A Phase 3 Study Comparing Daratumumab, VELCADE (Bortezomib), Lenalidomide, and Dexamethasone (D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects With Previously Untreated Multiple Myeloma Who Are Eligible for High-dose Therapy
Phase: PHASE3
Conditions: Multiple Myeloma
Sponsor: Stichting European Myeloma Network

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, 28 February 2024
Clinical Protocol
A Phase 3 Study Comparing Daratumumab, VELCADE (bortezomib), Lenalidomide,
and Dexamethasone (D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd)
in Subjects with Previously Untreated Multiple Myeloma who are Eligible for High-dose
Therapy
Protocol EMN17/54767414MMY3014; Phase 3
JNJ-54767414 (daratumumab)
AMENDMENT 5
The term “sponsor” is used throughout the protocol. The sponsor is identified on the Contact Information
page that accompanies the protocol.
EudraCT NUMBER: 2018-002992-16
EU TRIAL NUMBER: 2023-506125-10-00
Sponsor:
Stichting European Myeloma Network (EMN)
Sponsor representative: 
Status: 
Approved
Date: 
28 February 2024
Prepared by: Janssen Research & Development, LLC
EDMS number: EDMS-ERI-149334525, 9.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
PPD
PPD

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, 28 February 2024
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 7
SYNOPSIS.................................................................................................................................................. 10
ABBREVIATIONS...................................................................................................................................... 20
1. 
INTRODUCTION................................................................................................................................ 23
1.1. 
Background.................................................................................................................................... 23
1.1.1. 
Multiple Myeloma........................................................................................................................ 23
1.1.2. 
Treatment Options for Patients With Newly Diagnosed Multiple Myeloma................................ 23
1.1.3. 
VRd as Backbone Therapy Throughout Treatment.................................................................... 25
1.2. 
Daratumumab ................................................................................................................................ 26
1.2.1. 
Intravenous Daratumumab Administration in Combination Therapy Studies............................. 26
1.3. 
Summary........................................................................................................................................ 27
1.4. 
Overall Rationale for the Study...................................................................................................... 28
1.5. 
Benefit-risk Assessment................................................................................................................. 28
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 29
2.1. 
Objectives and Endpoints .............................................................................................................. 29
2.1.1. 
Objectives ................................................................................................................................... 29
2.1.2. 
Endpoints.................................................................................................................................... 30
2.2. 
Hypothesis ..................................................................................................................................... 30
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 31
3.1. 
Overview of Study Design.............................................................................................................. 31
3.2. 
Study Design Rationale.................................................................................................................. 33
4. 
SUBJECT POPULATION.................................................................................................................. 41
4.1. 
Inclusion Criteria ............................................................................................................................ 41
4.2. 
Exclusion Criteria ........................................................................................................................... 44
4.3. 
Prohibitions and Restrictions ......................................................................................................... 47
5. 
TREATMENT ALLOCATION AND BLINDING................................................................................. 48
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 48
6.1. 
Daratumumab ................................................................................................................................ 49
6.1.1. 
Daratumumab Subcutaneous Preparation ................................................................................. 49
6.1.2. 
Daratumumab Administration ..................................................................................................... 49
6.1.3. 
Guidelines for Prevention and Management of Injection Reactions .......................................... 50
6.1.3.1. 
Daratumumab Predose Medication......................................................................................... 50
6.1.3.2. 
Daratumumab Post-administration Medication ....................................................................... 51
6.2. 
Management of Injection-site and Infusion-related Reactions....................................................... 51
6.2.1. 
Daratumumab Local Injection-site Reactions............................................................................. 51
6.2.2. 
Daratumumab Infusion-related Reactions.................................................................................. 52
6.2.2.1. 
Infusion-related Reactions of Grade 1 or Grade 2 .................................................................. 52
6.2.2.2. 
Infusion-related Reactions of Grade 3 or Higher..................................................................... 52
6.2.2.3. 
Recurrent Infusion-related Reactions...................................................................................... 53
6.3. 
Bortezomib, Lenalidomide, and Dexamethasone (VRd)................................................................ 53
6.3.1. 
Bortezomib.................................................................................................................................. 53
6.3.1.1. 
Dose Calculation of Bortezomib.............................................................................................. 53

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, 28 February 2024
6.3.1.2. 
Bortezomib Administration....................................................................................................... 53
6.3.2. 
Lenalidomide Administration ...................................................................................................... 53
6.3.3. 
Dexamethasone Administration.................................................................................................. 54
6.4. 
Dose Delays and Dose Modifications ............................................................................................ 54
6.4.1. 
Cycle Delay................................................................................................................................. 54
6.4.2. 
Dose Modification Guidelines ..................................................................................................... 55
6.4.2.1. 
Daratumumab.......................................................................................................................... 55
6.4.2.1.1. 
Daratumumab Dose Modification......................................................................................... 55
6.4.2.1.2. 
Daratumumab-related Toxicity Management....................................................................... 55
6.4.2.1.3. 
Daratumumab Interruption or Missed Doses ....................................................................... 56
6.4.2.2. 
Lenalidomide ........................................................................................................................... 56
6.4.2.2.1. 
Dose Adjustments of Lenalidomide ..................................................................................... 56
6.4.2.2.2. 
Renal Impairment................................................................................................................. 57
6.4.2.3. 
Bortezomib............................................................................................................................... 57
6.4.2.3.1. 
Dose Adjustments of Bortezomib......................................................................................... 57
6.4.2.4. 
Dexamethasone ...................................................................................................................... 58
6.4.2.4.1. 
Dose Adjustments of Dexamethasone................................................................................. 58
7. 
TREATMENT COMPLIANCE............................................................................................................ 64
8. 
CONCOMITANT THERAPY.............................................................................................................. 64
8.1. 
Recommended Therapies.............................................................................................................. 64
8.1.1. 
Prevention of Deep Venous Thrombosis.................................................................................... 64
8.1.2. 
Therapy for Tumor Lysis Syndrome ........................................................................................... 65
8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia............................................................... 65
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 65
8.1.5. 
Prevention of Steroid Induced Gastritis...................................................................................... 65
8.1.6. 
Bisphosphonate Therapy............................................................................................................ 65
8.1.7. 
Management of Hepatitis B Virus Reactivation .......................................................................... 66
8.2. 
Permitted Therapies....................................................................................................................... 66
8.3. 
Prohibited Therapies...................................................................................................................... 66
8.4. 
Subsequent Therapies................................................................................................................... 67
9. 
STUDY EVALUATIONS.................................................................................................................... 68
9.1. 
Study Procedures........................................................................................................................... 68
9.1.1. 
Overview..................................................................................................................................... 68
9.1.2. 
Screening Phase ........................................................................................................................ 68
9.1.3. 
Treatment Phase ........................................................................................................................ 69
9.1.3.1. 
Induction Treatment (Cycles 1-4)............................................................................................ 69
9.1.3.2. 
Mobilization and Harvesting Stem Cells.................................................................................. 69
9.1.3.3. 
Conditioning (Melphalan off Study as per Standard of Care).................................................. 69
9.1.3.4. 
Transplant (as per Standard of Care)...................................................................................... 69
9.1.3.5. 
Engraftment/Recovery............................................................................................................. 70
9.1.3.6. 
Consolidation (Cycles 5-6) ...................................................................................................... 70
9.1.3.7. 
Post-consolidation Efficacy Assessment................................................................................. 70
9.1.3.8. 
Maintenance Treatment........................................................................................................... 70
9.1.4. 
End-of-Treatment Visit................................................................................................................ 70
9.1.5. 
Posttreatment Phase (Follow-up)............................................................................................... 71
9.2. 
Efficacy Evaluations....................................................................................................................... 72
9.2.1. 
Response Categories ................................................................................................................. 72
9.2.2. 
Myeloma Protein Measurements in Serum and Urine................................................................ 74
9.2.3. 
Albumin and Serum Calcium Corrected for Albumin.................................................................. 75
9.2.4. 
β2-microglobulin and Albumin .................................................................................................... 75
9.2.5. 
Bone Marrow Examination.......................................................................................................... 75
9.2.6. 
Minimal Residual Disease Assessment...................................................................................... 76
9.2.7. 
Assessment of Lytic Disease...................................................................................................... 76
9.2.8. 
Documentation of Extramedullary Plasmacytomas.................................................................... 77
9.3. 
Pharmacokinetics and Immunogenicity ......................................................................................... 78

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, 28 February 2024
9.3.1. 
Evaluations ................................................................................................................................. 78
9.3.2. 
Analytical Procedures................................................................................................................. 78
9.3.3. 
Pharmacokinetic Parameters ..................................................................................................... 78
9.3.4. 
Immunogenicity Assessments .................................................................................................... 79
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 79
9.5. 
Biomarkers/EMN Correlatives........................................................................................................ 80
9.6. 
Medical Resource Utilization.......................................................................................................... 81
9.7. 
Patient-reported Outcomes............................................................................................................ 81
9.8. 
Safety Evaluations ......................................................................................................................... 82
9.9. 
Sample Collection and Handling.................................................................................................... 86
10. SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL
FROM THE STUDY........................................................................................................................... 86
10.1. 
Completion ..................................................................................................................................... 86
10.2. 
Discontinuation of Study Treatment/Withdrawal From the Study.................................................. 86
10.3. 
Withdrawal From the Use of Research Samples........................................................................... 88
11. STATISTICAL METHODS................................................................................................................. 88
11.1. 
Subject Information ........................................................................................................................ 88
11.2. 
Sample Size Determination ........................................................................................................... 88
11.3. 
Efficacy Analyses........................................................................................................................... 88
11.4. 
Pharmacokinetic Analyses............................................................................................................. 89
11.5. 
Immunogenicity Analyses .............................................................................................................. 90
11.6. 
Biomarker Analyses ....................................................................................................................... 90
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 90
11.8. 
Medical Resource Utilization Analyses.......................................................................................... 90
11.9. 
Patient-reported Outcomes Analyses ............................................................................................ 90
11.10. Safety Analyses ............................................................................................................................. 91
11.11. Benefit-risk Analyses...................................................................................................................... 91
11.12. Interim Analysis.............................................................................................................................. 92
11.13. Independent Data Monitoring Committee ...................................................................................... 92
12. ADVERSE EVENT REPORTING ...................................................................................................... 93
12.1. 
Definitions ...................................................................................................................................... 93
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................... 93
12.1.2. 
Attribution Definitions.................................................................................................................. 94
12.1.3. 
Severity Criteria .......................................................................................................................... 94
12.2. 
Special Reporting Situations.......................................................................................................... 94
12.3. 
Procedures..................................................................................................................................... 95
12.3.1. 
All Adverse Events...................................................................................................................... 95
12.3.2. 
Serious Adverse Events ............................................................................................................. 96
12.3.3. 
Pregnancy................................................................................................................................... 97
12.4. 
Contacting Sponsor Regarding Safety........................................................................................... 97
13. PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 97
13.1. 
Procedures..................................................................................................................................... 97
13.2. 
Contact Information Regarding Product Quality ............................................................................ 98
14. STUDY DRUG INFORMATION......................................................................................................... 98
14.1. 
Physical Description of Study Drug................................................................................................ 98
14.2. 
Packaging ...................................................................................................................................... 98
14.3. 
Labeling.......................................................................................................................................... 98
14.4. 
Preparation, Handling, and Storage............................................................................................... 98
14.5. 
Drug Accountability........................................................................................................................ 98
15. STUDY-SPECIFIC MATERIALS....................................................................................................... 99
16. ETHICAL ASPECTS......................................................................................................................... 99
16.1. 
Study-specific Design Considerations ........................................................................................... 99

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, 28 February 2024
16.2. 
Regulatory Ethics Compliance..................................................................................................... 100
16.2.1. 
Investigator Responsibilities ..................................................................................................... 100
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................. 101
16.2.3. 
Informed Consent ..................................................................................................................... 102
16.2.4. 
Data Protection ......................................................................................................................... 103
16.2.5. 
Long-term Retention of Samples for Additional Future Research............................................ 104
16.2.6. 
Country Selection ..................................................................................................................... 104
17. ADMINISTRATIVE REQUIREMENTS............................................................................................ 104
17.1. 
Protocol Amendments.................................................................................................................. 104
17.2. 
Regulatory Documentation .......................................................................................................... 105
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 105
17.2.2. 
Required Prestudy Documentation........................................................................................... 105
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 106
17.4. 
Source Documentation................................................................................................................. 106
17.5. 
Case Report Form Completion .................................................................................................... 107
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 107
17.7. 
Record Retention ......................................................................................................................... 108
17.8. 
Monitoring .................................................................................................................................... 108
17.9. 
Study Completion/Termination..................................................................................................... 109
17.9.1. 
Study Completion/End of Study................................................................................................ 109
17.9.2. 
Study Termination..................................................................................................................... 109
17.10. On-Site Audits.............................................................................................................................. 110
17.11. Use of Information and Publication .............................................................................................. 110
18. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS.......................... 112
18.1. 
Appendix 1: Protocol Amendment History................................................................................... 112
REFERENCES.......................................................................................................................................... 130
INVESTIGATOR AGREEMENT............................................................................................................... 158
LIST OF ATTACHMENTS
Attachment 1: 
ECOG Performance Status Score Scale.................................................................. 134
Attachment 2: 
Modified Diet in Renal Disease Formula.................................................................. 135
Attachment 3: 
Serum Calcium Corrected for Albumin..................................................................... 136
Attachment 4: 
Asthma Guidelines ................................................................................................... 137
Attachment 5: 
Antihistamines That may be Used Predose ............................................................. 141
Attachment 6: 
Conversion Table for Glucocorticosteroid Dose....................................................... 142
Attachment 7: 
Body Surface Area Calculation ................................................................................ 143
Attachment 8: 
Individual and Myeloma-related Risk Factors .......................................................... 144
Attachment 9: 
Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE Interference
Test........................................................................................................................... 145
Attachment 10: 
EORTC QLQ-C30..................................................................................................... 146
Attachment 11: 
EORTC QLQ-MY20.................................................................................................. 148
Attachment 12: 
EQ-5D-5L.................................................................................................................. 150
Attachment 13: 
COVID-19 and Natural Disaster Guidance on Study Conduct and COVID-19
Vaccine Timing ......................................................................................................... 153

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, 28 February 2024
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Time and Events Schedule....................................................................................................... 12
Table 2: 
Pharmacokinetic and Immunogenicity Evaluations (Arm B Only) ............................................ 19
Table 3: 
Designations of Medicinal Products Used in the Study............................................................ 49
Table 4: 
Re-treatment Criteria Before the Start of Each Induction/Consolidation Cycle........................ 54
Table 5: 
Daratumumab-related Toxicity Management ........................................................................... 56
Table 6: 
Dose Modification Guidelines for Bortezomib, Lenalidomide, and Dexamethasone................ 58
Table 7: 
IMWG Consensus Recommendations for Multiple Myeloma Treatment Response
Criteria ...................................................................................................................................... 73
Table 8: 
Arm B Only (Section 6.1.2): Criteria for Loss of Complete Response Not Meeting
Criteria for Disease Progression (Per Table 7)......................................................................... 74
Table 9: 
Bone Marrow Testing................................................................................................................ 76
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 32
Figure 2: Daratumumab Serum Concentration at C3D1 Ctrough Following Daratumumab
Administered Subcutaneously (Study MMY1004) or Intravenously (Study MMY2002)........... 35
Figure 3: Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800 mg
(Subcutaneous Administration) and Dara-IV 16 mg/kg (Intravenous Administration).............. 37
Figure 4: Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (Ratio
of Trough Concentrations and Median Trough Concentration for Overall Population at
Each Dose) for Dara-MD 1800mg (Subcutaneous Administration) and Dara-IV
16mg/kg (Intravenous Administration)..................................................................................... 37
Figure 5: Progression-free Survival According to MRD Status 10-5 in Studies MMY3003 and
MMY3004.................................................................................................................................. 39

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, 28 February 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Original Protocol 
09 July 2018
Amendment 1 
04 September 2018
Amendment 2 
09 April 2019
Amendment 3 
20 March 2020
Amendment 4  
27 June 2022
Amendment 5 
28 February 2024
Amendment 5 (28 February 2024)
Overall Rationale for the Amendment: The key reasons for this protocol amendment are as follows:
To redefine the timing of the overall survival (OS) analyses after PFS superiority was established at
the first PFS interim analysis (clinical cutoff: 01 August 2023), including 1) forgoing the current first
OS interim analysis (185 PFS events); 2) keeping the interim OS analysis at 285 PFS events
(approximately 170 OS events; 55% of the total planned OS events) as the new first OS interim
analysis; 3) adding another interim OS analysis at 75% of the total planned OS events (233 events);
and 4) final OS analysis at 310 OS events.
To change the disease evaluation schedule for subjects who stopped treatment before Cycle 7 Day 1
without confirmed PD to every 4 weeks (±7 days) for the first 2 years and then every 8 weeks
(±14 days) relative to Cycle 1 Day 1 thereafter until confirmed PD, to align with standard of care.
To provide protocol clarifications for better understanding.
To align with EU CTR requirements.
The changes made to the clinical protocol EMN17/54767414MMY3014 as part of Protocol Amendment 5
are listed below, including the rationale of each change and a list of all applicable sections. Changes made
in previous protocol amendments are listed in Section 18, Appendix 1: Protocol Amendment History.
Section Number 
and Name
Description of Change 
Brief Rationale
Title page 
Updated EMN address. 
To update address to new office
location.
Title page; 
1.1 Synopsis 
Added EU TRIAL NUMBER. 
To align with EU CTR
requirements.
1.1 Synopsis 
Added EudraCT NUMBER.
Protocol Amendment 
Summary of 
Changes Table
Updated table header and moved previous 
amendments to new Section 18.1 (Appendix 1). 
To align with current protocol
template.
1.1 Synopsis 
Within Table 1, added that vital signs and serum 
chemistry assessments are required when 
daratumumab is restarted after stopping due to 
sustained MRD negativity. 
To clarify how often to monitor
vital signs and laboratory
assessments with daratumumab
restart.
1.1 Synopsis 
Within Table 1, clarified timing of patient- 
reported outcome (PRO) assessments post PD.
To align with Section 9.7.
1.1 Synopsis 
To the Table 1 footnote describing disease 
evaluations for subjects who discontinue treatment 
prior to Cycle 7 Day 1 without confirmed PD,
specified that these evaluations should be
performed every 4 weeks (±7 days) for the first
2 years and then every 8 weeks (±14 days) relative
to Cycle 1 Day 1 thereafter until confirmed PD.
To better align with standard of
care.

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, 28 February 2024
Section Number 
and Name
Description of Change 
Brief Rationale
1.1 Synopsis 
To Table 2, added a footnote indicating that for 
subjects who meet criteria to stop daratumumab 
due to sustained MRD negativity, posttreatment 
daratumumab PK, daratumumab immunogenicity, 
and rHuPH20 immunogenicity will be collected
8 weeks after the last dose of daratumumab. If the
subject restarts daratumumab, no further PK
samples need to be drawn.
To clarify that the last dose PK
should be done when daratumumab
is stopped and not wait until end of
treatment.
3.1 Overview of 
Study Design  
To footnote for Figure 1 (study schematic), 
changed footnote to read “Restart therapy upon
loss of CR or loss of MRD status” instead of
“Restart therapy upon relapse from CR or loss of
MRD status.”
For consistency across protocol.
Added text indicating that subjects who 
discontinued before disease progression must 
continue to have disease evaluations as specified
in Table 1 and should not initiate any subsequent
anticancer treatment until disease progression is
confirmed per IMWG criteria and approved by
medical monitor and documented in IWRS.
To clarify procedures for initiating
subsequent anticancer treatment.
6 Dosage and 
Administration  
Added table (Table 3) specifying the study 
medicinal products and their designations. 
To align with EU CTR
requirements.
6.1.2 Daratumumab 
Administration; 
9.1.4 End-of- 
Treatment Visit 
Clarified that subjects in Arm B who achieve 
MRD negativity and are continuing study
assessments but are not receiving study drug
should not complete an End-of-Treatment Visit.
For clarification.
6.1.2 Daratumumab 
Administration  
Added that, following daratumumab restart, vital 
signs and hematology and serum chemistry 
laboratory assessments should be monitored prior 
to each daratumumab administration. 
To clarify how often to monitor
vital signs and laboratory
assessments with daratumumab
restart.
6.1.3.1 
Daratumumab 
Predose Medication  
Clarified that subjects who restart daratumumab 
after interruption due to sustained MRD negativity  
should be given dexamethasone 20 mg IV or PO 
for the first 2 doses and 10 mg for all subsequent
doses.
To clarify dexamethasone
administration following
daratumumab restart.
6.2.2 Daratumumab 
Infusion-related 
Reactions 
Added that if ocular symptoms (including 
choroidal effusion, acute myopia, and acute angle 
closure glaucoma) occur, daratumumab should be
interrupted and immediate ophthalmologic
evaluation should be sought prior to restarting
daratumumab.
To align with updated safety data
for daratumumab.
8.2 Permitted 
Therapies 
Added that subjects may continue lenalidomide on 
the day of vaccine administration per institutional 
practice. 
To clarify that there is no need to
pause lenalidomide on the day of
vaccine administration per
institutional practice.
8.4 Subsequent 
Therapies 
Clarified that it is not permissible to start other 
anti-myeloma therapy until disease progression is 
confirmed by IMWG criteria and approved by the
medical monitor. Disease progression should be
monitored and documented in the CRF, according
to Table 1.
To clarify procedures for initiating
subsequent anticancer treatment.
9.2.1 Response 
Categories 
To the table describing criteria for loss of CR, 
added footnote stipulating that 2 consecutive 
assessments for reappearance of serum or urine 
M-protein are needed.
To clarify that confirmatory
samples are needed before
restarting daratumumab.

