-ASCT consolidation, 12 and 24 months (±3 weeks) during 
maintenance treatment. MRD will be monitored using ClonoSEQ Assay 2.0 on bone marrow
aspirate. The clonoSEQ assay has a sensitivity of 1 cancer cell in the background of ≥100,000 
white blood cells (<10-5) or greater, and will be utilized in this study to assess MRD.
NCT02874742


JNJ-54767414  (daratumumab)                         
                                                                 
           Statistical Analysis Plan 54767414MMY2004
38
Approved Date: 27 February 2019
8.1.1.
Definition
Post-ASCT consolidation MRD negative rate is defined as the proportion of subjects who 
achieved negative MRD at any time up to the post-ASCT consolidation disease evaluation visit, 
prior to subsequent antimyeloma therapy, after the first dose of study treatment for SRI subjects, 
and after randomization for the randomized subjects. MRD positive subjects include subjects 
of which all tested results were found to be MRD positive, or indeterminate, or 
unavailable (calibration failure or missing).  
8.1.2.
Analysis Methods
The MRD negative rate by using threshold of <10-5 will be analyzed similarly to the sCR rate
based on ITT analysis set. 
In addition, MRD negative rate up to the end of induction, up to 12-month of maintenance, and 
up to 24-month of maintenance will be presented in the same manner as the post-ASCT 
consolidation. 
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 6 months, or 12 months 
after the start of any MRD negativity) if sufficient data becomes available. Six-month durable 
MRD-negative is defined as MRD negative and confirmed by at least 6 months apart without 
MRD positive in between. One-year durable MRD-negative is defined as MRD negative and 
confirmed by at least 1 year apart without MRD positive in between.
A sensitivity analysis of MRD negative rate by using threshold of <10-4 will be performed in a 
similar manner as described above.  If data allow, an exploratory analysis using threshold of 
<10-6 will also be performed.
9.
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.
NCT02874742


JNJ-54767414  (daratumumab)                         
                                                                 
           Statistical Analysis Plan 54767414MMY2004
39
Approved Date: 27 February 2019
10.
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.
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.
3.
Sonneveld P, Avet-Loiseau H, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus 
of the International Myeloma Working Group. Blood. 2016 Jun 16;127(24):2955-62. 
NCT02874742


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Huiling Pei
09Apr2019, 20:08:32 PM, UTC
Document Approval
 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anil Londhe
09Apr2019, 20:15:31 PM, UTC
Document Approval
NCT02874742