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, 28 February 2024
Section Number 
and Name
Description of Change 
Brief Rationale
9.8 Safety 
Evaluations 
For total bilirubin, removed that direct bilirubin is 
required if total bilirubin is abnormal.
To align with current practice.
10.2 Discontinuation 
of Study 
Treatment/Withdrawl 
From the Study  
Removed the following text (shown in strikeout): 
A subject will not be automatically withdrawn
from the study if he or she must discontinue study
treatment before the end of the treatment regimen;
instead, the subject will enter the Follow-up Phase.
For clarification.
11.2 Sample Size 
Determination  
Removed the following text (shown in strikeout): 
Long-term follow-up for survival will continue 
until approximately 310 deaths have been
observed or 9 years have elapsed after the last
subject is randomized, whichever occurs earlier.
To align with the updated timing of
OS analyses.
11.12 Interim 
Analysis 
Indicated that descriptive analysis of OS was 
performed at the time of the first PFS interim 
analysis and updated the timing for subsequent OS 
analyses. 
To redefine the timing of the OS
analyses after PFS superiority was
established at the first PFS interim
analysis (clinical cutoff:
01 August 2023).
11.13 Independent 
Data Monitoring 
Committee 
Added that no further IDMC meetings will be 
scheduled after the primary endpoint was met, and 
safety data will continue to be reviewed by the 
sponsor. Clarified that the medical monitors will 
remain blinded regarding OS. 
The primary endpoint was met at
the first interim analysis of PFS,
the study data were unblinded, and
no new safety signals were
observed; therefore, no further
IDMC meetings will be scheduled.
16.2.4 Data 
Protection  
Retitled section to “Data Protection” and made 
title of section (“Privacy of Personal Data”) a 
subheading.
To be consistent with EU CTR data
protection requirements.
17.7 Record 
Retention  
Added that for trials performed under Regulation 
[EU] No. 536/2014, the sponsor and the 
investigator shall archive the content ofthe
clinical trial master file for at least 25 years after
the end of the clinical trial.
To comply with EU CTR data
requirements.
17.9.1 Study 
Completion/End of 
Study  
Removed the following text (shown in strikeout): 
The study is considered completed when 310 
deaths have been observed or 9 years have elapsed
after the last subject is randomized.
To align with the updated timing of
OS analyses.
17.11 Use of 
Information and 
Publication  
Clarified that the use of information applies to the 
study site as well as the investigator.
For clarification.
Updated disclosure of results. 
To align with Section 11.2.
18 Supporting 
Documentation and 
Operational 
Considerations
Added section for protocol amendment history and 
moved description of previous amendments to this 
section.
To align with current protocol
template.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted.

JNJ-54767414 (daratumumab)
Clinical Protocol EMN17/54767414MMY3014 Amendment 5
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, 28 February 2024
SYNOPSIS
EudraCT NUMBER: 2018-002992-16
EU TRIAL NUMBER: 2023-506125-10-00
A Phase 3 Study Comparing Daratumumab, VELCADE (bortezomib), Lenalidomide, and Dexamethasone
(D-VRd) vs VELCADE, Lenalidomide, and Dexamethasone (VRd) in Subjects with Previously Untreated
Multiple Myeloma who are Eligible for High-dose Therapy
BENEFIT-RISK ASSESSMENT
Subjects in this study will be assigned in a randomized manner to receive either 1800 mg daratumumab SC
in combination with VRd (D-VRd) as induction and consolidation therapy and in combination with
lenalidomide maintenance therapy or VRd alone as induction and consolidation therapy and lenalidomide
alone as maintenance therapy. The sequence of VRd induction/ASCT/VRd consolidation/lenalidomide
maintenance is the global standard of care (SOC). While treatment with D-VRd has demonstrated a
manageable safety profile consistent with the known safety profile of daratumumab SC and VRd alone,
management guidelines for potential toxicities are detailed in the protocol. Overall, there is a positive
benefit/risk profile for this patient population.
OBJECTIVES
The primary objective is to determine if the addition of daratumumab to bortezomib, lenalidomide, and
dexamethasone (VRd) will prolong progression-free survival (PFS) defined as the time from the date of
randomization to the date of disease progression (assessed by International Myeloma Working Group
[IMWG] criteria) or death, compared with VRd alone.
Key secondary objectives include the following:
To determine if the addition of daratumumab to VRd will improve clinical outcome as measured by:
Minimal residual disease (MRD) negativity rate post-consolidation and overall MRD negativity
rate achieved at any time during the study
Overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of
complete response (CR) or better, rate of stringent CR (sCR) at post-induction, post-transplant,
post-consolidation, and overall
Time to response
Duration of response
Progression-free survival on the next line of therapy (PFS2)
Overall survival (OS)
To assess the safety profile of daratumumab+VRd (D-VRd)
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, multicenter study evaluating subjects with newly diagnosed multiple
myeloma who are deemed eligible for high-dose therapy. Approximately 690 subjects will be stratified by
International Staging System (ISS) Stage I, II, or III disease (β-2 microglobulin and albumin) and
cytogenetics (standard risk or high risk as defined by presence of del17p, t[4;14] or t[14;16]), and then
randomized in a 1:1 ratio. In Arm A, subjects will receive VRd for induction and consolidation, followed
by lenalidomide (R) maintenance until disease progression. Subjects in Arm B will receive D-VRd for
induction and consolidation followed by daratumumab and lenalidomide maintenance until disease
progression. Subjects in Arm B who have a response of CR or better will stop therapy with daratumumab

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after sustained MRD negativity (at or below the threshold of 10-5) for 12 months and a minimum of
24 months of maintenance therapy. These subjects will continue lenalidomide maintenance therapy until
disease progression. After stopping daratumumab therapy, subjects with sustained MRD negativity should
restart therapy with daratumumab if there is a recurrence of MRD at 10-4  or higher or a confirmed loss of
CR without disease progression, as evidenced by the reappearance of serum or urine monoclonal protein
(M-protein) or increase to ≥5% plasma cells in bone marrow. After reinitiating daratumumab, the subject
will continue daratumumab and lenalidomide therapy until disease progression.
DOSAGE AND ADMINISTRATION
Subjects will receive 6 cycles of treatment (4 cycles of treatment for induction and 2 cycles of treatment
for consolidation) followed by maintenance (Cycle 7+).
Daratumumab will be given subcutaneously (SC) at 1800 mg to subjects in Arm B once every week for
Cycles 1 to 2, then every 2 weeks for Cycles 3-6. For maintenance Cycles 7+, subjects will receive
daratumumab (1800 mg) once every 4 weeks until documented disease progression or unacceptable
toxicity.
Bortezomib will be given as a SC injection (1.3 mg/m2) twice a week for 6 cycles.
Lenalidomide will be administered PO at 25 mg for 6 cycles. Subjects will start maintenance therapy
(Cycle 7+), during which they will receive lenalidomide 10 mg daily PO on Days 1 to 28 (continuously) of
each 28-day cycle until disease progression or unacceptable toxicity.
Dexamethasone will be administered PO at 40 mg on Days 1-4 and 9-12 during Cycles 1-6 as part of the
VRd backbone regimen.
EFFICACY EVALUATIONS
Assessment of tumor response and disease progression will be conducted in accordance with the IMWG
response criteria. Efficacy evaluations will include measurements of tumor burden/residual disease,
myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary plasmacytomas, and serum
calcium corrected for albumin.
OTHER EVALUATIONS
Blood samples will be drawn from all subjects in Arm B to characterize the pharmacokinetics (PK) of
daratumumab to the incidence of anti-daratumumab antibodies, and the prevalence and incidence of
anti-rHuPH20 antibodies. Blood and bone marrow aspirate samples may be used to obtain information
about potential markers of clinical response.
Data regarding subjects’ health-related quality of life (HRQoL), symptoms, functioning, and general well-
being will be captured using 3 patient-reported outcome (PRO) measures. Medical resource utilization
(MRU) data will be collected.
SAFETY EVALUATIONS
Safety evaluations include adverse event (AE) monitoring, physical examinations, electrocardiograms
(ECGs), echocardiogram (ECHO) or multigated acquisition (MUGA) scan (only required for subjects
≥65 years old), SC injection-site evaluations, clinical laboratory parameters (hematology and chemistry),
vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance status.
STATISTICAL METHODS
Response to study treatment and progressive disease (PD) will be evaluated by a validated computer
algorithm. The assumption is that the addition of daratumumab will decrease the risk of progression or
death by 31% (hazard ratio [HR]=0.69).

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Table 2: 
Pharmacokinetic and Immunogenicity Evaluations (Arm B Only)
Induction Treatment 
(Cycles 1-4) 
Consolidation 
Treatment 
(Cycles
5-6)
Maintenance Treatment
(Cycles 7+)
Follow-up
Phase
Cycle 1 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 7 
Cycle 9 
Cycle 12
Posttreatment
Week 8
(±1 week)
D1a 
D4b 
D1a 
D4b 
D15 
D1a 
D4 b 
D1a 
D1a 
D1a
Daratumumab 
pharmacokinetics (serum) 
Xa 
predose 
X 
Xa 
predose 
X 
Xa 
predose 
Xa 
predose 
X 
Xa 
predose 
Xa 
predose 
Xa
predose
Xf 
Daratumumab 
immunogenicityc,d 
Xa 
predose 
Xa 
predose 
Xa 
predose 
Xa,e 
predose 
Xa 
predose
Xf
rHuPH20 
immunogenicity  
(plasma)d
Xa 
predose 
Xa 
predose 
Xa 
predose 
Xa,e 
predose 
Xa 
predose
Xf
a. 
Predose timepoints have a window of 0 days as they should always be predose on the day of dosing. On dosing days, sample collection may occur up to 2 hours before but not after
the start of daratumumab administration. Samples collected on dosing days with visit windows should be collected on the actual day of daratumumab administration.
b. 
Day 4 timepoints have a window of ±1 day.
c. 
No additional sample needed; will be aliquoted from PK sample.
d. 
When an IRR occurs associated with the second or later daratumumab administration, 2 separate blood samples should be obtained, if possible, for determination of
anti daratumumab antibodies and anti rHuPH20 antibodies.
e. 
Daratumumab and rHuPH20 immunogenicity required only at C7D1 for subjects not receiving consolidation treatment (ie, C5 C6) after transplant.
f. 
For subjects who meet criteria to stop daratumumab due to sustained MRD negativity, posttreatment daratumumab PK, daratumumab immunogenicity, and rHuPH20 immunogenicity
will be collected 8 weeks after the last dose of daratumumab. If the subject restarts daratumumab, no further PK samples need to be drawn.
Abbreviations: IRR injection related reaction; PK pharmacokinetic; rHuPH20 recombinant human hyaluronidase.

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ABBREVIATIONS
AE  
adverse event(s)
ALT  
alanine aminotransferase
ANC  
absolute neutrophil count
Anti-HBc 
antibodies to hepatitis B core antigen
Anti-HBs 
antibodies to hepatitis B surface antigen
ASCT  
autologous stem cell transplant
AST  
aspartate aminotransferase
BSA 
body surface area
BUN  
blood urea nitrogen
Cmax  
maximum observed concentration
Cmin  
minimum observed concentration
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CRAB  
calcium, renal, anemia, bone
CrCl 
creatinine clearance
CRF  
case report form
CT  
computed tomography
Ctrough  
lowest drug concentration reached before the next dose is administered
Dara-IV  
daratumumab for intravenous infusion
Dara-MD  
daratumumab and recombinant human hyaluronidase for subcutaneous injection: mix
and deliver
Dara-SC 
daratumumab administered subcutaneously
DLCO  
diffusing capacity of the lung for carbon monoxide
DLT  
dose-limiting toxicity
DNA  
deoxyribonucleic acid
D-Rd 
daratumumab in combination with lenalidomide and dexamethasone
D-Vd 
daratumumab in combination with bortezomib and dexamethasone
DVMP  
daratumumab in combination with bortezomib, melphalan, and prednisone
D-VRd 
daratumumab in combination with bortezomib, lenalidomide, and dexamethasone
ECG  
electrocardiograms
ECHO  
echocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire
EORTC QLQ-MY20 
European Organization for Research and Treatment of Cancer Multiple Myeloma
Module
EOT  
End-of-Treatment
EQ-5D-5L 
EuroQol Group Five Dimensions Five Levels
ESM  
External Safety Monitor
ESMO  
European Society for Medical Oncology
FACS  
fluorescence-activated cell sorting
FDA  
Food and Drug Administration
FEV1 
forced expiratory volume in 1 second
FLC  
free light chain
FOIA  
Freedom of Information Act
GCP  
Good Clinical Practice
G-CSF  
granulocyte colony-stimulating factor
GHS  
Global Health Status
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HR  
hazard ratio
HRQoL 
health-related quality of life
IAT  
indirect antiglobulin test
ICF  
informed consent form

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ICH  
International Conference on Harmonisation
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFM  
Intergroupe Francophone du Myélome
Ig 
immunoglobulin
IMWG  
International Myeloma Working Group
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IRR  
infusion-related reaction
ISS  
International Staging System
IV  
intravenous
IWRS  
interactive web response system
MDRD  
Modified Diet in Renal Disease
MoA  
mechanism of action
M-protein  
monoclonal protein
MRD  
minimal residual disease
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
MUGA  
multigated acquisition
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events
nCR  
near complete response
NGS  
next-generation sequencing
ORR  
overall response rate
OS  
overall survival
PCR  
polymerase chain reaction
PD 
progressive disease
PET  
positron emission tomography
PFS  
progression-free survival
PFS2 
progression-free survival on the next line of therapy
PK 
pharmacokinetic(s)
PO 
orally
PQC  
product quality complaint
PR 
partial response
PRO  
patient-reported outcome(s)
R 
lenalidomide
RBC  
red blood cell
Rd 
lenalidomide-dexamethasone
rHuPH20 
recombinant human hyaluronidase
SAE 
serious adverse event
SC 
subcutaneous
sCR  
stringent complete response
SIFE 
serum immunofixation
sIPPM  
site Investigator Product Procedures Manual
SOC  
standard of care
SPEP  
serum M-protein quantitation by electrophoresis
SUSAR  
suspected unexpected serious adverse reaction
SVR  
sustained virologic response
TEAE  
treatment-emergent adverse event
UIFE 
urine immunofixation
ULN  
upper limit of normal
UPEP  
urine M-protein quantitation by electrophoresis
VCd 
bortezomib, cyclophosphamide, and dexamethasone
Vd 
bortezomib and dexamethasone
VGPR  
very good partial response
VMP  
bortezomib, melphalan, and prednisone
VRd 
bortezomib, lenalidomide, and dexamethasone
VTd 
bortezomib, thalidomide, and dexamethasone

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Definition of Study Terms
daratumumab=study drug
daratumumab+VRd=study treatment

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1. 
INTRODUCTION
Daratumumab has multiple mechanism of actions (MoAs), including the direct targeting of tumor
cells by selectively binding to CD38 molecules, immune mediated activity with
antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and
complement-dependent cytotoxicity (CDC), decreased immunosuppression and CD38 enzymatic
inhibition. 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.
Recombinant human hyaluronidase (rHuPH20) cleaves the repeating disaccharide subunits
(N-acetyl-D-glucosamine and D-glucuronic acid) of hyaluronan, a polymeric, gel-like
glycosaminoglycan (mucopolysaccharide) that are present in the subcutaneous (SC) tissue matrix.
rHuPH20 acts locally and transiently within the SC space to increase the tissue dispersion and
absorption of other injected drugs and fluids. A new presentation of daratumumab as a
co-formulated product of daratumumab and rHuPH20 allows for the SC administration of
daratumumab.
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 is characterized by uncontrolled and progressive proliferation of a plasma cell
clone. Patients with multiple myeloma produce a monoclonal protein (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. The proliferation of myeloma cells causes displacement
of the normal bone marrow. Normal Ig levels are compromised, leading to susceptibility to
infections in affected patients. Hypercalcemia, renal insufficiency or failure, and neurological
complications are frequently reported signs and symptoms of the disease.
1.1.2. 
Treatment Options for Patients With Newly Diagnosed Multiple
Myeloma
Over the past decade, the introduction of new classes of drugs, such as immunomodulatory drugs
and proteasome inhibitors have changed the frontline treatment of patients with multiple myeloma
(NCCN 2017, Durie 2017, Moreau 2013, Cavo 2011, Palumbo 2014). Multiple-drug combinations
are superior to single- or double-agent combinations in treating multiple myeloma (Cavo 2012,
van der Veer 2011). Bortezomib-based treatment regimens have demonstrated significant
improvements in response, progression-free survival (PFS) and overall survival (OS) compared
with non-bortezomib-based therapy, both in newly diagnosed transplant-ineligible patients and
those suitable for induction and transplant (Sonneveld 2013, Dimopoulos 2009). Conventional
means of assessing response are not sufficiently sensitive to measure low levels of residual bone

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marrow disease so-called minimal residual disease (MRD). Therefore, currently, the goal of
multiple myeloma treatment is achievement of MRD negativity per the most recent IMWG
response criteria (Kumar 2016).
Patients with newly diagnosed multiple myeloma are classified as eligible for high-dose therapy
or ineligible for high-dose therapy based on a patient’s age, comorbidities, and functional status.
The standard treatment approach for newly diagnosed patients who are considered eligible for
high-dose therapy includes induction, high-dose chemotherapy and stem cell transplantation, and
consolidation and maintenance.
Induction Therapy
Transplant-eligible patients are treated with an induction regimen to reduce the plasma cell disease
burden and improve the depth of response. Response rates to induction therapy have been
significantly increased using triple combination chemotherapy. Bortezomib-based induction
regimens 
including 
bortezomib-lenalidomide-dexamethasone 
(VRd), 
bortezomib-
cyclophosphamide-dexamethasone (VCd), and bortezomib-thalidomide-dexamethasone (VTd)
improve response and prolong PFS/OS compared with the same regimens without bortezomib.
The addition of bortezomib results in a higher rate of side effects, most notably peripheral
neuropathy, but does not increase the risk of death during induction (Sonneveld 2013). For newly
diagnosed patients who are eligible for autologous stem cell transplant (ASCT), VRd, VCd, and
VTd are now considered standard induction regimens (Richardson 2010, Engelhardt 2014,
Moreau 2013, NCCN 2017, Moreau 2017).
High-dose Chemotherapy and Stem Cell Transplantation
Autologous stem cell transplantation following high-dose therapy has now become the standard
approach to improve and deepen response. After attaining at least a partial response (PR) on
induction therapy, blood stem cells are mobilized in peripheral blood with the use of granulocyte
colony-stimulating factor (G-CSF) with either cyclophosphamide, or in some cases, plerixafor
(Mozobil) (Giralt 2009). ASCT in addition to combination chemotherapy has been shown to
improve complete response (CR) rates and prolong median OS by approximately 12 months
compared with chemotherapy without ASCT (Child 2003, Blade 2000).
Consolidation Therapy
Improved rates of CR and near CR (nCR), in the range between 10% and 30%, have been reported
with post-ASCT use of bortezomib or lenalidomide as single agents (Mellqvist 2009, Attal 2009).
Both VTd and VRd consolidation (2 cycles) following ASCT increased response and prolonged
PFS (Leleu 2013, Sonneveld 2016).
Maintenance Therapy
Maintaining response after successful induction, high-dose chemotherapy with transplant and
consolidation is an important goal in treating patients with multiple myeloma. Lenalidomide, given
as maintenance therapy after ASCT, has been approved by the European Medicines Agency and Food
and Drug Administration (FDA) based on 2 randomized Phase 3 studies. (McCarthy 2012,
Attal 2012, Revlimid SmPC, Revlimid USPI). A meta-analysis including 3 studies evaluated

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1208 subjects who received either lenalidomide or placebo post-ASCT as maintenance therapy and
demonstrated improvement of both PFS and OS with lenalidomide maintenance therapy (McCarthy
2017).
1.1.3. 
VRd as Backbone Therapy Throughout Treatment
The VRd regimen initially was studied by Richardson and colleagues (Richardson 2010) in a
Phase 1-2 study comparing VRd to lenalidomide and dexamethasone (Rd) for newly diagnosed
patients with multiple myeloma, regardless of eligibility for high-dose therapy and ASCT.
Sixty-six subjects were treated on this single-arm study. Overall response rate (ORR) was 100%,
CR was 29%, and nCR was 11%. Twenty-eight subjects (42%) proceeded to undergo ASCT. Stem
cell harvesting and engraftment were not affected adversely by the three-drug induction regimen.
Thus, this study established VRd as a safe and effective induction regimen prior to ASCT.
The Intergroupe Francophone du Myélome (IFM) conducted a Phase 2 study of VRd in newly
diagnosed patients with multiple myeloma who were eligible for ASCT (Roussel 2014). In this
study, 31 subjects received 3 cycles of VRd followed by stem cell harvest and transplantation,
followed by an additional 2 consolidation cycles of VRd, and one year of lenalidomide
maintenance therapy. The ORR after 3 cycles of induction therapy was 94%, CR rate was 13%,
and stringent CR (sCR) rate was 10%. Responses improved over the duration of the study with an
overall CR rate of 10%, sCR rate of 48%, and 68% of subjects achieving MRD-negative status (at
a sensitivity of 10 4) by flow cytometry. Thus, this study demonstrated the improvement of
response with the addition of VRd consolidation and lenalidomide maintenance therapy after
ASCT.
The IFM cooperative group evaluated the VRd regimen in 700 newly diagnosed transplant-eligible
subjects with multiple myeloma. Subjects were treated with 3 cycles of induction therapy with
VRd; immediate ASCT; 2 cycles of consolidation with VRd; and 1 year of lenalidomide
maintenance (n 350) or 8 cycles of VRd induction and 1 year of lenalidomide maintenance
(salvage ASCT was to take place at the time of disease group) (n 350). Median PFS was
significantly improved in the subjects with transplant as part of their initial therapy (50 months
compared with 36 months, HR 0.65, 95% CI 0.53-0.8; p value <0.001). The CR rate was 59% in
the VRd transplant arm compared with 48% in the VRd alone arm. The MRD negativity rate as
measured by 7-color flow cytometry (between 10 4  and 10 5) was 79% in the VRd transplant arm
compared with 65% in the VRd alone arm (Attal 2017). Overall survival at 4 years did not differ
between the 2 groups; 82% in VRd alone compared with 81% in the VRd transplant group. This
study demonstrated the superiority of initial transplant with the VRd regimen with prolongation of
PFS in addition to improvement of CR rate and MRD negativity rate.
The Spanish Myeloma Group (PETHEMA/GEM) evaluated the VRd regimen in a Phase 3 study
with 458 patients enrolled and treated with 6 cycles of VRd followed by randomization to
conditioning with Melphalan-200 mg vs Busulphan 9.6 mg/kg plus melphalan 140 mg prior to
ASCT followed by 2 cycles of VRd after ASCT for both arms of the study (Rosinol 2019). Initial
results showed an ORR of 85% at the end of induction therapy, with 39% of subjects achieving
CR or better. Grade 3/4 neutropenia and thrombocytopenia were reported in 11% and 6% of

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patients respectively. Grade 3 peripheral neuropathy was only 1% with no Grade 4 events. Dose
reductions due to toxicity occurred in 31% of patients with 18% bortezomib reductions, 10%
lenalidomide reductions, and 3% dexamethasone reductions. Sixty-one (61) patients (13%)
discontinued the study prior to ASCT, 32 patients due to progressive disease (PD), 9 patients due
to toxicity, 7 due to death, and 13 for other reasons. The median stem cell collection was 4.66×106.
This study demonstrates the tolerability and deep responses with the VRd regimen.
1.2. 
Daratumumab
1.2.1. 
Intravenous Daratumumab Administration in Combination Therapy
Studies
Two Phase 3 studies examined the safety and efficacy of daratumumab for intravenous infusion
(Dara-IV) in combination with other therapies in the treatment of relapsed multiple myeloma:
In Study MMY3003, subjects with multiple myeloma received intravenous (IV) daratumumab
in combination with lenalidomide and dexamethasone (DRd). At the time of the first interim
analysis, treatment with DRd resulted in a 63% reduction in the risk of disease progression or
death compared with Rd alone. The median PFS was not reached in the daratumumab group;
median PFS was 18.4 months in the Rd group. The ORRs were 93% for the DRd group and
76% for Rd group. The safety profile was consistent with the known safety profile of
daratumumab and the backbone regimen, and no new safety signals were identified.
In Study MMY3004, subjects with multiple myeloma received IV daratumumab in
combination with bortezomib and dexamethasone (DVd). At the time of the first interim
analysis, treatment with DVd showed a 61% reduction in the risk for disease progression or
death compared with bortezomib and dexamethasone (Vd) alone. The median PFS was not
estimable in the DVd group; median PFS was 7.2 months in the Vd group. The ORRs were
83% for the DVd group and 63% for the Vd group. The safety profile was consistent with the
known safety profile of daratumumab and the backbone regimen, and no new safety signals
were identified.
Three Phase 3 studies examined the safety and efficacy of IV daratumumab in combination with
other therapies in previously untreated multiple myeloma:
In Study  MMY3007, subjects with multiple myeloma received IV daratumumab in
combination with bortezomib, melphalan, and prednisone (DVMP). At the time of the primary
analysis, treatment with DVMP resulted in a 50% reduction in the risk of disease progression
or death compared with bortezomib, melphalan, and prednisone (VMP) alone. The median
PFS was not reached in the daratumumab group; median PFS was 18.1 months in the VMP
group. The ORRs were 91% for the DVMP group and 74% for the VMP group. The safety
profile was consistent with the known safety profile of daratumumab and the backbone
regimen, and no new safety signals were identified.
In Study MMY3008, subjects with multiple myeloma received IV daratumumab in
combination with lenalidomide and dexamethasone (DRd).
In Study MMY3006, subjects with multiple myeloma received IV daratumumab in
combination with bortezomib, thalidomide, and dexamethasone (D-VTd).

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Collectively, the data from Studies MMY3003, MMY3004, and MMY3007 demonstrate a
favorable benefit-risk profile of the triplet DVd and DRd regimens for the treatment of subjects
with relapsed or refractory multiple myeloma who have received at least 1 prior therapy and the
quadruplet regimen of daratumumab and VMP in transplant-ineligible subjects with newly
diagnosed multiple myeloma.
One Phase 2 study is examining the safety and efficacy of Dara-IV in combination with VRd. In
Study MMY2004 (NCT02874742), Dara-IV in combination with VRd, (D-VRd) is being
compared to VRd alone in subjects with newly diagnosed multiple myeloma eligible for high-dose
chemotherapy and ASCT. The primary endpoint of this study is sCR rate post-consolidation.
Subjects will receive 4 cycles of VRd induction therapy followed by ASCT and 2 cycles of VRd
consolidation therapy followed by maintenance therapy until disease progression or unacceptable
toxicity.
The initial 16 subjects were enrolled in the safety run-in and data after all subjects completed
4 cycles of induction therapy is provided below (Voorhees 2017). During Cycle 1, 3 subjects
experienced the following AEs that met the protocol-specified dose-limiting toxicity (DLT)
criteria: 1 subject with Grade 3 fatigue on Day 15, 1 subject with Grade 3 gastroenteritis on Day
21, and 1 subject with Grade 3 pneumonitis (due to infection) and Grade 3 hypotension on Day 5.
No DLT required treatment discontinuation. All 16 subjects experienced at least 1 treatment-
emergent adverse event (TEAE) during Cycles 1 to 4. Three subjects (19%) had at least 1 serious
adverse event (SAE) and 2 subjects (13%) had SAEs that were considered by the investigator to
be related to daratumumab (gastroenteritis and pneumonitis). Eight subjects (50%) had Grade 3 or
Grade 4 TEAEs, for 6 subjects (38%) these events were considered by the investigator to be related
to daratumumab. The most commonly reported Grade 3 or Grade 4 TEAEs were neutropenia and
thrombocytopenia (19% each), and lymphopenia and leukopenia (13% each). Six subjects (38%)
experienced infections, including 1 Grade 3 SAE of gastroenteritis. There were no AEs of febrile
neutropenia. No subject died or discontinued treatment due to TEAEs. Daratumumab
infusion-related reactions (all Grade ≤2) were reported in 31% of subjects during Cycles 1 to 4.
All 16 subjects in the safety run-in had undergone stem cell mobilization with a median stem cell
yield of 6.0×106 (range 3.5-10.6) CD34+ cells/kg.
The initial safety profile was consistent with that previously reported for daratumumab as
monotherapy and the regimen of VRd. No new safety signals were identified with the addition of
daratumumab to VRd during the first 4 cycles of treatment in these 16 subjects with newly
diagnosed multiple myeloma. As per protocol, the study continued to enroll approximately
200 subjects randomized 1:1 to D-VRd vs VRd. A prespecified interim analysis for safety after at
least 50 patients completed 4 cycles of induction treatment and stem cell mobilization occurred on
4 April 2018, the Independent Data Monitoring Committee (IDMC) recommended that the study
continue without modification.
1.3. 
Summary
VRd is now considered a standard of care (SOC) regimen for newly diagnosed patients with
multiple myeloma (Moreau 2017, NCCN 2017). Daratumumab in combination with therapies

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commonly used for the treatment of multiple myeloma has demonstrated improved efficacy with
an acceptable safety profile in patients with previously treated and untreated multiple myeloma.
The combination of D-VRd is being evaluated in Study MMY2004 and initial data from the safety
run-in phase of the study shows that daratumumab can be combined safely with VRd.
1.4. 
Overall Rationale for the Study
Induction, high-dose therapy with stem cell rescue followed by consolidation and maintenance is
a common treatment strategy in newly diagnosed patients with multiple myeloma who are deemed
eligible to receive this therapy. The superiority of the VRd regimen has been established by the
results of the Phase 3 study by Attal and colleagues (Attal 2017). That study also demonstrated
greater depth of response, including a higher CR rate and MRD negativity rate as well as increased
PFS in the VRd plus ASCT arm versus VRd alone.
While the treatment of newly diagnosed patients with multiple myeloma continues to improve,
patients are still not cured. The most active combination to date is the VRd regimen previously
described. The sponsor has observed preclinical synergism of daratumumab in combination with
bortezomib and lenalidomide, which translated to compelling clinical data with daratumumab in
combination with either bortezomib or lenalidomide in the relapsed/refractory setting, and
bortezomib in the frontline setting. Thus, the combination of daratumumab with VRd is anticipated
to further improve response rates in patients and may lead to improved long-term outcomes in
newly diagnosed patients with multiple myeloma. Given this potential and based upon the initial
safety and efficacy observed in the ongoing Phase 2 Study MMY2004, as well as continued
positive results with daratumumab in various disease settings and combination regimens, this
Phase 3 study is designed to demonstrate improved outcomes for patients treated with
daratumumab+VRd. The Phase 3 study will utilize the SC formulation of daratumumab instead of
the IV formulation utilized in the Phase 2 study, which may limit additional toxicity to patients
treated with the quadruplet regimen.
1.5. 
Benefit-risk Assessment
Subjects in this study will be assigned in a randomized manner to receive either 1800 mg D-VRd
as induction and consolidation therapy and in combination with lenalidomide maintenance therapy
or VRd alone as induction and consolidation therapy and lenalidomide alone as maintenance
therapy. The sequence of VRd induction/ASCT/VRd consolidation/lenalidomide maintenance is
the global SOC. While treatment with D-VRd has demonstrated a manageable safety profile
consistent with the known safety profile of daratumumab SC and VRd alone, management
guidelines for potential toxicities are detailed in Section 6.2 and Section 6.4. Overall, there is a
positive benefit/risk profile for this patient population.

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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 VRd will prolong PFS
defined as the time from the date of randomization to the date of disease progression (assessed by
International Myeloma Working Group [IMWG] criteria) or death, compared with VRd alone.
Secondary Objectives
The secondary objectives are:
To determine if the addition of daratumumab to VRd will improve clinical outcome as
measured by:
MRD negativity rate post-consolidation and overall MRD negativity rate achieved at any
time during the study
ORR, rate of VGPR or better, rate of CR or better, rate of sCR at post-induction,
post-transplant, post-consolidation, and overall
Time to response
Duration of response
Progression-free survival on the next line of therapy (PFS2)
OS
To assess the safety profile of daratumumab+VRd (D-VRd)
To evaluate pharmacokinetics (PK) of daratumumab
To determine the immunogenicity of daratumumab and rHuPH20
To evaluate patient-reported outcomes (PROs) and medical resource utilization (MRU)
To evaluate stem cell yield after mobilization
To evaluate time to engraftment post ASCT
To evaluate the benefit/risk of stopping daratumumab upon sustained MRD negative status
Exploratory Objectives
The exploratory objectives are:
To evaluate durability of MRD negativity.
To evaluate whether the loss of MRD negative status through the monitoring of peripheral
blood will be more sensitive than standard clinical evaluations to detect relapse of CR.
To evaluate MRD negativity thresholds and durability of clinical response.

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To evaluate length of sustained MRD negative status and durability of clinical response.
2.1.2. 
Endpoints
Primary Endpoint
PFS is defined as the time from the date of randomization to the date of disease progression or
death due to any cause, whichever occurs first.
Secondary Endpoints
The secondary efficacy endpoints are:
Post-consolidation MRD negativity rate, defined as the proportion of subjects who achieve
MRD negativity (at or below the threshold of 10 5) at the end of consolidation.
Overall MRD negativity rate, defined as the proportion of subjects who achieve MRD
negativity (10 5) at any time during the study.
Overall ORR, rate of VGPR or better, rate of CR or better, and rate of sCR, defined as the
proportions of subjects who achieved PR or better (or VGPR or better, or CR or better, or
sCR) per the IMWG criteria at post-induction, post-transplant, post-consolidation, and overall.
Progression-free survival on the next line of therapy (PFS2) is defined as the time from
randomization to progression on the next line of treatment or death, whichever comes first.
OS, measured from the date of from randomization to the date the subject’s death.
Time to response (PR or better), time to CR/sCR are defined as the time from randomization
to date of initial response (or initial CR/sCR,).
Duration of response (PR or better), duration of CR, duration of sCR, and duration of MRD
negative status, are calculated from the date of the initial documentation of a response (PR or
better), or CR or better, or sCR, or MRD negative status to the date of the first documented
evidence of disease progression, as defined in the IMWG criteria, or death due to PD,
whichever occurs first.
Pharmacokinetic concentrations of daratumumab (further defined in Section 9.3).
Immunogenicity of daratumumab and rHuPH20.
Change in HRQoL, symptoms, and functioning using 2 European Organization for Research
and Treatment of Cancer (EORTC) questionnaires and the EuroQol Group Five Dimensions
Five Levels Questionnaires (EQ-5D-5L).
Stem cell yield after mobilization (further defined in Section 9.1.3.2).
Time to engraftment post ASCT defined as absolute neutrophil count (ANC) ≥0.5 x 109/L and
platelet count ≥20 x 109/L.
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypothesis
The primary hypothesis is that the addition of daratumumab to VRd will prolong the PFS (assessed
by the IMWG criteria) compared with VRd alone.

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3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a randomized, open-label, multicenter study evaluating subjects with newly diagnosed
multiple myeloma who are deemed eligible for high-dose therapy. Approximately 690 subjects
will be stratified by International Staging System (ISS) Stage I, II, or III disease (β-2 microglobulin
and albumin) and cytogenetics (standard risk or high risk as defined by presence of del17p, t[4;14]
or t[14;16]) and then randomized in a 1:1 ratio.
The study will consist of 3 phases: a Screening Phase, a Treatment Phase, and a Follow-up Phase.
The Screening Phase will start up to 28 days before randomization. The Treatment Phase will
extend from Cycle 1 Day 1 to discontinuation of all study treatment. The Treatment Phase will
consist of six 28-day cycles, 4 cycles of induction, followed by ASCT, then 2 cycles of
consolidation, followed by maintenance therapy until disease progression or unacceptable toxicity.
In Arm A, subjects will receive VRd for induction and consolidation, followed by lenalidomide
(R) maintenance until disease progression or unacceptable toxicity. Subjects in Arm B will receive
D-VRd for induction and consolidation followed by daratumumab and lenalidomide maintenance
until disease progression or unacceptable toxicity. Subjects in Arm B who have a response of CR
or better will stop therapy with daratumumab after sustained MRD negativity (at the threshold of
10 5) for 12 months and after a minimum of 24 months of maintenance therapy. These subjects
will continue lenalidomide maintenance therapy until disease progression or unacceptable toxicity.
After stopping daratumumab therapy, subjects with sustained MRD negativity should restart
therapy with daratumumab if there is a recurrence of MRD at 10 4  or higher or a confirmed loss of
CR without IMWG-defined disease progression as evidenced by the reappearance of serum or
urine monoclonal protein (M-protein) by immunofixation or electrophoresis by central laboratory
or development of ≥5% plasma cells in bone marrow (refer to Table 7). After reinitiating
daratumumab, the subject will continue daratumumab and lenalidomide therapy until disease
progression or unacceptable toxicity.
A diagram of the study design is provided in Figure 1.

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Figure 1: 
Schematic Overview of the Study
Key: CR=complete response; Dara=daratumumab; D-VRd=daratumumab in combination with bortezomib, lenalidomide, and dexamethasone; MRD=minimal residual
disease; PD=progressive disease; PFS2=progression-free survival on the next line of therapy; R=lenalidomide; VRd=bortezomib, lenalidomide, and dexamethasone.
RANDOM ZE
Primary Endpoint PFS
Arm A: Maintenance
Revlimid
until PD or unacceptable toxicity
Arm B:
Maintenance
Dara+R
Dara+R
until PD
MRD
negative
Discontinue
Dara therapy
only
(minimum of
1y sustained
MRD
negativity)*
MRD
positive
Long Term
Safety, PFS2
& Survival
Follow-up (+
monitoring for
new
malignancies,
subsequent
treatment and
PROs)
Arm A:
Consolidation
VRd
2 Cycles
Stem Cell
mobilization,
conditioning,
and
transplant
Arm B:
Induction
D-VRd
4 Cycles
(n=345)
Minimum
24 months
Arm A:
Induction VRd
4 Cycles
(n=345)
Arm B:
Consolidation
D-VRd
2 Cycles
*Restart therapy upon loss of CR or loss of MRD status
Stem Cell
mobilization,
conditioning,
and
transplant

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Subjects will enter the Follow-up Phase once they experience documented disease progression or
unacceptable toxicity leading to all study treatment discontinuation or if they have not achieved a
response of PR or better by C7D1. In the Follow-up Phase, subjects who discontinued before
disease progression must continue to have disease evaluations according to the Time and Events
Schedule (Table 1) and should not initiate any subsequent anticancer treatment until disease
progression is confirmed per IMWG criteria (Table 7). In addition, disease progression must be
approved by the medical monitor and documented in interactive web response system (IWRS).
After disease progression is documented, follow-up will be obtained at least every 4 months
±2 weeks. Subsequent anticancer treatment, disease progression data (per investigator assessment)
on the first line of subsequent therapy, new malignancies, PRO assessments, and survival status
will also be recorded.
3.2. 
Study Design Rationale
Rationale for Study Design
The VRd regimen in this study is based upon both the IFM 2009 Study that utilized 3 cycles of
VRd induction followed by ASCT followed by 2 cycles of VRd consolidation therapy followed
by 1 year of maintenance therapy with lenalidomide alone and the Gem2012Menos65 Study that
utilized 6 cycles of VRd induction therapy followed by ASCT and 2 cycles of VRd consolidation
therapy. The IFM 2009 Study utilized 21-day cycles vs the Gem2012Menos65 Study which
utilized 28-day cycles. Current European Society for Medical Oncology (ESMO) guidelines
recommend 4-6 cycles of induction therapy prior to ASCT, thus given the high response rates in
both the IFM 2009 and the Gem2012Menos65 Studies, this study will utilize 4 cycles of induction
therapy with a 28-day cycle to increase the lenalidomide dose intensity per cycle. This study will
implement SC bortezomib (as in the Gem2012Menos65) as opposed to IV bortezomib, which was
used in the IFM 2009 Study, as subcutaneous bortezomib decreases the rate and severity of
neuropathy as compared to the intravenous formulation (Moreau 2011).
A meta-analysis of these 2 Phase 3 studies with 1,208 patients (605 patients in the lenalidomide
maintenance group and 603 in the placebo or observation group) demonstrated superior PFS with
lenalidomide maintenance compared to no maintenance. The median PFS was 52.8 months for the
lenalidomide group and 23.5 months for the placebo or observation group (HR 0.48; 95% CI:
0.41, 0.55). At a median follow-up of 79.5 months for all surviving patients, the median OS had
not been reached for the lenalidomide maintenance group and was 86.0 months for the placebo or
observation group (HR 0.75; 95% CI: 0.63, 0.90; p .0001) (McCarthy 2017). Based on these data
lenalidomide is approved as maintenance therapy post ASCT until disease progression
(Revlimid SMPc). Thus, in the current protocol, lenalidomide maintenance therapy will continue
until disease progression or unacceptable toxicity in both arms. In the experimental (Arm B)
daratumumab is added to the standard lenalidomide maintenance. Daratumumab is planned to be
discontinued during the maintenance phase in subjects who achieve sustained MRD negativity
(10 5) for at least 12 months and after receiving at least 24 months of maintenance treatment. The
proposal for a daratumumab treatment-free interval will provide important data for patient
management. After stopping daratumumab therapy, subjects with sustained MRD negativity

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should restart therapy with daratumumab if there is a recurrence of MRD at 10 4  or higher or a
confirmed loss of CR without disease progression (refer to Table 8).
Rationale for Subcutaneous Daratumumab
A new formulation of daratumumab for SC administration has been developed to avoid the long
infusion time that frequently requires hospitalization with IV administration of daratumumab and
to lessen the rate and severity of infusion-related reactions observed with IV daratumumab.
Further, a recombinant human hyaluronidase PH20 (rHuPH20) was used to facilitate the SC
administration in order to decrease the volume required for SC administration.
This SC formulation of daratumumab is currently being evaluated in Study MMY1004 an
open-label, multicenter, dose escalation Phase 1b Study. This study assessed the safety, PK, and
efficacy of SC administration of daratumumab plus rHuPH20 (Dara-PH20) in subjects with
relapsed or refractory multiple myeloma. After a median treatment duration of 5.6 months (clinical
cutoff date of 13 Dec 2017), 25 subjects received at least 1 dose of 1800 mg daratumumab
administered subcutaneously (Dara-SC) in Study MMY1004 (San-Miguel 2018). The
infusion-related reaction rate was 16% and consisted of Grade 1 or 2 chills, dyspnea, sneezing and
allergic rhinitis, and 2 Grade 3 events of hypertension. None of the injection-related reaction (IRR)
events led to treatment discontinuation. Injection-site reactions occurred in 12% of subjects, all
were Grade 1. The events were discoloration/injection-site induration, hematoma, and erythema.
The ORR was 52% with 28% VGPRs. Median PFS has not been reached. The efficacy and AE
profile are consistent with that of IV daratumumab with a lower rate of infusion-related reactions.
Based on these clinical data and supported by the PK profile of Dara-SC (as described in the
section below), the safety and efficacy of Dara-SC appear equivalent to and may be better than
Dara-IV. The SC formulation is currently being further tested in Study, MMY3012, a Phase 3
study of Dara-IV versus Dara-SC in subjects with relapsed or refractory multiple myeloma.
Rationale for Daratumumab Dose Regimen
Previous exposure-response analyses have demonstrated a strong correlation between ORR and
the maximum trough concentration (Ctrough,), which occurs at the end of weekly dosing (just prior
to the C3D1 dose in the monotherapy schedule). These analyses have also demonstrated the lack
of relationship between daratumumab concentrations and AEs in the therapeutic dose range.
Therefore, the dose of Dara-SC selected is intended to achieve a similar or greater maximum Ctrough
compared with 16 mg/kg IV administration.
As of 03 Aug 2017, 18 subjects were evaluable for PK in Study MMY1004 Part 2. Analysis of the
preliminary PK data indicated the 1800 mg Dara-SC (co-formulated) dose achieved maximum
Ctrough values comparable to, or higher than, those observed for Dara-IV 16 mg/kg. The maximum
Ctrough  mean value was 904.42 µg/mL for the 1800 mg Dara-SC cohort (n 18), compared with
754.62 µg/mL for the 1800 mg daratumumab and recombinant human hyaluronidase for
subcutaneous injection: mix and deliver formulation (Dara-MD) cohorts (n 38), 617.17 µg/mL in
Study GEN501 Part 2 (n 27), and 573.49 µg/mL in Study MMY2002 (n 73). The median value
for maximum Ctrough  for Dara-SC (798.85 µg/mL) was similar to the value for 1800 mg Dara-MD
(795.48 µg/mL) and slightly higher than the 16 mg/kg IV median values from Studies MMY2002

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(559.62 µg/mL) and GEN501 (713.85 µg/mL). The range of maximum Ctrough observations for the
SC cohort is contained within the range observed following 16 mg/kg IV dosing and variability
was similar with a % CV of 46 to 58% across the SC and IV doses (Figure 2).The observed mean
maximum observed concentration (Cmax) values following the last (8th) weekly dose for the Dara-
SC cohort was 1012.4 µg/mL, similar to the mean Cmax of 914.9 µg/mL observed after the C3D1
(9th) dose for Dara-IV in Study MMY2002. The observed Cmax values from the Dara-SC cohort is
within the range observed for Dara-MD and 16 mg Dara-IV.
Figure 2: 
Daratumumab Serum Concentration at C3D1 Ctrough Following Daratumumab Administered
Subcutaneously (Study MMY1004) or Intravenously (Study MMY2002)
Footnotes:
Dots are individual observations; PK evaluable population is presented
1200 mg MD  MMY1004 Part 1, 1200 mg mix & deliver cohort
1800 mg MD  MMY1004 Part 1, 1800 mg mix & deliver cohorts
1800 mg SC  MMY1004 Part 2, 1800 mg co formulant
16 mg/kg IV data are from Study MMY2002
Study MMY1004 Part 2 also showed that 1800 mg Dara-SC can be administered subcutaneously
by injection with a median of 5 minutes (ranging from 2 to 11 minutes) and it is associated with a
low incidence of IRRs, as noted above. The overall safety profile for the Dara-SC cohort is
consistent with previously reported safety profiles for daratumumab IV administration and SC
administration with Dara-MD. There are no new safety signals with the Dara-SC administration.
Therefore, based on the available safety and PK data, the dose of 1800 mg Dara-SC is selected for
study in Phase 3 studies, including this study.
The schedule utilized for this study begins with daratumumab administered once every week for
2 cycles (28-day cycles) then every 2 weeks for 2 cycles to quickly achieve and maintain effective
daratumumab concentrations. This is the same initial schedule studied with Dara-SC monotherapy
in Studies MMY1004 and MMY3012. Following ASCT, consolidation will begin with

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every-2-week dosing and then every-4-week dosing in maintenance; this progression to
every-2-week and every-4-week dosing intervals is similar to other approved Dara-IV dosing
regimens and Dara-SC. Subjects in Arm B who have delayed recovery post ASCT and exceed
12 weeks off daratumumab will skip the consolidation phase (Cycles 5-6) and proceed directly to
maintenance therapy; these subjects will restart daratumumab dosing every 2 weeks for 4 doses
(Cycles 7-8) to regain effective concentrations, and then continue every 4 weeks thereafter (for
Cycles 9+). Subjects who achieve MRD negativity and go on to restart daratumumab after a
daratumumab-free interval, will follow the same approved daratumumab schedule used for
monotherapy (weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter) to
quickly achieve and maintain effective daratumumab concentrations.
Rationale for Fixed Dose
The body weight range in Part 1 of Study MMY1004 was 48 to 133 kg, which was similar to that
in daratumumab IV studies (MMY2002 and GEN501, 38.4 to 160.2 kg). The preliminary
maximum Ctrough  data for the Dara-MD 1800 mg dose were assessed across a range of simulated
body weights and compared with the body weight based daratumumab IV dosing. Across the
quartiles of weights for the simulated patients (n 1000), similar exposure was predicted for each
dosing approach (either Dara-MD  1800 mg or daratumumab IV  16 mg/kg) (Figure 3).
Furthermore, the variability in the exposure for Dara-MD 1800 mg in all weight quartiles was
predicted to be similar compared with that for daratumumab IV 16 mg/kg. The fixed Dara-MD
1800 mg dose results in a median concentration that is close to the overall population median
concentration, with a ratio of approximately 1 in each weight quartile (Figure 4). Based on these
simulations and observations in the ongoing Study MMY1004, fixed dosing for SC administration
is a feasible approach and will be used in this study. Dara-IV exhibits a wide therapeutic window
and there is no apparent relationship between drug exposure in the therapeutic dose range and AEs
of interest, which further supports the feasibility of utilizing a fixed dose approach in SC
administration.

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Figure 3: 
Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800 mg
(Subcutaneous Administration) and Dara-IV 16 mg/kg (Intravenous Administration)
Dara-MD 1800 mg 
Dara-IV 16 mg/kg
Footnotes: Dashed line is the effective concentration of 274 µg/mL.
C3D1=Cycle 3 Day 1.
Figure 4: 
Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (Ratio of
Trough Concentrations and Median Trough Concentration for Overall Population at Each
Dose) for Dara-MD 1800 mg (Subcutaneous Administration) and Dara-IV 16 mg/kg
(Intravenous Administration)
Dara-MD 1800 mg 
Dara-IV 16 mg/kg
Footnotes: C3D1=Cycle 3 Day 1.
Ideal trough concentration is 1.0.

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Rationale for rHuPH20 Concentration
In this study, the concentration of rHuPH20 in Dara-SC will be 2000 U/mL. This is the same
concentration and total amount of rHuPH20 administered in Part 2 of Study MMY1004 and other
ongoing Phase 3 studies using Dara-SC. Products approved for commercial use, such as Herceptin
SC (trastuzumab) and MabThera SC (rituximab), also contain 2000 U/mL of rHuPH20. A study
in minipigs supports the use of this concentration ofrHuPH20 for Dara-SC. The study evaluated
100 mg/mL daratumumab formulated with 50, 500, 2000, or 5000 U/mL of rHuPH20. Sixteen
(16) mL of each formulation was infused SC into the abdomen of sedated animals at a rate of
3 mL/minute. Infusion pressures showed a dose-dependent trend where pressures were reduced as
the concentration of rHuPH20 increased. Formulations with ≥500 U/mL of rHuPH20 showed
relatively small areas of local swelling that was mainly soft to the touch with mild to no erythema.
These all resolved by the following day, with many resolving within an hour.
Rationale for Pharmacokinetic and Immunogenicity Evaluations
Data obtained from this study will provide information about the PK profile of Dara-SC in subjects
with multiple myeloma who are eligible for ASCT. Therefore, samples will be obtained from all
subjects receiving daratumumab for PK assessments. Data may also be used for a population PK
analysis to estimate additional PK parameters and provide information about the determinants of
inter-subject variability in this population.
Immunogenicity to daratumumab and rHuPH20 is possible. Therefore, samples to determine the
presence of anti-daratumumab antibodies and anti-rHuPH20 antibodies (immunogenicity) will be
collected from all subjects receiving daratumumab. The information from these samples and data
from other studies will be used to determine the immunogenicity of daratumumab and rHuP20.
Rationale for MRD as a Key Secondary Endpoint
Deepening the magnitude of response is an attainable goal with the advent of combination therapy
with novel agents and ASCT. However, conventional means of assessing response are not
sufficiently sensitive to measure low-levels of residual bone marrow disease, so-called MRD
(Martinez-Lopez 2014). Achievement of MRD negativity by flow or next-generation sequencing
(NGS) at a cutoff of both 10 4 and 10 5 has been correlated with improvement of both PFS and OS
(Landgren 2016, Lahuerta 2017, Munshi 2016).
Furthermore, data from 2 studies utilizing daratumumab in combination with either Rd
(MMY3003) or Vd (MMY3004) in subjects with relapsed/refractory multiple myeloma have
shown improvement in both the number of subjects achieving MRD negativity as compared to the
control arms as well as improvement in PFS for subjects who achieved MRD negative status
(Avet-Loiseau 2016) (Figure 5). These studies utilized a NGS-based MRD assay to allow for
the consistent evaluation in these global clinical studies. Data shown below reflect a sensitivity of
10 5.

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Figure 5: 
Progression-free Survival According to MRD Status 10-5 in Studies MMY3003 and MMY3004
Sensitive methodologies to detect MRD following a clinical response may define deeper levels of
response that correlate with improved long-term outcome (Paiva 2015). The most commonly used
sensitive methods to monitor MRD include NGS, allele-specific oligonucleotide polymerase chain
reaction (PCR), and multiparametric flow cytometry (Rawstron 2008, Sarasquete 2005). Each
method offers distinct advantages and disadvantages. Multiparametric flow cytometry has been
widely applied in the diagnostic and prognostic evaluations of patients with myeloma and that it
may have value in response assessment, particularly in the context of patients undergoing ASCT.
(Owen 2005, Sarasquete 2005). The clonoSEQ MRD assay is an analytically validated NGS assay
and is the most sensitive assay available that is seeking FDA approval with the ability to detect
one malignant cell in the background of a million normal cells.
MRD will be initially evaluated at suspected CR when a subject has achieved a deep clinical
response. For subjects who achieve CR, have not progressed, and remain on the study, additional
bone marrow aspirate samples will be obtained at specific landmarks to allow for the statistical
analysis of the association of MRD with PFS/OS and to evaluate the durability of MRD negativity
in these subjects.
Rationale for Biomarker Evaluations
Biomarkers collected in this study will provide information about daratumumab in multiple
myeloma and will focus on 2 key objectives: the evaluation of MRD and the efficacy of
daratumumab+VRd (compared to VRd alone) in high-risk molecular subgroups. Exploratory
MRD assessment in whole blood may be evaluated as a more sensitive biomarker than standard
clinical evaluations to detect loss ofCR. In addition, exploratory studies may examine the effects
of daratumumab+VRd on daratumumab’s MoA following transplant by DNA/RNA sequencing.
Samples may be used for immunophenotyping, which could include analysis of specific subsets
of immune cells, such as cytotoxic T cells, regulatory T cells, and activated natural killer (NK)
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Medical Resource Utilization
MRU data will be collected to determine the medical cost impact of D-VRd and VRd treatment
regimens. The data collected will be used to conduct exploratory analyses that may be used to
support the value story and cost-effectiveness modeling for market access.
Rationale for Patient-reported Outcomes Endpoints
PRO data complement data collected by clinicians and laboratory findings to describe the patient
experience, directly reported by the subject. PRO data are supportive of the clinical endpoints and
capture inputs required for cost-effectiveness modeling. In addition, the PRO data provide the
patient perspective to communicate the value of treatment to patients, clinicians, regulators, and
payers.
Summary of Anticipated Benefits and Risks
The combination of VRd with subcutaneously administered daratumumab is anticipated to have a
positive benefit-risk profile when used for the treatment of patients with previously untreated
multiple myeloma who are eligible for high-dose therapy, as proposed for investigation in Study
MMY3014. This assessment is based upon the following:
As presented in Section 1.1.2, there are several treatment options that exist for the treatment
of patients with previously untreated multiple myeloma; however, strategies directed at
improving and maintaining effective response for longer periods of time, as well as new
treatment options directed at alternative MoAs are still needed to improve clinical outcomes
for patients with the disease.
The VRd backbone regimen to be used in this study is now considered a SOC regimen for
newly diagnosed patients with multiple myeloma. Further details of studies conducted using
this regimen, which has demonstrated a positive benefit-risk profile, are outlined in
Section 1.1.3.
The addition of daratumumab to the VRd backbone regimen may improve initial disease
control and long-term outcomes. Daratumumab has been successfully combined with either
lenalidomide or bortezomib in multiple myeloma patients. In Study MMY3003
(daratumumab+Rd) and MMY3004 (daratumumab+Vd) a significant improvement was seen
in PFS in the DRd and DVd arms of the studies. In the newly diagnosed transplant-ineligible
setting, Study MMY3007 (studying the combination of daratumumab with VMP vs VMP)
also showed a statistically significant improvement in PFS in the D-VMP arm of the study
(see Section 1.2.1 for further details). Furthermore, data available from Study MMY2004
suggest that daratumumab can be combined safely with VRd (refer to Section 1.2.1).
Preclinical synergism has also been observed with daratumumab in combination with
bortezomib and lenalidomide.
Given the potential advantages of SC administration, SC daratumumab will be used in this
study. As presented earlier in this section and in the current daratumumab Investigator's
Brochure, the safety and tolerability of SC daratumumab has been demonstrated in early phase
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The potential risks for the study will be mitigated with monitoring by the IDMC and the
sponsor’s medical monitor during the conduct of the study, as described throughout the
protocol (refer to Section 11.13).
In summary, there is a strong rationale for evaluating SC daratumumab in combination with VRd
for the treatment of patients with previously untreated multiple myeloma who are eligible for
high-dose therapy.
4. 
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before randomization of the study
drug. The inclusion and exclusion criteria for enrolling subjects in this study are described in the
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the
investigator must consult with the appropriate sponsor representative and resolve any issues before
enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, Sample
Size Determination.
4.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. 
18 to 70 years of age, inclusive.
2. 
Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven
plasmacytoma and documented multiple myeloma satisfying at least one of the calcium,
renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:
CRAB criteria:
1. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limit
of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
2. Renal insufficiency: creatinine clearance <40mL/min or serum creatinine
>177 μmol/L (>2 mg/dL)
3. Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin
<10 g/dL
4. Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or
PET-CT
Biomarkers of Malignancy:
a. Clonal bone marrow plasma cell percentage ≥60%
b. Involved: uninvolved serum FLC ratio ≥100
c. >1 focal lesion on magnetic resonance imaging (MRI) studies

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3. 
Measurable disease as defined by any of the following:
a. Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein
level ≥200 mg/24 hours; or
b. Light chain multiple myeloma without measurable disease in the serum or the
urine: Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum
immunoglobulin kappa lambda FLC ratio
4. 
Newly diagnosed subjects for whom high-dose therapy and autologous stem cell
transplantation is part of the intended treatment plan.
5. 
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
(see Attachment 1).
6. 
Clinical laboratory values meeting the following criteria during the Screening Phase
(screening hematology and chemistry tests should be repeated if done more than 3 days
before C1D1):
Adequate bone marrow function:
a. Hemoglobin ≥7.5 g/dL (≥4.65 mmol/L; prior red blood cell [RBC] transfusion or
recombinant human erythropoietin use is permitted however transfusions are not
permitted within 7 days of randomization to achieve this minimum hemoglobin
count);
b. Absolute neutrophil count (ANC) ≥1.0 x 109/L (G-CSF use is permitted);
c. Platelet count ≥50 x 109/L if bone marrow is >50% involved in myeloma.
Otherwise ≥75 x 109/L
Adequate liver function:
a. Aspartate aminotransferase (AST) ≤2.5 x ULN;
b. Alanine aminotransferase (ALT) ≤2.5 x ULN;
c. Total bilirubin ≤1.5 x ULN (except in subjects with congenital bilirubinemia, such
as Gilbert syndrome, direct bilirubin ≤1.5 x ULN)
Adequate renal function:
a. Estimated creatinine clearance ≥30 mL/min. Creatinine clearance may be
calculated using Cockcroft-Gault, eGFR (Modified Diet in Renal Disease
[MDRD]; Attachment 2), or CKD-epi formula
b. Corrected serum calcium ≤13.5 mg/dL (≤3.4 mmol/L); or free ionized calcium
≤6.5 mg/dL (≤1.6 mmol/L) (see Attachment 3)
NOTE: For Criteria 7-11, contraceptive (birth control) use by men or women should be
consistent with local regulations regarding the acceptable methods of contraception for those
participating in clinical studies. 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 in clinical studies.

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7. 
Criterion modified per Amendment 2.
7.1 Female subjects of reproductive childbearing potential (defined as post-menarche
until post-menopause unless permanently sterilized) must commit to either abstain
continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth
control simultaneously during the treatment period, during any dose interruptions, and
for 3 months after the last dose of any component of the treatment regimen. 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
and is consistent with the usual lifestyle of the subject. This birth control method must
include one highly effective form of contraception (tubal ligation, intrauterine device
[IUD], hormonal [birth control pills, injections, hormonal patches, vaginal rings or
implants] or partner’s vasectomy with confirmation of procedure) and one additional
effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical
cap). Contraception must begin 4 weeks prior to dosing. Reliable contraception is
indicated even where there has been a history of infertility, unless due to hysterectomy
or bilateral oophorectomy.
8. 
A woman of childbearing potential must have 2 negative serum or urine pregnancy tests
at screening, first within 10 to 14 days prior to dosing and the second within 24 hours
prior to dosing. For requirements during the Treatment Phase, refer to Section 4.3.
9. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 3 months after receiving the last dose
of any component of the treatment regimen.
10. 
Male subjects of reproductive potential who are sexually active with females of
reproductive potential must always use a latex or synthetic condom during the study
and for 3 months after discontinuing study treatment (even after a successful
vasectomy).
11. 
Male subjects of reproductive potential must not donate sperm during the study or for
3 months after the last dose of study treatment.
12. 
Criterion modified per Amendment 2
12.1 Signed an informed consent form (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. Subjects in emergency situations
that do not allow for collection of informed consent are excluded.
13. 
Able to adhere to the prohibitions and restrictions specified in this protocol

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4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
Prior or current systemic therapy or SCT for any plasma cell dyscrasia, with the
exception of emergency use of a short course (equivalent of dexamethasone 40 mg/day
for a maximum 4 days) of corticosteroids before treatment.
2. 
Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE)
Version 5.
3. 
Prior or concurrent invasive malignancy (other than multiple myeloma) within 5 years
of date of randomization (exceptions are adequately treated basal cell or squamous cell
carcinoma of the skin, carcinoma in situ of the cervix or breast, or other non-invasive
lesion that in the opinion of the investigator, with concurrence with the sponsor’s
medical monitor, is considered cured with minimal risk of recurrence within 3 years).
4. 
Criterion modified per Amendment 2
4.1 Radiation therapy for treatment of plasmacytoma within 14 days of randomization
(palliative radiation for pain control secondary to lytic lesion is allowed within 14 days
of randomization).
5. 
Plasmapheresis within 28 days of randomization.
6. 
Clinical signs of meningeal involvement of multiple myeloma.
7. 
Criterion modified per Amendment 2
7.1 Pulmonary:
a. Subjects <65 years old with chronic obstructive pulmonary disease (COPD)
with a Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal
b. Subjects ≥65 years old with a FEV1 <50% or diffusing capacity of the lungs for
carbon monoxide [DLCO] <50%
8. 
Moderate or severe persistent asthma within the past 2 years (see Attachment 4), or
currently has uncontrolled asthma of any classification. (Note that subjects who
currently have controlled intermittent asthma or controlled mild persistent asthma are
allowed in the study).

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9. 
Criterion modified per Amendment 2
9.1 Criterion modified per Amendment 4
Any of the following:
a. Known to be seropositive for human immunodeficiency virus (HIV). HIV
antibody testing at screening should be performed per local health guidelines.
b. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg
negative but positive for antibodies to hepatitis B core antigen [Anti-HBc]
and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened
using real-time PCR measurement of hepatitis B virus (HBV) DNA levels.
Those who are PCR positive will be excluded. EXCEPTION: Subjects with
serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the
only serologic marker) AND a known history of prior HBV vaccination, do not
need to be tested for HBV DNA by PCR.
c. Known to be seropositive for hepatitis C, (except in the setting of a sustained
virologic response [SVR], defined as aviremia at least 12 weeks after
completion of antiviral therapy).
10. 
Concurrent medical or psychiatric condition or disease (such as, but not limited to,
systemic amyloidosis, POEMS, active systemic infection, uncontrolled diabetes, acute
diffuse infiltrative pulmonary disease) that is likely to interfere with the study
procedures or results, or that in the opinion of the investigator, would constitute a hazard
for participating in this study.
11. 
Criterion modified per Amendment 2
11.1 Any of the following:
a. myocardial infarction within 6 months before randomization, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function
(eg, unstable angina, congestive heart failure, New York Heart Association
Class III-IV)
b. uncontrolled cardiac arrhythmia
c. screening 12-lead ECG showing a baseline QT interval >470 msec (exception:
subjects with pacemaker)
d. screening ECHO or MUGA scan for subjects aged >65-70: left ventricular
ejection fraction (LVEF) <40%
12. 
Received a strong CYP3A4 inducer within 5 half-lives prior to randomization
(Flockhart 2016: http://medicine.iupui.edu/flockhart/)

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13. 
Allergy, hypersensitivity, or intolerance to boron or mannitol, corticosteroids,
monoclonal antibodies or human proteins, or their excipients (refer to the Investigator’s
Brochure), or sensitivity to mammalian-derived products or lenalidomide or its
excipients.
14. 
Criterion modified per Amendment 2
14.1 Not able to comply with the study protocol (eg, because of alcoholism, drug
dependency, or psychological disorder). Subject has any condition for which, in the
opinion of the investigator, participation would not be in the best interest of the subject
(eg, compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments. Subject is taking any prohibited medications as per
Section 8.3. Subject is deprived of their freedom by a judicial or administrative decision,
or subject is in psychiatric care. Subject is subjected to a legal protection measure or
unable to provide their consent.
15. 
Pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study
or within 3 months after the last dose of any component of the treatment regimen. Or,
subject is a man who plans to father a child while enrolled in this study or within
3 months after the last dose of any component of the treatment regimen.
16. 
Major surgery within 2 weeks before randomization or will not have fully recovered
from surgery, or has surgery planned during the time the subject is expected to
participate in the study. Kyphoplasty or Vertebroplasty is not considered major surgery.
17. 
Criterion modified per Amendment 2
17.1 Received an investigational drug (including investigational vaccines) or used an
invasive investigational medical device within 4 weeks or 5 half-lives of the respective
drug/investigational medicinal product (IMP) (whichever is longer) before
randomization or is currently enrolled in an interventional investigational study.
18. 
Contraindications to the use of any components of the backbone treatment regimens,
per local prescribing information.
19. 
Gastrointestinal disease that may significantly alter the absorption of oral drugs
20. 
Vaccination with live attenuated vaccines within 4 weeks of first study agent
administration.
21. 
Unable or unwilling to undergo antithrombotic prophylactic treatment.
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 the first dose of study drug is given such
that he or she no longer meets all eligibility criteria, then the subject should be excluded from

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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 study to be eligible for participation. For restrictions related to concomitant medications,
please refer to Section 8.3.
1. 
A woman of childbearing potential must remain on a highly effective method of birth
control (see inclusion criteria). Contraception must begin 4 weeks before initiating
treatment in the study, and continue during the Treatment Phase, during dose
interruptions and continuing for 4 weeks after the last dose of lenalidomide and
3 months following of the last dose of daratumumab. Reliable contraception is indicated
even where there has been a history of infertility, unless due to hysterectomy or bilateral
oophorectomy. In addition, women must not donate ova during the study, for 4 weeks
after the last dose of lenalidomide, and for 3 months after the last dose of daratumumab.
2. 
A man who has not had a vasectomy and who is sexually active with a woman of
childbearing potential must agree to use a barrier method of birth control eg, condom
with spermicidal foam/gel/film/cream/suppository, and all men must not donate sperm
during the study, for 4 weeks after the last dose of lenalidomide, and for 3 months after
the last dose of daratumumab. The exception to this restriction is that if the subject’s
female partner is surgically sterile, a second method of birth control is not required.
3. 
All Investigators will comply with the respective Celgene country-specific Revlimid
Risk Minimization Program (ie, pregnancy prevention program) as implemented in the
post-marketing setting.
4. 
During the Treatment Phase, pregnancy tests are required 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 pregnancy test is also required at
the End-of-Treatment Visit. Additional pregnancy tests may be required, as specified in
the Celgene country-specific Revlimid Risk Minimization Program (ie, pregnancy
prevention program).
5. 
Typically, IV contrast is not used in computed tomography (CT) scanning of subjects
with secretory multiple myeloma because of the risk to the kidney. If administration of
IV contrast is necessary, then adequate precautions including hydration are indicated.
6. 
Subjects must not donate blood during therapy and for at least 3 months following
discontinuation of all study treatment.

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5. 
TREATMENT ALLOCATION AND BLINDING
This is an open-label study. Subjects will be assigned in a randomized manner to receive either
1800 mg daratumumab SC in combination with VRd as induction and consolidation therapy and
in combination with lenalidomide maintenance therapy or VRd alone as induction and
consolidation therapy and lenalidomide alone as maintenance therapy.
Subjects will be stratified prior to randomization by ISS Stage I, II, or III (based upon central
laboratory results for β-2 microglobulin and albumin) and by cytogenetics (standard risk or high
risk as defined by presence of del17p, t[4;14] or t[14;16]), as centrally confirmed during screening.
For stratification purposes, if cytogenetic results are not available (ie, due to technical reasons),
local cytogenetic results may be used with the approval of the sponsor’s medical monitor. If central
and local cytogenetic results are not available, the subject will be assumed to be standard risk. The
investigator will screen and if eligible randomize each subject using an IWRS. Each subject will
be assigned a unique subject number.
6. 
DOSAGE AND ADMINISTRATION
Cycles 1-6 in induction and consolidation are 28 days (4 weeks) in duration, and treatment will be
for a maximum of 4 induction cycles and 2 consolidation cycles. The cycles during the
maintenance period Cycles 7+ are 28 days (4 weeks) in duration, and treatment will continue until
disease progression or unacceptable toxicity.
On dosing days where the combination products are given with daratumumab, the study drug and
chemotherapy should be administered in the following order:
lenalidomide, dexamethasone, daratumumab, and bortezomib
The start of each cycle may occur ±3 days of the scheduled day to accommodate the schedule of
the site or subject. Day 1 of subsequent cycles should be adjusted accordingly to maintain the
intended cycle duration. All treatment cycles are 28 days.
In Cycles 1 and 2 with weekly daratumumab and Cycles 3-6 with bi-weekly daratumumab,
administrations may be given within ±1 day of the scheduled day to accommodate the schedule of
the site or subject. Additionally, twice weekly bortezomib or dexamethasone doses may be given
within ±1 day of the scheduled day to accommodate the schedule of the site or subject. Changes
to within-cycle dosing should not affect Day 1 of the next cycle. Subjects will be treated for the
allowed maximal treatment period or until disease progression, unacceptable toxicity, or other
reasons as listed in Section 10.2.
The study medicinal products and their designations are listed in Table 3.

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Table 3: 
Designations of Medicinal Products Used in the Study
Designation  
Product
Investigational Medicinal Product 
Daratumumab SC
AxMP/NIMP* 
Bortezomib SC
Lenalidomide PO
Dexamethasone PO or IV
AxMP=auxiliary medicinal product; IV= intravenous; NIMP=noninvestigational medicinal product; PO=per os
(oral); SC=subcutaneous
AxMP=EU CTR, NIMP=EU CTD
*The AxMP are authorized products in the European Economic Area.
6.1. 
Daratumumab
6.1.1. 
Daratumumab Subcutaneous Preparation
Dara-SC will be provided as a fixed-dosed (1800 mg), combination drug product containing
rHuPH20 drug substance (2000 U/mL) and daratumumab drug substance (120 mg/mL) in a single
vial. Manuals with detailed descriptions for preparation and administration of daratumumab will
be supplied to each pharmacy and site.
6.1.2. 
Daratumumab Administration
Daratumumab (1800 mg) will be administered by SC injection by manual push over approximately
3 to 5 minutes in the abdominal SC tissues in left/right locations, alternating between individual
doses. The volume of the SC solution will be 15 mL for the 1800 mg dose. Refer to the
Investigational Product Preparation Instructions (IPPI) for additional guidance on SC
administration of Dara-SC. All subjects will be observed for at least 6 hours after the end of the SC
injection during Cycle 1 Day 1 and, if deemed necessary by the investigator, after subsequent
injections. Reasons for continued observation on subsequent daratumumab injections may include,
but are not limited to, the following: subjects with a higher risk of respiratory complications
(eg, subjects with mild asthma or subjects with COPD who have an FEV1 <80% at screening or
developed FEV1 <80% during the study without any medical history), subjects with an IRR with
the first injection of study drug, subject condition on the day of dosing compared with prior dosing
days. The dose of daratumumab will remain constant throughout the study.
Daratumumab will be given to subjects in Arm B once every week for Cycles 1 to 2, then every
2 weeks for Cycles 3-6. For maintenance Cycles 7+, subjects will receive daratumumab (1800 mg)
once every 4 weeks until documented disease progression or unacceptable toxicity.
Subjects in Arm B who have a post ASCT recovery period that requires greater than 12 weeks off
daratumumab and skip consolidation should restart therapy on the following schedule:
daratumumab dosing every 2 weeks for 4 doses (Cycles 7-8 of maintenance therapy) then continue
every 4 weeks, thereafter (for Cycles 9+).
In Arm B, subjects who achieve MRD negativity that is sustained for 12 months and have been
treated on maintenance for at least 24 months will stop daratumumab treatment. MRD negative
subjects are defined as those who achieve CR or better and achieve MRD negativity (at 10 5
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After stopping study daratumumab, subjects will continue lenalidomide maintenance therapy until
disease progression or unacceptable toxicity. Subjects who previously stopped lenalidomide due
to toxicity will stop daratumumab, continue study assessments as per the Treatment Phase even
though the subject is not receiving active study treatment, and should not complete an
End-of-Treatment Visit.
All subjects who stop daratumumab due to sustained MRD negativity will be monitored for loss
of CR (Table 8) by urine and serum M-protein by central laboratories or development of ≥5%
plasma cells in the bone marrow by local laboratories as outlined in the Time and Events Schedule
(Table 1) and IMWG criteria as well as MRD status via bone marrow aspirate by central
laboratories as per Table 1 and Table 9. Upon confirmed loss of CR or recurrence of MRD at 10 4
or higher, subjects must restart daratumumab until disease progression or unacceptable toxicity.
Upon re-initiation of daratumumab treatment during maintenance, daratumumab will be given at
a dose of 1800 mg SC:
weekly for 8 weeks
then every 2 weeks for 16 weeks
then every 4 weeks until disease progression or unacceptable toxicity
All injections will be administered in an outpatient setting. As this is a restart of daratumumab,
subjects will receive pre-administration medications and post-administration medications as
outlined in Section 6.1.3 and Table 1 to prevent the reoccurrence of infusion-related reactions.
Monitor vital signs, hematology, and serum chemistry prior to each daratumumab administration.
NOTE: Once treatment with lenalidomide is stopped due to toxicity, it cannot be restarted.
For subjects in Arm B whose MRD negativity at 10 5 threshold cannot be determined by NGS (due
to lack of MRD index clone or non-unique clone sequence), MRD by next-generation flow (NGF)
may be used to guide daratumumab stopping and restarting in agreement with the sponsor.
6.1.3. 
Guidelines for Prevention and Management of Injection Reactions
6.1.3.1. 
Daratumumab Predose Medication
To decrease the risk of IRRs, all subjects will receive the following medications 1 to 3 hours prior
to each study drug administration:
Paracetamol (acetaminophen) 650-1000 mg IV or orally (PO).
An antihistamine: diphenhydramine 25-50 mg IV or PO, or equivalent (see Attachment 5 for
a list of antihistamines that may be used). Avoid IV promethazine.
Dexamethasone 20 mg IV or PO prior to the first 2 doses and 10 mg for all subsequent doses
(must have absence of IRR AEs for 2 doses prior to decreasing dose). Backbone therapy
substitutes for the premedication dexamethasone. Accordingly, 40 mg dexamethasone will be
administered PO or IV prior to daratumumab in Cycles 1-6. Substitutions for dexamethasone
are allowed (refer to Attachment 6). For subjects who restarted daratumumab after
interruption due to sustained MRD negativity, give dexamethasone 20 mg IV or PO for the
first 2 doses and 10 mg for all subsequent doses.

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Predose administration of a leukotriene inhibitor (montelukast 10 mg PO) is recommended on
Cycle 1 Day 1. The leukotriene inhibitor may be administered up to 24 hours before injection.
If necessary, due to timing constraints, all PO pre-administration medications may be administered
outside of the clinic on the day of the injection, provided they are taken 1-3 hours before the
injection.
6.1.3.2. 
Daratumumab Post-administration Medication
Consider administering low-dose oral methylprednisolone (≤20 mg) or equivalent on the day after
the injection. However, if a VRd background regimen-specific corticosteroid (eg, dexamethasone)
is administered on the day after the injection, additional post-injection corticosteroid is not
required.
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or
subjects with COPD who have an FEV1 <80% at screening or developed FEV1 <80% during the
study without any medical history), the following post-administration medications should be
considered:
Antihistamine (diphenhydramine or equivalent)
Leukotriene inhibitor (montelukast or equivalent)
Short-acting β2 adrenergic receptor agonist such as salbutamol
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such as
tiotropium or salmeterol ± inhaled corticosteroids for subjects with COPD).
In addition, subjects at risk for respiratory complications may be hospitalized for monitoring for
up to 2 nights after daratumumab administration. If subjects are hospitalized, then their FEV1
should be documented prior to 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 injections. 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 SAE. Investigators may prescribe
bronchodilators, antihistamines, and corticosteroids that are deemed necessary to provide adequate
supportive care in the event that bronchospasm occurs after a subject is released from the
hospital/clinic. If, after 4 full doses, an at-risk subject experiences no major IRR, then these post-
administration medications may be stopped.
6.2. 
Management of Injection-site and Infusion-related Reactions
6.2.1. 
Daratumumab Local Injection-site Reactions
In Study MMY1004 Part 1, SC administration of daratumumab in abdominal SC tissue was
associated with local injection-site reactions, such as induration and erythema, in some subjects.
The reactions usually resolved within 60 minutes. Local injection-site reactions should be managed
per institutional standards.

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6.2.2. 
Daratumumab Infusion-related Reactions
Subjects should be observed carefully during daratumumab administrations. Trained study staff at
the clinic should be prepared to intervene in case of any IRRs, and resources necessary for
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, medical equipment
such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at the
bedside. Attention to staffing should be considered when multiple subjects will be dosed at the
same time.
If an IRR develops, then daratumumab administration should be temporarily interrupted. Please
see the IPPI for further details. Subjects who experience AEs during daratumumab administration
must be treated for their symptoms. Subjects should be treated with paracetamol (acetaminophen),
antihistamine, or corticosteroids, as needed. Intravenous saline may be indicated. For
bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, corticosteroids,
or bronchodilators. For hypotension, subjects may require vasopressors. If ocular symptoms
(including choroidal effusion, acute myopia, and acute angle closure glaucoma) occur, interrupt
daratumumab administration and seek immediate ophthalmologic evaluation prior to restarting
daratumumab. In the event of a life-threatening IRR (which may include pulmonary or cardiac
events) or an anaphylactic reaction, daratumumab should be permanently discontinued.
6.2.2.1. 
Infusion-related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR AE to be related to administration of study drug, then
the daratumumab administration  should be paused. When the subject’s condition is stable,
daratumumab administration may be restarted 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 permanently discontinued from daratumumab
treatment.
6.2.2.2. 
Infusion-related Reactions of Grade 3 or Higher
For IRR AEs (other than laryngeal edema or bronchospasm) that are Grade 3, the daratumumab
administration must be stopped and the subject must be observed carefully until resolution of the
AE or until the intensity of the event decreases to Grade 1, at which point daratumumab
administration may be restarted at the investigator’s discretion. Please refer to the IPPI for further
details regarding continuation of daratumumab administration.
If the intensity of the AE returns to Grade 3 after restart of the daratumumab administration, then
the subject must be permanently discontinued from daratumumab treatment.
For IRR AEs that are Grade 4, the daratumumab administration must be stopped and the subject
must be permanently discontinued from daratumumab treatment.

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6.2.2.3. 
Recurrent Infusion-related Reactions
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of
bronchospasm) recurs during or within 24 hours after a subsequent daratumumab administration,
the subject must be permanently discontinued from daratumumab treatment.
If daratumumab is interrupted for a longer period, for example during transplant period or in
treatment-free period in maintenance, infusion-related reactions can re-occur.
6.3. 
Bortezomib, Lenalidomide, and Dexamethasone (VRd)
6.3.1. 
Bortezomib
6.3.1.1. 
Dose Calculation of Bortezomib
The amount (in mg) of bortezomib to be administered will be determined by body surface area
(BSA), which will be calculated according to a standard nomogram (Attachment 7), there is no
maximum dose. The calculated dose of bortezomib may be rounded to the nearest tenth of a mg
(eg, a calculated dose of 2.34 mg may be rounded to 2.3 mg).
6.3.1.2. 
Bortezomib Administration
Subjects will receive 1.3 mg/m2 bortezomib as a SC injection twice a week (Days 1, 4, 8, and 11)
for Cycles 1-6; four 28-day induction cycles (Cycles 1 to 4), and two 28-day consolidation cycles
(Cycles 5-6). Subjects will not receive bortezomib after Cycle 6. On treatment days when both
bortezomib and daratumumab are administered, bortezomib must be administered after the
daratumumab administration.
If a subject’s weight changes by more than 10% from baseline, the dose of bortezomib will be
re-calculated. Bortezomib dosing may be delayed up to 48 hours, however subsequent doses must
be adjusted to account for the delay. Note that there must be at least 72 hours between doses of
bortezomib. Skipped doses of bortezomib will not be made up later in the cycle.
For subjects with unacceptable toxicity at the local injection site despite dose modifications or
change in injection concentration, bortezomib can be administered intravenously as a 3 to 5 sec
bolus injection. Please refer to local prescribing information for further details on either SC or IV
administration. On daratumumab administration days, bortezomib will be administered at the end
of the daratumumab administration. No subjects will receive bortezomib after the first 6 cycles of
treatment.
6.3.2. 
Lenalidomide Administration
Lenalidomide will be administered PO at 25 mg on Days 1 to 21 in Cycles 1-6; four 28-day
induction cycles and two 28-day consolidation cycles. Subjects will start maintenance therapy at
10 mg daily PO on Days 1 to 28 (continuously) of each 28-day cycle until disease progression or
unacceptable toxicity. After 3 cycles of maintenance therapy, if well tolerated, the lenalidomide
dose may be increased to 15 mg daily, at the discretion of the investigator.

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On daratumumab administration days, it is recommended that lenalidomide is administered either
prior to or at the same time (preferred) as the pre-administration medications. If a daily
lenalidomide dose is missed, it may be taken if <12 hours have elapsed since the time that it should
have been taken. If the next dose is scheduled to be taken within 12 hours, the missed lenalidomide
dose should be skipped.
Lenalidomide should be taken as a single dose at approximately the same time daily. Lenalidomide
can be taken with or without food. Breaking or dividing the lenalidomide capsule is strongly
discouraged.
6.3.3. 
Dexamethasone Administration
Dexamethasone will be administered on scheduled days as indicated in the Time and Events
Schedule (Table 1) at 40 mg daily on Days 1-4 and Days 9-12 of each 28-day cycle during
induction and consolidation (Cycles 1-6) as part of the VRd backbone regimen. On daratumumab
administration  days, dexamethasone backbone therapy substitutes for the premedication
dexamethasone. Accordingly, 40 mg dexamethasone will be administered PO or IV 1-3 hours
before the daratumumab administration. On days when daratumumab is not administered,
dexamethasone is administered PO. Dexamethasone tablets are to be taken with or immediately
after a meal or snack, preferably in the morning.
6.4. 
Dose Delays and Dose Modifications
Bortezomib, lenalidomide and dexamethasone doses may be reduced, or the treatment schedule
may be modified for the management of the study drug-related toxicities. Subjects who need to
discontinue treatment with any one component of study treatment (daratumumab, bortezomib,
lenalidomide or dexamethasone) may continue to receive treatment with the other components of
study treatment, as assigned. Investigators should refer to the bortezomib, lenalidomide and
dexamethasone updated summary of product characteristics (SmPC) for further recommendations
for dose delays and modifications.
6.4.1. 
Cycle Delay
On the first day of each new treatment cycle and before each daratumumab dose, the subject will
be evaluated by the treating physician for possible toxicities that may have occurred after the
previous dose(s). Toxicities are to be assessed according to NCI-CTCAE, Version 5. Dose
modifications or delays will be made based on the toxicity experienced during the previous cycle
of therapy or newly encountered on Day 1 of a cycle (see also Table 6). For any neurological
deficits that develop, it is strongly recommended that these be evaluated by the same physician
who performed the neurological assessment at baseline. The parameters in Table 4 should be met
on the first day of a new cycle (ie, the following represent baseline inclusion criteria levels):
Table 4: 
Re-treatment Criteria Before the Start of Each Induction/Consolidation Cycle
Laboratory parameter 
Requirements before each study agent administration
ANC  
1.0 x 109/L
Platelet count 
70 x 109/L
Hemoglobin  
7.5 g/dL (≥4.96 mmol/L)

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If the above parameters are not met, the start of the next cycle will be held for a minimum of
1 week and a maximum of 28 days until recovery to the specified levels. Supportive care
medications including transfusions should be administered at the investigator discretion.
Subjects should have adequate hematologic recovery (ANC≥1.0 x 109/L and platelets 75 x 109/L)
following ASCT prior to initiating consolidation or maintenance therapy.
Should a subject be unable to tolerate therapy due to toxicity during the consolidation phase of
therapy, the subject may proceed with the maintenance phase of the study (Cycle 7+) and skip the
remaining consolidation cycles after discussion with the sponsor’s medical monitor. If there is a
delay in the start of a new cycle (ie, none of the study medications are given during this period)
for more than 28 days during induction or maintenance phases due to insufficient recovery from
toxicity, subjects will discontinue taking the study treatment(s) permanently unless continuation
approved by the sponsor’s medical monitor. If subject permanently discontinues therapy
procedures should be performed as outlined in Section 9.1.4.
6.4.2. 
Dose Modification Guidelines
Toxicities should be attributed, whenever possible, to a specific study drug. Reduction of all agents
considered related to a toxicity should occur as per the guidelines below. When multiple toxicities
are attributed to a study treatment, a dose adjustment should be made according to the guidelines
for the most severe toxicity. Please refer to the tables below for dose reduction steps and dose
modification guidelines. Once dose reduction for a medication has been implemented, unless
otherwise stated specifically in the table below, dose re-escalation should not occur, unless in the
judgment of the investigator, and in consultation with the sponsor’s medical monitor, there is
clinical benefit and a reasonable and acceptable risk profile.
6.4.2.1. 
Daratumumab
6.4.2.1.1. 
Daratumumab Dose Modification
Individual dose modification of daratumumab is not permitted, dose delay is recommended as the
primary method for managing daratumumab-related toxicities.
6.4.2.1.2. 
Daratumumab-related Toxicity Management
Refer to Section 6.1.3 for details on management of IRRs. If any of the following criteria are met
and the toxicity is more than expected for the backbone therapy (lenalidomide, bortezomib,
dexamethasone), or underlying multiple myeloma, the daratumumab injection must be held to
allow for recovery from toxicity as noted below. If attribution is unclear, then daratumumab should
be held until recovery from toxicity as noted below.
The criteria for a dose delay are:
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
Grade 3 thrombocytopenia with bleeding
Febrile neutropenia

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Neutropenia with infection, of any grade
Grade 3 or higher non-hematologic toxicities with the following exceptions:
Grade 3 nausea that responds to antiemetic treatment within 7 days
Grade 3 vomiting that responds to antiemetic treatment within 7 days
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully
recovered.
If daratumumab administration does not commence within the prespecified window (Table 5) of
the scheduled administration date, then the dose will be considered a missed dose. Administration
may resume at the next planned dosing date. A missed dose will not be made up.
Table 5: 
Daratumumab-related Toxicity Management
Cycles 
Frequency  
Dose Missed  
Dosing Resumption
1 2 
Weekly 
>3 days 
next planned weeklydosing date
3 6 
Every 2 weeks 
>7 days 
next planned every 2 weeks dosing date
7+ 
Every 4 weeks 
>14 days 
next planned every four weeks dosing date
If a dose is delayed, then the dates of all subsequent doses must be adjusted. Any AE deemed to
be related to daratumumab that requires a dose hold of more than 28 days will require consultation
with the sponsor and the review of safety and efficacy to determine if daratumumab dosing may
continue.
6.4.2.1.3. 
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 5) from the per-protocol
administration date for any reason other than toxicities suspected to be related to daratumumab
should be brought to the attention of the sponsor at the earliest possible time. Subjects whose dose
was delayed for more than 28 days, upon consultation with the sponsor and the review of safety
and efficacy, may continue daratumumab dosing.
6.4.2.2. 
Lenalidomide
Lenalidomide dose adjustments are described in Section 6.4.2.2.1 and Section 6.4.2.2.2. See
Table 6 for further dose modifications.
6.4.2.2.1. 
Dose Adjustments of Lenalidomide
Dose adjustments of lenalidomide will follow the approved labeling as follows:

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Induction/consolidation (Cycles 1-6):
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 level -5: Discontinue lenalidomide permanently
Maintenance (Cycles 7+)
Starting dose (10 mg) 
If dose increased (15 mg) a
Dose level 1 
5 mg 
10 mg
Dose level 2 
5 mg (days 1 21 every 28 days) 
5 mg
Dose level 3 
Not applicable 
5 mg (days 1 21 every 28 days)
Do not dose below 5 mg (days 1 21 every 28 days)
a 
After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated, at
the discretion of the investigator.
Dose adjustments should be based on the highest grade oftoxicity that is ascribed to lenalidomide
as noted in Table 6.
6.4.2.2.2. 
Renal Impairment
Adjustment to the dose of lenalidomide is recommended to provide appropriate drug exposure in
subjects with moderate or severe renal impairment, because lenalidomide is primarily excreted
unchanged by the kidney. Lenalidomide dose adjustment should be instituted for subjects with a
creatinine clearance (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 CrCl ≥30 mL/min. If during treatment a subject’s renal status changes, the dose should be
adjusted as shown in Table 6.
6.4.2.3. 
Bortezomib
6.4.2.3.1. 
Dose Adjustments of Bortezomib
Dose adjustments of bortezomib will follow the approved labeling 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

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7. 
TREATMENT COMPLIANCE
Study drug (daratumumab) and the components of the backbone regimens will be administered or
prescribed by qualified site staff, and the details of each administration will be recorded in the
electronic case report form (eCRF). Additional details are provided in the Site Investigator Product
Procedures Manual (sIPPM).
8. 
CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which
prohibited therapies are administered.
Routine systemic use of concomitant medications will be collected in the eCRF and recorded in
the source documents beginning with signing of the ICF to 30 days after the last dose of the last
component of study treatment or until the start of subsequent anticancer treatment, if earlier.
During the transplant period (defined as the period from the first day of hospitalization to the day
before C5D1) only the concomitant treatments used to treat AEs specified in Section 9.1.3. should
be recorded. Concomitant medications to manage AEs and SAEs will be recorded as per
Section 12.3.1. The sponsor must be notified in advance (or as soon as possible thereafter) of any
instances in which prohibited therapies are administered.
8.1. 
Recommended Therapies
8.1.1. 
Prevention of Deep Venous Thrombosis
Lenalidomide has been associated with an increased risk of deep vein thrombosis and pulmonary
embolism. Therefore, prophylaxis of venous thromboembolism (VTE) for all subjects is
recommended according to IMWG guidelines (Palumbo 2008, Attachment 8). Both individual and
myeloma-related risks of VTE should be considered in determining the type of
thromboprophylaxis. In summary:
Myeloma Risk factors:
All subjects during induction therapy Cycles 1-4 and for subsequent cycles in any subject
for whom any myeloma therapy-related risk factor is present, low molecular weight
heparin (LMWH) (equivalent of 40 mg enoxaparin once daily) or full-dose warfarin
(target international normalized ratio [INR] 2-3) is recommended.
Individual Risk factors:
If no risk factor, or any one risk factor is present, aspirin 81-325 mg once daily is
recommended or dose per institutional standards.
If 2 or more risk factors are present, LMWH (equivalent of enoxaparin 40 mg once daily)
or full-dose warfarin, INR 2-3, is recommended.

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8.1.2. 
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor lysis
syndrome, including increasing hydration and treating hyperkalemia, hyperuricemia, and
hypocalcemia, is highly recommended. It is also recommended that high-risk subjects, ie, those
with a high tumor burden, be treated prophylactically in accordance with local standards
(eg, increased hydration; allopurinol 300 mg daily and medication to increase urate excretion).
Subjects are to be provided prophylactic therapy to manage injection reactions during the
Treatment Phase, as described in Section 6.1.3.1.
8.1.3. 
Prophylaxis Against Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia prophylaxis should be considered, as per institutional guidelines.
8.1.4. 
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase and
continue for 3 months following treatment with daratumumab. Initiate antiviral prophylaxis to
prevent herpes zoster reactivation within 1 week after starting study treatment and continue for
3 months following study treatment. Acceptable antiviral therapy includes acyclovir (eg, 400 mg
given PO 3 times a day, or 800 mg given PO 2 times a day or per institutional standards),
famcyclovir (eg, 125 mg given, twice a day or per institutional standards), or valacyclovir
(eg, 500 mg given PO, twice a day or per institutional standards).
8.1.5. 
Prevention of Steroid Induced Gastritis
Dexamethasone and other corticosteroids 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) may be used.
8.1.6. 
Bisphosphonate Therapy
Bisphosphonate therapy is strongly recommended for all subjects with evidence of lytic
destruction of bone or with osteopenia. Bisphosphonate therapy should be continued per treatment
guidelines (Moreau 2013, NCCN 2017). Commercially available IV bisphosphonates
(pamidronate and zoledronic acid) are preferred, when available, and should be used according to
the manufacturer’s 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. It is preferred that investigators use the same
route of bisphosphonate therapy for all subjects at their sites.
Subjects who are using bisphosphonate therapy when they enter the study should continue the
same treatment. Subjects with evidence of lytic destruction of bone or with osteopenia who are not
using a bisphosphonate at the time of randomization should start a bisphosphonate as soon as
possible during Cycle 1 or 2 of treatment. Investigators should not start bisphosphonate therapy
during the study, unless it has been agreed with the sponsor that there is no sign of disease
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8.1.7. 
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local SOC. Per protocol, HBV DNA testing by
PCR is mandatory for subjects at risk for HBV reactivation. See Section 9.8.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should
be interrupted until the infection is adequately controlled. If the benefits outweigh the risks, study
treatment may be resumed with concomitant antiviral prophylaxis as per local SOC. Consult a
liver disease specialist as clinically indicated.
8.2. 
Permitted Therapies
Subjects are to receive full supportive care during the study. The following medications and
supportive therapies are examples of support therapies that may be used during the study:
Colony-stimulating factors, erythropoietin, and transfusion of platelets and red cells.
Loperamide is recommended for the treatment of diarrhea, starting at the time of the first
watery stool. The loperamide dose and regimen is according to institutional guidelines.
Prophylactic loperamide is not recommended.
Prevention of constipation (eg, adequate hydration, high-fiber diet, and stool softeners, if
needed).
Adequate hydration is recommended for prevention of myeloma-related kidney disease.
Prophylactic antiemetics, except for corticosteroids.
An emergency short course of corticosteroid (equivalent of dexamethasone 40 mg/day for a
maximum 4 days) is permitted before treatment.
Vaccination is allowed per local guidelines (including annual influenza and inactivated SARS-
CoV-2 vaccines, including mRNA-based vaccines), but vaccines should not be administered
on the same day as study treatment administration; however, the subject may continue
lenalidomide on the day of vaccine administration per institutional practice. Some types of
vaccines (eg, live, attenuated or with suspected replication capabilities) are not permitted. Note
that antibody responses to vaccines may be suboptimal during study treatment (Ariza-Heredia
2015; see Section 8.3 and Attachment 13).
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered (see Section 8.3).
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. Investigators should refer to the local bortezomib,
lenalidomide and dexamethasone updated SmPC for drugs prohibited or to be used with
precautions. Use of the treatments listed below is prohibited during the study:
Concomitant administration of strong CYP3A4 inducers is prohibited with the use of
bortezomib. Administration of strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir) should
be avoided and is not recommended in subjects receiving bortezomib. If a strong CYP3A4

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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, please refer to Flockhart 2016 (http://medicine.iupui.edu/flockhart/).
Other agents that target CD38.
Medications used for other indications that have antimyeloma properties (for example,
interferon and clarithromycin) (Ghosh 2013, Rossi 2013, Niesvizky 2008).
Approved or investigational treatments for multiple myeloma (including but not limited to
conventional chemotherapies, immunomodulatory drugs [IMiDs], or proteasome inhibitors).
Concomitant administration of investigational agents is prohibited, including administration
of commercially available agents with activity against or under investigation for multiple
myeloma.
Systemic corticosteroids (>10 mg dexamethasone per day or equivalent or a total
maximum dose of 140 mg dexamethasone or equivalent in 14 days) other than those given
for IRRs as described in Section 6.2.2 is prohibited. Non-steroidal anti-inflammatory
agents should be avoided as they may exacerbate myeloma-related kidney disease.
Administration of investigational, live attenuated, or replication-competent viral vector
vaccines <4 weeks prior to the start of study treatment, during study treatment, or initiated
<90 days after last dose of study treatment are prohibited.
In the absence of disease progression, should a subject require emergency orthopedic surgery or
radiotherapy, upon recovery the subject may continue treatment after consultation with, and
approval by, the sponsor’s medical monitor. 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.
8.4. 
Subsequent Therapies
It is not permissible to start other antimyeloma therapy until disease progression is confirmed by
IMWG criteria and approved by the medical monitor.
After confirmation of PD, subsequent therapy is left to the investigator’s discretion. Subsequent
therapy for multiple myeloma (including start and end date, best response, and date of progression
by local laboratory) should be documented in the appropriate section of the eCRF.
Administration of any other antimyeloma therapy to subjects who discontinue study drug for
reasons other than disease progression should be monitored, and disease progression on such
treatment should be monitored and documented in the CRF, according to the Time and Events
Schedule (Table 1).

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9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The Time and Events Schedules (Table 1 and Table 2) summarize the frequency and timing of
assessments applicable to this study. Study assessments will be performed only after written
informed consent is obtained. Every effort should be made to keep subjects on the study schedule
as planned from Cycle 1 Day 1. At each visit, study assessments should be completed before the
administration of any treatment. Any missed visits, tests not performed, or examinations that are
not conducted must be reported as such in the eCRF.
PRO measures will be completed by the subject at the clinical site or by telephone, as an option,
for assessments during the Follow-up Phase. All visit-specific PRO assessments should be
completed before any tests, procedures, or other consultations for that visit to prevent influencing
subject perceptions. If the subject is unable to complete the PRO assessments, the reason for not
completing the questionnaires will be documented (ie, too ill, subject refused, etc). Refer to
Section 9.7 for details.
Urine and blood collections should be kept as close to the specified time as possible. Other
measurements may be done earlier than specified, if needed. Additional pregnancy tests may be
performed, as determined necessary by the investigator or required by local regulation, to establish
the absence of pregnancy at any time during the subject’s participation in the study.
The total blood volume for the study is estimated at approximately 95 mL during screening,
approximately 340 mL in the Induction/ASCT/Consolidation Phase (Cycles 1-6), approximately
370 mL in Year 1 of the Maintenance Phase, and approximately 280 mL annually in Year 2 and
beyond of the Maintenance Phase. This includes laboratory assessments associated with safety,
efficacy, and PK evaluations, as well as scientific research samples. At the End-of-Treatment Visit,
approximately 15 mL of blood will be collected and approximately 10 mL will be collected for
PK testing in the Follow-up Phase. Unscheduled samples may be taken for safety reasons (eg,
IRR) or repeat samples may be taken in the event of technical issues with the samples taken.
9.1.2. 
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. The
Screening Phase begins when the first screening assessment is conducted. During the Screening
Phase, eligibility criteria will be reviewed, and a complete clinical evaluation will be performed as
specified in the Time and Events Schedule (Table 1). Screening procedures will be performed
within 28 days before randomization; however, results of tests such as hematology or chemistry to
document CRAB criteria, skeletal survey or other radiologic tests (eg, CT scans or MRI) to
document baseline lytic lesions or size of known or suspected extramedullary plasmacytomas,
ECG, ECHO or MUGA (only required for subjects >65 years old), chest x-rays or full dose chest
CT scans, spirometry, DLCO (only required for subjects >65 years old), or bone marrow
aspirate/biopsy performed up to 6 weeks (42 days) before randomization as routine SOC for the
subject’s disease can be used. A negative pregnancy test for women of childbearing potential must

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be documented within 10 to 14 days and again within 24 hours before the first dose of any
component of the treatment regimen.
Subjects who fail to meet the inclusion criteria or who fulfill any of the 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 then will be assigned a new screening number.
9.1.3. 
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and
Events Schedules (Table 1 and Table 2). The Treatment Phase begins on Cycle 1 Day 1 and
continues until disease progression, unacceptable toxicity, or for the other reasons outlined in
Section 10.2. Subjects will be monitored closely for AEs, laboratory abnormalities, and clinical
response. Clinical evaluations and laboratory studies may be repeated more frequently, if clinically
indicated. If disease progression is diagnosed, then the subject will discontinue study treatment,
complete the End-of-Treatment Visit, and enter the Follow-up Phase.
9.1.3.1. 
Induction Treatment (Cycles 1-4)
Subjects will receive four 28-day cycles of VRd induction therapy (Cycles 1-4) as described in
Section 6.2. Subjects in Arm B will receive daratumumab in addition to VRd as described in
Section 6.1. Efficacy will be assessed at the start of each cycle.
9.1.3.2. 
Mobilization and Harvesting Stem Cells
Stem cell mobilization should be performed within 6 weeks after completion of Cycle 4 using local
SOC. Sites should be prepared to utilize plerixafor in addition to standard agents such as
cyclophosphamide and G-CSF to ensure adequate mobilization. Additional use of plerixafor is
recommended if there is a suspicion of inadequate mobilization. The use of a second mobilization
as per local SOC or alternatively a bone marrow harvest should occur to ensure adequate stem cell
yield as per institutional practice, if the stem cell yield is deemed to be suboptimal per investigator
discretion. An assessment of the efficiency of mobilization/harvesting will be recorded in the
eCRF (please see Section 9.2).
9.1.3.3. 
Conditioning (Melphalan off Study as per Standard of Care)
Subjects should proceed to conditioning within 2 weeks after stem cell mobilization. Subjects will
receive melphalan 200 mg/m2 as conditioning therapy over a period of 24 to 48 hours prior to
ASCT. Melphalan may be given at a lower dose of 140 mg/m2, per institutional standards (ie, renal
insufficiency).
9.1.3.4. 
Transplant (as per Standard of Care)
There should be no more than 12 weeks between end of induction and transplant. Subjects will
have a single re-infusion of stem cells 24 to 48 hours after high-dose melphalan.

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9.1.3.5. 
Engraftment/Recovery
Subjects will be monitored for successful engraftment by means of hematopoietic reconstitution
(defined as ANC ≥0.5 x 109/L and platelet count ≥20 x 109/L). Supportive therapy will be
administered according to institutional standards.
During the immediate post-transplant period (defined as the first day of high-dose melphalan
administration to the day before Cycle 5 Day 1), neutropenia and thrombocytopenia resulting from
bone marrow aplasia will not be recorded as AEs in the eCRF with the exception of failure to
achieve adequate hematological values that are required to start consolidation. Only the following
AEs, concomitant medications and procedures, and MRU associated with these AEs have to be
recorded in the eCRF during this period:
any evolution of an ongoing AE at the time of ASCT
any new AE related, or that appears to be related, to daratumumab
any new infection toxicity Grade 3 or higher
any new oral mucositis toxicity Grade 3 or higher
9.1.3.6. 
Consolidation (Cycles 5-6)
Consolidation therapy should commence within 12 weeks of transplant when engraftment is
complete (defined as ANC ≥0.5 x 109/L and platelet count ≥20 x 109/L) and when in the opinion
of the investigator the subject is fit enough to tolerate subsequent systemic therapy (30-60 days
post ASCT). In addition, subjects also need to meet the consolidation start criteria in Section 6.4.1.
Subjects will receive two 28-day cycles of VRd as described in Section 6.3. Subjects assigned to
Arm B will receive daratumumab as described in Section 6.1.2. For subjects who achieve
hematopoietic reconstitution >12 weeks after ASCT, subjects should discuss continuation to
consolidation versus maintenance therapy with the sponsor’s medical monitor. Efficacy will be
assessed at the start of each cycle.
9.1.3.7. 
Post-consolidation Efficacy Assessment
Subjects with a response of VGPR or better will be assessed for response and MRD once
consolidation therapy is complete prior to Cycle 7 Day 1 study drug administration in subjects who
are unable to complete consolidation due to toxicity or delayed engraftment consolidation.
9.1.3.8. 
Maintenance Treatment
Subjects will receive lenalidomide in 28-day cycles as described in Section 6.3.2. Subjects in
Arm B will also receive daratumumab as described in Section 6.1.2. Efficacy will be assessed as
per the Time and Events Schedule (Table 1).
9.1.4. 
End-of-Treatment Visit
Unless a subject withdraws consent for study participation, or is lost to follow-up, an End-of-
Treatment Visit should be performed within 30 days after the last dose of all components of the
treatment regimen have been discontinued. Subjects in Arm B who stop daratumumab due to

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sustained MRD negativity and who have stopped lenalidomide due to toxicity should not complete
an End-of-Treatment Visit but should continue assessments per Table 1 and Section 6.1.2.
Every effort should be made to conduct the End-of-Treatment Visit before the subject starts
subsequent therapy. Posttreatment PK and immunogenicity samples should still be collected, even
if a subsequent therapy has been initiated. If a subject is unable to return to the site for the End-of-
Treatment Visit, then the subject should be contacted to collect AEs and concomitant therapies
that occur within 30 days after the last dose of any component of the treatment regimen. Additional
information on reporting of AEs can be found in Section 12.
9.1.5. 
Posttreatment Phase (Follow-up)
The Follow-up Phase will begin once a subject permanently discontinues treatment with study
medications. For all subjects who discontinue study drug without disease progression, disease
evaluations by central laboratory should continue to be performed as specified in the Time and
Events Schedule (Table 1) until documented disease progression. For subjects who discontinue
study treatment without disease progression prior to transplant, disease evaluations at the central
lab should continue to be performed as specified in the Time and Events Schedule (Table 1) until
documented disease progression. Subsequent antimyeloma therapy must not start until after
disease progression is confirmed per IMWG criteria (see Table 7) and approved in the IWRS
system.
After documented disease progression, follow-up information will be obtained every 16 weeks
(±14 days). The every 16-week follow-up contacts should be scheduled from the date of confirmed
disease progression. Subsequent anticancer treatment and the associated response to treatment by
local laboratories, including date of subsequent progression (PFS2) will be recorded. In accordance
with the 2016 IMWG consensus recommendations for the purposes of the study a line of
subsequent therapy is defined as one or more cycles of a planned treatment program. A new line
of therapy starts when a planned course of therapy is modified to include other treatment agents
(alone or in combination) as a result of a disease progression, relapse, or toxicity. (Rajkumar 2011).
Survival status will be obtained every 16 weeks. If the information is obtained via telephone
contact, written documentation of the communication must be available for review in the source
documents. If the subject has died, the date and cause of death will be collected and documented
in the eCRF.
NOTE: Subjects in Arm B who stop daratumumab due to sustained MRD  negativity should
continue study assessments as per the Time and Events Schedule (Table 1). These subjects remain
on study as this period is not considered posttreatment follow-up.

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9.2. 
Efficacy Evaluations
Assessment of tumor response and disease progression will be conducted in accordance with the
IMWG response criteria. Efficacy evaluations will include measurements of tumor burden/residual
disease, myeloma proteins, bone marrow examinations, skeletal surveys, extramedullary
plasmacytomas, and serum calcium corrected for albumin.
9.2.1. 
Response Categories
Disease evaluations must be performed as outlined in the Time and Events Schedule (Table 1) on
the scheduled assessment day (±7 days). Disease evaluations scheduled for treatment days should
be carried out before study drug is administered. Testing of specimens use for disease evaluation
will be performed by a central laboratory (unless otherwise specified).
This study will use the IMWG consensus recommendations for multiple myeloma treatment
response criteria (Rajkumar 2011) presented in Table 7. For M-protein and immunofixation
measurements in serum and 24-hour urine, and FLC measurements, the investigator will use results
provided by the central laboratory. For subjects in Arm B, once the criteria for discontinuation of
daratumumab has been met as per Section 6.1.2, subjects will be followed for loss of CR. If a
subject meets the criteria for loss of CR without disease progression as noted in Table 8, the subject
will then restart daratumumab as per Section 6.1.2. The criteria for loss of CR without disease
progression is presented in Table 8 and only applies to subjects in Arm B who meet the above
criteria. For subjects with suspected daratumumab interference on serum M-protein quantitation
by electrophoresis (SPEP) and immunofixation (IFE), a reflex assay will be performed
(Attachment 9). Subjects with confirmed daratumumab interference who meet all other clinical
criteria for CR or sCR will be considered to have achieved CR/sCR.

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Table 7: 
IMWG Consensus Recommendations for Multiple Myeloma Treatment Response Criteria
Response 
Response Criteria
Stringent 
complete 
Response (sCR) 
CR as defined below, plus
Normal FLC ratio, and
Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2 to 4 color flow
cytometry
Complete 
response (CR)* 
Negative immunofixation on the serum and urine, and
Disappearance of any soft tissue plasmacytomas, and
<5% PCs in bone marrow
Very good partial 
Response 
(VGPR)*
Serum and urine M component detectable by immunofixation but not on electrophoresis, or
≥90% reduction in serum M protein plus urine M protein <100 mg/24 hours
Partial response 
(PR) 
≥50% reduction of serum M protein and reduction in 24 hour urinary M protein by ≥90% or to
<200 mg/24 hours
If the serum and urine M protein are not measurable, a decrease of ≥50% in the difference between
involved and uninvolved FLC levels is required in place of the M protein criteria
If serum and urine M protein are not measurable, and serum free light assay is also not measurable,
≥50% reduction in bone marrow PCs is required in place of M protein, provided baseline bone
marrow plasma cell percentage was ≥30%
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue
plasmacytomas is also required.
Stable disease 
(SD)
Not meeting criteria for CR, VGPR, PR, or PD
Progressive 
disease (PD)† 
Increase of 25% from lowest response value in any one of the following:
Serum M component (absolute increase must be ≥0.5 g/dL),
Urine M component (absolute increase must be ≥200 mg/24 hours),
Only in subjects without measurable serum and urine M protein levels: the difference between
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)
Only in subjects without measurable serum and urine M protein levels and without measurable
disease by FLC levels, bone marrow PC percentage (absolute percentage must be ≥10%)
Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the
size of existing bone lesions or soft tissue plasmacytomas
Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed
solely to the PC proliferative disorder
CR complete response; FLC free light chain; IMWG International Myeloma Working Group; M protein monoclonal
paraprotein; PC plasma cell; PD progressive disease; PR partial response; sCR stringent complete response; SD stable
disease; VGPR very good partial response
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the
institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or
new bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies
regardless of whether disease at baseline was measurable on serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be
confirmed. For PD, serum M component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting
M component is ≥5 g/dL.
*Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC
levels: CR in such subjects indicates a normal FLC ratio in addition to CR criteria listed above. VGPR in such subjects
requires a >90% decrease in the difference between involved and uninvolved FLC levels.
†Clarifications to IMWG criteria for coding PD: “25% increase” refers to M protein and FLC, and does not refer to bone
lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not need to be a confirmed
value.
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
Reference: Rajkumar 2011

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Table 8: 
Arm B Only (Section 6.1.2): Criteria for Loss of Complete Response Not Meeting Criteria for
Disease Progression (Per Table 7)
Loss of CR 
One or more of the following criteria:
Reappearance of serum M protein by immunofixation or electrophoresis (any value without
confirmed PD)a
Reappearance of urine M protein by immunofixation or electrophoresis (any value without
confirmed PD)a
Development of ≥5% plasma cells in the bone marrow
a 
Two consecutive assessments needed.
9.2.2. 
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a
central laboratory.
IgG, IgA, IgM, IgD, and IgE at screening
Serum M-protein quantitation by electrophoresis (SPEP)
Serum immunofixation (SIFE) at screening and thereafter when M-protein is non-quantifiable
up to confirmation of CR
24-hour urine M-protein quantitation by electrophoresis (UPEP)
Urine immunofixation (UIFE) at screening and thereafter when a M-protein is non-
quantifiable up to confirmation of CR
FLC assessment for subjects with light chain only myeloma AND for all subjects to confirm
sCR
Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule
(Table 1) 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 performed at least
one day later. Disease evaluations will continue beyond loss of CR until disease progression is
confirmed. Serum and urine immunofixation tests will be performed at screening and thereafter
when serum or 24-hour urine M-protein electrophoresis [by SPEP or UPEP] is negative or non-
quantifiable. For subjects with light chain multiple myeloma, both serum and urine
immunofixation tests will be performed at every cycle.
As an IgG1 kappa immunoglobulin, daratumumab has been shown to interfere with serum protein
electrophoresis (SPE) and IFE (McCudden 2010). For subjects in Arm B with daratumumab
interference on serum IFE, the SEBIA Hydrashift 2/4 Daratumumab IFE Interference test
(Attachment 9) will be used to distinguish a positive SPEP/IFE due to the presence of
daratumumab versus the presence of the underlying (endogenous) monoclonal protein. This reflex
assay will be implemented as part of response criteria. For those subjects who meet all other
clinical criteria for CR/sCR, with confirmed daratumumab interference on SPE/IFE, will be
considered CR/sCR.
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

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circumstances, the local laboratory results of blood and urine M-protein measurements may be
used to determine eligibility, but only if the results are clearly (eg, 25% or more) above the
thresholds for measurability. In such cases, central laboratory results are still required to be
obtained in order to establish baseline values and confirm the results from the local laboratory.
9.2.3. 
Albumin and Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected and analyzed
at the central laboratory, as specified in the Time and Events Schedule (Table 1) until the
development of confirmed disease progression. Development of hypercalcemia (corrected serum
calcium >11.5 mg/dL or 2.8 mmol/L) may indicate disease progression or relapse if it is not
attributable to any other cause (see disease response criteria in Table 7). 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 3.
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 hypercalcemic for purposed of safety and efficacy reporting in this study.
9.2.4. 
β2-microglobulin and Albumin
Blood samples for β2 microglobulin and albumin are to be collected at screening and will be
analyzed by the central laboratory.
9.2.5. 
Bone Marrow Examination
Bone marrow aspirate or biopsy will be performed at screening for clinical staging (morphology,
central FISH evaluation of high-risk cytogenetic anomalies (del17p, t[4;14]) and t[14;16]), and
immunohistochemistry [IHC] or immunofluorescence or flow cytometry), to establish baseline
multiple myeloma clonality, to monitor for MRD, and to perform molecular subtyping. FISH
evaluation of amp(1q21) may be performed as an exploratory risk anomaly. Clinical staging may
be performed locally; however, a portion of the bone marrow aspirate/biopsy must be sent to the
central lab for analysis of MRD and molecular subtyping. A fresh bone marrow aspirate at
screening is required (archived samples will not be accepted). A core bone marrow biopsy/aspirate
will be performed to confirm sCR and CR. If a bone marrow core biopsy cannot be obtained or is
not available, morphologic review of the bone marrow aspirate smear may be reviewed by the
local laboratory for confirmation of CR. Bone marrow aspirates are acceptable for determination
of loss of CR (IHC or immunofluorescence) and to monitor for MRD. Bone marrow aspirates
performed for assessment of MRD or confirmation of CR should be repeated if the collection was
inadequate.
While archived samples will not be accepted for MRD or cytogenetic evaluation at screening,
archived samples may be requested to be sent to the central laboratory, if available, in cases in
which there is difficulty in establishing baseline clonality for MRD. If baseline clonality is still not
established, no further bone marrow samples should be collected for MRD assessments.

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Table 9: 
Bone Marrow Testing
Local Testing 
Central Testing
Screening 
Disease characterization(morphology, 
and either immunohistochemistry, 
immunofluorescence, or flow 
cytometry). 
A fresh bone marrow aspirate will be collected at
screening and sent to a central laboratory for
cytogenetic analysis by conventional FISH while a
second portion of the bone marrow aspirate will be
used for MRD index clone identification
(calibration). If the MRD index clone is not
identified, then an archived sample might be
requested in order to repeat the clone identification
assay. A third portion of the bone marrow may be
used for additional biomarker assessments.
During 
Treatment/Follo 
w-Up 
At time ofsuspected CR/sCR: 
-Evaluate Plasma cell percentage in  
the bone marrow to confirm CR  
-Evaluate clonality ofplasma cells (by
flow cytometry, IHC or IFa) in the bone 
marrow to confirm sCR  
(IfsCRcriteria are not met, repeat local 
testing for sCRwith subsequent bone 
marrow testing.)
MRD Assessments: Bone marrow aspirates will
be collected as follows:
-During post-consolidationb in subjects with VGPR
or better.
-At time of suspected CR/sCR.
-For subjects who achieve CR/sCR, have not
progressed and remain on the study, additional bone
marrow aspirate will be obtained at 12, 18, 24, 30,
and 36 months post Cycle 1 Day 1 (±1 month) and
yearly thereafter (±1 month).c
EMN correlative studies: Bone marrow aspirates
will be collected:
-If feasible, for all subjects during post-consolidation
and at disease progression.
CR=complete response; FISH=fluorescence in  situ  hybridization; IF=immunofluorescence;
IHC=immunohistochemistry; MRD=minimal residual disease; sCR=stringent complete response; VGPR=very
good partial response
a
Immunohistochemistryor immunofluorescence(both require kappa/lambda ratio from analysis of>100 cells) or
2- to 4-color flow cytometryare acceptable methods to evaluate plasma cell clonality.
b
Obtain prior to C7D1 study drug administration.
c
Ifone ofthese time points for MRD sampling occurs within 1 month ofsuspected CR/sCR, a repeat bone marrow
will not be requested. These bone marrow tests will only be required if subject’s response is near CR or better by
blood and urine evaluations.
9.2.6. 
Minimal Residual Disease Assessment
In this study, bone marrow and whole blood samples will be collected for MRD assessment when
a bone marrow aspirate is performed at screening and at the subsequent timepoints outlined in
Table 9 and the Time and Events Schedule (Table 1). Bone marrow aspirates performed for
assessment of MRD should be repeated if the collection was inadequate. Note: for subjects who
achieve CR/sCR, whole blood samples are collected every 3 months (±1 month) from 12 to
36 months post C1D1, and yearly thereafter; bone marrow samples are collected at Month 12, 18,
24, 30, and 36 months post C1D1, and yearly thereafter (±1 month).
9.2.7. 
Assessment of Lytic Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, femora,
and any other bones for which the investigator suspects involvement by disease) is to be performed

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and evaluated by the local radiologist. An alternative (eg low-dose CT) may be used in accordance
with local SOC. Please note that the same methodology used at Screening should be used
throughout the study for comparison purposes. During the Treatment Phase and before disease
progression is confirmed, imaging should be performed whenever clinically indicated based on
symptoms, to document response or progression. MRI or low-dose CT scan 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 7). If a radionucleotide bone scan 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. However, a radionucleotide bone scan does
not replace a complete skeletal survey.
Some subjects present with disease progression manifested by symptoms of pain due to bone
changes. In these cases, disease progression may be documented by skeletal survey or other
imaging tests, depending on the symptoms that the subject experiences. If the diagnosis of disease
progression is obvious by imaging investigations, then no repeat confirmatory x-rays are
necessary. In instances when changes are subtler, a repeat x-ray should be performed in 1 to
3 weeks.
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. CT scan
evaluations are an acceptable alternative if there is no contraindication to the use of intravenous
contrast. PET 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 every 4 weeks (by physical examination) for subjects with a history of
plasmacytomas or as clinically indicated during treatment for other subjects until disappearance of
the plasmacytoma or confirmed disease progression. If assessment can only be performed using
imaging, then evaluation of extramedullary plasmacytomas should be done every 12 weeks
starting from Cycle 1 Day 1 until disappearance of the plasmacytoma or confirmed disease
progression. 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%, from the smallest measurable
size during the study and new plasmacytomas must not have developed (see the disease response
criteria in Table 7). 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

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diameters of the reported plasmacytomas have increased by at least 50%, this will also qualify as
disease progression.
9.3. 
Pharmacokinetics and Immunogenicity
Serum samples will be used to evaluate the PK of daratumumab, as well as anti-daratumumab
antibodies. Plasma samples will be used to evaluate anti-rHuPH20 antibodies. Serum samples
collected for PK and immunogenicity analyses may additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these samples. Subject confidentiality will be maintained.
9.3.1. 
Evaluations
Samples to assess both the serum concentration (PK) of daratumumab and the generation of
anti-daratumumab antibodies (immunogenicity) will be drawn from all subjects in Arm B
according to the Time and Events Schedule (Table 2). At specified time points, venous blood
samples (5 mL per sample) will be collected, and the serum will be divided into 3 aliquots
(1 aliquot for PK analysis, 1 aliquot for immunogenicity assessment [when appropriate], and
1 aliquot as a back-up).
Samples will also be collected from all subjects in Arm B to evaluate the anti-rHuPH20 antibodies
according to the Time and Events Schedule (Table 2). The exact dates and times of blood sampling
must be recorded. Refer to the laboratory manual or equivalent document for sample collection
requirements. Collected samples must be stored under the specified and controlled conditions for
the temperatures indicated in the laboratory manual. Samples collected for determining serum
concentrations/immunogenicity of daratumumab or immunogenicity of rHuPH20 in this study
may be retained to address questions about drug characteristics.
9.3.2. 
Analytical Procedures
Serum samples will be analyzed to determine concentrations of anti-daratumumab antibodies using
validated immunoassay methods.
For the daratumumab immunogenicity assessments, serum samples will be screened for antibodies
binding to daratumumab and serum titer will also be determined from confirmed positive samples.
Other immunogenicity analyses (eg, assessment of neutralizing capabilities) may be performed to
further characterize the immune responses that are generated.
For the rHuPH20 immunogenicity assessments, plasma samples will be screened for antibodies
binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary.
Neutralizing antibody assessments may also be performed to further characterize immune
responses that are generated.
9.3.3. 
Pharmacokinetic Parameters
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained from
subjects in Arm B. The PK parameters are defined as:

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Cmax  
Maximum observed concentration
Cmin  
Minimum observed concentration
The parameters, Cmin, and Cmax, will be determined based on the assigned collection timepoints. If
there are sufficient data, population PK analysis of serum concentration-time data of daratumumab
may be performed and may include data from other clinical studies. If performed, details will be
provided in a population PK analysis plan and results of the analysis will be presented in a separate
report.
9.3.4. 
Immunogenicity Assessments
Serum from venous blood samples collected from all subjects in Arm B will be assessed for the
generation of anti-daratumumab antibodies (immunogenicity) according to the Time and Events
Schedule. Daratumumab concentrations will be evaluated at all immunogenicity time points to
ensure appropriate interpretation of immunogenicity data. When both daratumumab serum
concentration and immunogenicity analyses are specified, they will be performed on aliquots from
the same blood draw and no additional sampling is required. Plasma samples will also be collected
from all subjects receiving daratumumab and assessed for anti-rHuPH20 antibodies. Procedures
for sample collection, preparation, identification, storage, and shipment will be provided in the
laboratory manual or equivalent document.
When an IRR occurs, associated with the second or later daratumumab administration, serum and
plasma samples should be obtained, if possible, for determination of anti-daratumumab antibodies
and anti-rHuPH20 antibodies. No unscheduled samples need to be collected for injection reactions
associated with the first administration of daratumumab. Daratumumab serum concentration will
also be determined from the daratumumab injection reaction sample for interpreting
immunogenicity data. If the injection reaction results in treatment discontinuation, then subjects
should undergo all scheduled safety and efficacy evaluations. Procedures for sample collection,
preparation, identification, storage, and shipment will be provided in the laboratory manual or
equivalent document. Samples collected for the analysis of daratumumab immunogenicity/serum
concentration or rHuPH20 immunogenicity may be used to evaluate safety or efficacy questions
that arise during or after the study period or for the evaluation of relevant biomarkers by the
sponsor or sponsor’s designee.
Subjects who discontinue treatment or withdraw from the study before confirmation of disease
progression should have samples collected at the time of early discontinuation. Subjects who
discontinue treatment will also be asked to return  for immunogenicity evaluation during the
Follow-up Phase.
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations
Pharmacokinetic/pharmacodynamic modeling may be performed, including exploring the
relationship between serum concentrations of daratumumab and endpoints of clinical efficacy or
safety. Details and results of any analysis performed will be presented in a separate report.

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9.5. 
Biomarkers/EMN Correlatives
As permitted by local rules and regulations, bone marrow aspirates in the D-VRd and VRd cohorts
will be collected at screening and following treatment as outlined in the Time and Events Schedule
(Table 1) for MRD monitoring. Baseline fresh bone marrow aspirate samples will be subjected to
DNA sequencing to establish a multiple myeloma clone for MRD monitoring (calibration) and for
cytogenetics evaluations by the central laboratory. A fresh bone marrow aspirate at screening is
required (archived samples will not be accepted). Fresh bone marrow aspirates will be utilized for
assessment of MRD by NGS of Ig heavy and light chains as specified in Table 9. If this
methodology is unavailable, or determined to be scientifically inferior, then alternative methods
for MRD assessment may be utilized.
While archived samples will not be accepted for MRD or cytogenetic evaluation at screening,
archived samples may be requested to be sent to the central laboratory, if available, in cases in
which there is difficulty in establishing baseline clonality for MRD. If baseline clonality is not
established or for subjects with non-unique clone sequence, no further bone marrow samples
should be collected for MRD assessments for subjects in the VRd arm, however subjects in the
D-VRd arm without baseline clonality or with non-unique clone sequence may have MRD
assessment by NGF for the purpose of determining daratumumab continuation.
Whole blood samples will be collected from subjects, as specified in the Time and Events
Schedule, for processing to plasma and peripheral blood mononuclear cells and for peripheral
MRD evaluation. Exploratory evaluation of MRD using whole blood may also be performed to
determine the utility as a more sensitive biomarker than standard clinical evaluations to detect loss
of CR. To explore the impact of the VRd regimen on daratumumab’s mechanisms of action, the
whole blood samples may be used to evaluate daratumumab’s immunomodulatory MoA, where
specific subsets of immune cells such as cytotoxic T cells, regulatory T cells, and activated NK
cells may be evaluated by fluorescence-activated cell sorting (FACS) or cytometry/time-of-flight
mass spectrometry and T-cell receptor sequencing. Proteomic analysis may also be used to
evaluate changes in proteins in circulation to evaluate potential markers of clinical response.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the
end of the study, it becomes clear that the analysis will not have sufficient scientific value for
biomarker evaluation, or if there are not enough samples or 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.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a
formalin-fixed, paraffin-embedded (FFPE) tumor sample for the successful completion of the
protocol-specified analyses, the sponsor may request that additional material be retrieved from
existing samples. Also, based on emerging scientific evidence, the sponsor may request additional
material from previously collected tumor samples during or after study completion for a

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retrospective analysis. In this case, such analyses would be specific to research related to the study
drug(s) or diseases being investigated.
9.6. 
Medical Resource Utilization
MRU data, associated with medical encounters, will be collected in the eCRF by the investigator
and study-site personnel for all subjects throughout the study. These data will be analyzed to assess
MRU across treatment arms and may be used for modeling purposes. Protocol-mandated
procedures, tests, and encounters are excluded. Data collected will include:
Number and characteristic of diagnostic and therapeutic tests and procedures (inpatient and
outpatient)
Number and duration of hospitalization (total days length of stay [days], including duration
by each hospital unit (intensive care unit)
Number and duration of medical care encounters, including surgeries, and other selected
procedures (inpatient and outpatient)
Outpatient medical encounters and treatments (including physician, nurse practitioner,
emergency room visits, tests and procedures, and medications)
Please see eCRF completion guidelines.
9.7. 
Patient-reported Outcomes
Subjects health-related quality of life (HRQoL), symptoms, functioning, and general well-being
will be captured using 3 PRO measures: the European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) (Attachment 10), European
Organization for Research and Treatment of Cancer Multiple Myeloma Module (EORTC
QLQ-MY20) (Attachment 11), and the EQ-5D-5L (Attachment 12). These measures will be
administered according to the Time and Events Schedule (Table 1) to understand how subjects
self-reported health state changes over time and the difference between-treatment arms during
induction, consolidation, maintenance, and post-progression. The hypothesis that treatment with
daratumumab maintains a subject’s HRQoL when added to a triplet regimen will be tested using
established meaningful change thresholds and statistical significance between groups.
The PRO measures will be provided in the local language. If a subject requires assistance
completing the PRO, a study coordinator may assist but should not prompt the subject in selecting
their response. The PRO measures should be completed before any conversation on status with the
health care provider. At completion, the study coordination should check that the questionnaires
are completed or document why they are missing. Full training documentation will be provided to
site coordinators before the start of data collection.
EORTC QLQ-C30 version 3 includes 30 items resulting in 5 functional scales (physical
functioning, role functioning, emotional functioning, cognitive functioning, and social
functioning), 1 Global Health Status (GHS) 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 (“past week Item”) and responses are reported

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using a verbal rating scale. The item and scale scores are transformed to a 0 to 100 scale. A higher
score represents greater HRQoL, better functioning, and more (worse) symptoms. The EORTC
QLQ-C30 has been widely used among patients with multiple myeloma. Reliability, validity, and
clinically meaningful change have been demonstrated (Wisloff1996, Wisloff1997). The EORTC
Multiple Myeloma Module (QLQ-MY20) has been designed to use alongside the EORTC
QLQ-C30 to address issues of more relevance to myeloma patients (Cocks 2007). The 20-items
make up 4 scales: disease symptoms, side effects of treatment, future perspective, and body image.
Recall, response options, and interpretation is similar to the EORTC QLQ-C30. Together the
EORTC QLQ-C30 and the EORTC QLQ-MY20 administration time is less than 30 minutes. Key
PRO endpoints include the GHS, physical functioning, fatigue, and pain scales from the EORTC
QLQ-C30 and the Disease Symptoms scale from the EORTC QLQ-MY20.
The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that
assesses 5 domains including mobility, selfcare, usual activities, pain/discomfort and
anxiety/depression plus a visual analog scale rating “health today” with anchors ranging from 0
(worst imaginable health state) to 100 (best imaginable health state) (Herdman 2011). The scores
for the 5 separate questions are categorical and are 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 EQ-5D-5L asks
respondents to select their response based on their current health (“today”) and takes less than
5 minutes to complete.
The EQ-5D-5L will be performed until death or study end. Following disease progression, sites
should attempt to administer the EQ-5D-5L every 4 months, unless death or study end occurs first.
Subjects who visit the site for the follow-up assessments should complete the EQ-5D-5L
questionnaire at that time. If the EQ-5D-5L is conducted via a telephone call with the subject, then
the subject’s questionnaire responses will be read over the telephone to the site staff who will
record the data in the eCRF. If the subject is unable to complete the EQ-5D-5L, the reason for not
completing the questionnaire will be documented (ie, too ill, subject refused). This can be done by
interview as part of the telephone contact documented in the eCRF.
9.8. 
Safety Evaluations
Safety evaluations will include AE monitoring, physical examinations, ECG monitoring, ECHO
or MUGA (only required for subjects >65 years old), clinical laboratory parameters (hematology
and chemistry), vital sign measurements, and ECOG performance status. All toxicities will be
graded according to the NCI-CTCAE Version 5. Clinically relevant changes that occur during the
study must be recorded in the Adverse Event eCRF page. 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 previous experience with daratumumab in humans, in vitro studies, and animal
toxicological findings, IRRs/allergic reactions, haemolysis, and thrombocytopenia will be closely
monitored. As a biologic agent, immunogenicity also will be monitored. Any of the safety

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monitoring assessments may be performed more frequently, and AEs should be evaluated by the
investigator according to the standard practice, if clinically indicated.
Adverse Events
Adverse events (with the exception of progression of multiple myeloma) will be reported by the
subject (or, when appropriate, by a caregiver, surrogate, or the subject’s legally acceptable
representative) from the time a signed and dated informed consent is obtained until 30 days
following the last dose of any component of the treatment regimen. Adverse events will be
followed by the investigator as specified in Section 12, Adverse Event Reporting. For AE reporting
during the transplant period, please see Section 9.1.3.5.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must
review the laboratory report, document this review, and record any clinically relevant changes
occurring during the study in the Adverse Event eCRF page. The laboratory reports must be filed
with the source documents.
The following tests will be performed by the local laboratory, unless otherwise specified:
Hematology Panel
-hemoglobin 
-absolute neutrophil count
-white blood cell count 
-absolute lymphocyte count
-platelet count
Serum Chemistry Panel
During screening and induction and consolidation Cycles 1-6:
-blood urea nitrogen (BUN) or urea 
-alkaline phosphatase
-creatinine 
-lactic acid dehydrogenase (LDH)
-sodium  
-potassium
-glucose 
-uric acid
-AST 
-total bilirubin (direct bilirubin if total
bilirubin is abnormal)
-ALT 
-total protein
During maintenance treatment Cycles 7+:
-AST 
-BUN or urea
-ALT 
-creatinine
-total bilirubin
Other Laboratory Tests

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HBV Serology:
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface
antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) at screening. Additionally,
subjects ongoing in the Treatment Phase who are within 6 months of starting study treatment when
Protocol Amendment 2 is implemented will be required to have HBV serology performed locally
upon signing the updated ICF.
HBV serology is not required at screening or for subjects ongoing in the Treatment Phase who are
within 6 months of starting study treatment if this was performed as part of SOC within 3 months
prior to first dose.
HBV DNA Tests:
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by
PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the
only serologic marker) and a known history of prior HBV vaccination do not need to be tested for
HBV DNA by PCR. During and following study treatment, subjects who have history of HBV
infection will be closely monitored for clinical and laboratory signs of reactivation of HBV as
specified in the Time and Events Schedule (Table 1). Where required by local law, the results of
HBV testing may be reported to the local health authorities.
Serum Pregnancy Test: Women of childbearing potential only. Urine pregnancy test allowed if
results from a serum pregnancy test will not be promptly available. Lenalidomide is
contraindicated for use during pregnancy, as even a single dose can induce a high frequency of
severe and life-threatening birth defects. Guidelines presented in the Celgene lenalidomide
pregnancy prevention program as per local lenalidomide labeling must be followed. If pregnancy
or a positive pregnancy test does occur, then lenalidomide study treatment must be discontinued
immediately, and the subject should be referred to an obstetrician experienced in reproductive
toxicity for further evaluation and counselling.
Calcium and Albumin Adjusted Calcium: These parameters will be part of the efficacy
evaluations as specified in Section 9.2.3). Albumin will be analyzed by the central and local
laboratories. Measurement of calcium and albumin should follow the schedule for disease
assessments. Measurement of free ionized calcium is an acceptable alternative to corrected serum
calcium for determining hypercalcemia.
Indirect Antiglobulin Test (IAT):
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 administration.
Daratumumab interferes with the 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

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(Indirect Coombs Test). This positive result masks the detection of antibodies to minor antigens
and may prevent or delay blood banks from issuing donor blood for transfusion. This effect occurs
during daratumumab treatment and for up to 6 months after treatment ends. Subjects will receive
a patient identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT
or phenotyping) determined before the first injection 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 interference with IAT by treating reagent RBCs with dithiothreitol
(DTT) (Chapuy 2015, Chapuy 2016).
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) 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 Investigator’s Brochure.
Stem Cell Harvest: For subjects who receive ASCT, record number of CD34+ cells collected and
transplanted, agents used for mobilization, and hematopoietic engraftment information.
Pulmonary Function Test: All subjects with known or suspected COPD must have a FEV1 test
during Screening. Additionally, all subjects ≥65 years old must have FEV1 and DLCO assessment
at Screening for confirmation of eligibility. Refer to Section 6.1.3.2 for details on subjects with
higher risk of respiratory complications.
Electrocardiogram (ECG): 12-lead ECGs will be performed as specified in the Time and Events
Schedule (Table 1). Whenever possible, ECGs should be taken immediately before chemistry and
PK assessments. 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, then
the procedures should be performed in the following order: ECG(s), vital signs, blood draw.
Echocardiogram (ECHO)/Multigated Acquisition (MUGA) scan: All subjects ≥65 years old
will have an ECHO or MUGA scan performed to assess LVEF for confirmation of eligibility in
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Physical Examination and Vital Signs: A complete physical examination (including neurological
examination) should be performed during the Screening Phase. Height will be measured at
screening only; weight will be measured regularly as specified in the Time and Events Schedule
(Table 1). Thereafter, only a symptom and disease directed physical examination is required.
Abnormalities will be recorded in the appropriate sections of the eCRF.
Vital signs (heart rate, temperature, blood pressure) will be performed as specified in the Time and
Events Schedule (Table 1). It is recommended that blood pressure (sitting) and heart rate
measurements be preceded by at least 5 minutes of rest in a quiet setting without distractions
(eg, television, cell phones). Only vital signs taken at screening or associated with an AE will be
recorded in the eCRF; all measurements will be recorded in the source documents.
Eastern Cooperative Oncology Group (ECOG) Performance Status: Eastern Cooperative
Oncology Group performance status will be used to evaluate the effect of the disease status on the
activities of daily living. When scheduled, ECOG Performance Status assessments should be
obtained prior to any other study procedures planned for the same day whenever possible.
9.9. 
Sample Collection and Handling
The actual dates and times of sample collection must be recorded on the laboratory requisition
form. Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature, conditions as indicated
in the laboratory manual.
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/
WITHDRAWAL FROM THE STUDY
10.1. Completion
A subject will be considered to have completed the study if he or she has finished all protocol-
specified procedures before the end of the study, has not been lost to follow-up, and 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 he or she must discontinue study
treatment; instead, the subject will enter the Follow-up Phase. The End-of-Treatment Visits and
follow-up visit assessments should continue as specified in the Time and Events Schedule
(Table 1).
A subject’s study treatment must be discontinued if:
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the subject to discontinue study treatment.

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The subject becomes pregnant unless the subject (or the subject's legally acceptable
representative), investigator, and sponsor agree the benefits outweigh the risks to the fetus and
continuation of study treatment is in the best interests of the subject (at a minimum,
lenalidomide must be permanently discontinued if a subject becomes pregnant or has a
positive pregnancy test). Discontinuation of all study treatment is also acceptable if mandated
by local regulations.
The subject (or the subject’s legally acceptable representative) withdraws consent for
administration of study drug.
The subject experiences unacceptable toxicity, including IRRs described in Section 6.2,
Management of Injection-site and Injection-related Reactions.
The subject experiences disease progression (please see below); loss of CR is not considered
as disease progression.
The subject experiences a new malignancy that cannot be treated by surgery alone (however,
a subject who develops a malignancy that can be cured surgically may continue to receive the
assigned study treatment and should continue to be followed for subsequent progression of
multiple myeloma). Subjects who require radiation therapy for treatment of new malignancy
must have study treatment discontinued unless, upon consultation with the sponsor’s medical
monitor and review of data, continuation is agreed upon. Subjects who require systemic
treatment of a new malignancy must end study treatment but should continue to be followed
for PFS2 and OS.
The primary reason for discontinuation of study treatment will be recorded in the eCRF.
Study treatment will continue until confirmation of disease progression. Before subjects are
discontinued from study treatment because of suspected disease progression:
1. The investigator (or designee) will provide documentation of disease progression (for
example, by completing a disease progression form or by contacting the IWRS) as soon as
possible and within 48 hours of confirmation of disease progression.
2. The sponsor’s medical monitor will review the provided documentation and confirm disease
progression has occurred per IMWG criteria (see Section 9.2.1, Response Categories) and that
study treatment should be discontinued.
3. After confirmation of disease progression by the sponsor, the subject will discontinue study
treatment and enter the Follow-up Phase.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent for study participation
Death
Sponsor terminates the study

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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 consent before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Study treatment assigned to the withdrawn
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a
subject discontinues study treatment and withdraws from the study before the end of the Treatment
Phase, End-of-Treatment assessments should be obtained If the reason for withdrawal from the
study is withdrawal of consent then no additional assessments are allowed.
10.3. Withdrawal From the Use of Research Samples
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5). In
such a case, samples will be destroyed after they are no longer needed for the clinical study. Details
of the sample retention for research are presented in the main ICF.
11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
11.1. Subject Information
The primary analysis population will be the intent-to-treat population, which will include all
randomized subjects. Safety will be evaluated for the population of all treated subjects.
Continuous variables will be summarized using descriptive statistics such as mean, standard
deviation, median and range. Categorical variables will be summarized using frequency tables. For
time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
11.2. Sample Size Determination
It is assumed that median PFS is 63 months for the VRd group, and the addition of daratumumab
will decrease the risk of progression or death by 31% (HR  0.69; estimated median PFS of
91 months for D-VRd group). To achieve 85% power with a 2-sided alpha of 0.05, 285 PFS events
are needed. Assuming a 12-month accrual and 64-month of additional follow-up, approximately
690 subjects (345/arm) will be needed.
Long-term follow-up for survival will continue until approximately 310 deaths have been
observed. This will provide approximately 70% power to detect a 25% reduction in the risk of
death (HR  0.75) with a log-rank test at a 2-sided alpha of 0.05.
11.3. Efficacy Analyses
Response to study treatment and PD will be evaluated by a validated computer algorithm.

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Primary Endpoint
For PFS, the primary analysis will consist of a stratified log-rank test for the comparison of the
PFS distribution between the 2 treatment groups. The Kaplan-Meier method will be used to
estimate the distribution of overall PFS for each treatment. The treatment effect (HR) and its
2-sided 95% confidence intervals are to be estimated using a stratified Cox regression model with
treatment as the sole explanatory variable. In addition, sensitivity analyses, utilizing landmark PFS
approach or time-dependent Cox regression method, may also be performed to further characterize
the treatment effect.
Secondary Endpoints
Secondary time-to-event efficacy endpoints, including PFS2 and OS, will be analyzed using the
same method as for PFS. For OS, the final analysis will occur after approximately 310 deaths have
been observed. Earlier analyses, in which OS is analyzed, will be considered as interim analyses.
Even if the significance of PFS has already been established, testing of OS will continue as planned
until a definitive conclusion on OS is reached. The details about testing of OS over time are
specified in Section 11.12.
Comparison between the 2 treatment groups of response-related endpoints at different timepoints
and other binary endpoints will be conducted using the stratified Cochran Mantel-Haenszel test.
The Mantel-Haenszel odds ratio will be provided along with its 2-sided 95% confidence interval
and will be provided as the measure of treatment effect. Time to and duration of response (PR or
better), CR/sCR, and MRD  negative status will be summarized descriptively without formal
statistical comparison.
A hierarchical testing will be used for the secondary efficacy endpoints to achieve strong control
of the overall familywise Type I error rate at a 2-sided significance level of 0.05. The details of
the testing procedure will be prespecified in a Statistical Analysis Plan that will be finalized prior
to the first interim analysis for the primary endpoint.
11.4. Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the PK-evaluable population, defined as subjects
assigned to Arm B who have received at least 1 dose of daratumumab and have at least one PK
sample concentration value after the first administration of daratumumab.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. 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.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling time point and PK parameters of daratumumab: Cmin, and Cmax.
If sufficient data are available, then population PK analysis of serum concentration-time data of
daratumumab may be performed and may include data from other studies. If the population PK

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analysis is conducted, details will be given in a population PK 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 will be summarized for all subjects who receive at
least 1 dose of daratumumab and have appropriate samples for detection of anti-daratumumab
antibodies (ie, subjects with at least 1 sample obtained after their first dose of daratumumab). The
incidence of anti-rHuPH20 antibodies will be summarized for all subjects who receive a dose of
daratumumab and have appropriate samples for detection of anti-rHuPH20 antibodies. A listing of
subjects who are positive for anti-daratumumab antibodies or anti-rHuPH20 antibodies will be
provided.
11.6. Biomarker Analyses
Baseline bone marrow aspirate samples will be evaluated by a NGS assay to establish the myeloma
clone (calibration) and for MRD monitoring. MRD assessment by NGS is an emerging tool in the
assessment of patients with multiple myeloma (Ladetto 2014) and for cytogenetics evaluations.
Several studies have demonstrated that MRD status is correlated with PFS and OS
(Martinez-Lopez 2014). In this study, bone marrow and whole blood samples will be collected
when a bone marrow aspirate is performed at screening and at the subsequent timepoints outlined
in Table 9 and Time and Events Schedule (Table 1). Whole blood sample will be collected from
subjects as outlined in the Time and Events Schedule and processed to plasma and peripheral blood
mononuclear cells and may be used to evaluate daratumumab’s immunomodulatory MoA.
Evaluation of MRD in whole blood may be performed to determine the utility in monitoring loss
of CR.
11.7. Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamic modeling may be performed, including exploring the
relationship between serum concentrations of daratumumab and endpoints of clinical efficacy or
safety. Details and results of any analysis performed will be presented in a separate report.
11.8. Medical Resource Utilization Analyses
MRU  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 Analyses
The EORTC QLQ-C30 and EORTC QLQ-MY20 scale scores and EQ-5D-5L utility and visual
analog scores will be descriptively summarized by treatment group at each time point. Within-
group and between-group treatment effects of the PRO endpoints will be assessed by change from
baseline using mixed models for repeated measures. Full details on meaningful change thresholds
and statistical analyses will be provided in the Statistical Analysis Plan.

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11.10. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
latest Medical Dictionary for Regulatory Activities (MedDRA) dictionary. In general, AEs that
occurred during the induction/consolidation and maintenance stages will be summarized
separately. Treatment-emergent adverse events for each stage will be defined as events that occur
or worsen after administration of the first dose of during that stage and through 30 days after the
last dose of study drug in that stage and before the next phase of treatment begins. Adverse events
will be summarized by system organ class and preferred terms, NCI toxicity grade, and by action
taken with study treatment.
Summaries, listings, datasets, or subject narratives will be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a SAE
event. These will be provided using the same formats as those used for AEs.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for each laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled time point.
Worst toxicity grade during treatment will be presented, per NCI-CTCAE Version 5. A listing of
subjects with any markedly abnormal laboratory results will also be provided.
Vital Signs
Descriptive statistics of pulse, temperature, 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.
11.11. Benefit-risk Analyses
Benefit-risk assessment of daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd)
vs bortezomib, lenalidomide, and dexamethasone (VRd) will be conducted by comparing
between-treatment differences of key efficacy and safety endpoints. Efficacy endpoints may
include PFS, PFS2, MRD negativity rate overall and post-consolidation, OS, duration of response
and improvement in PRO measures. Safety endpoints may include serious infections (eg,
pneumonia, lower respiratory tract infection), atrial fibrillation, diarrhea, injection reactions and
other SAEs or events of special interest. Safety endpoints that show no between-treatment
differences will be noted, but may be excluded from the benefit-risk analyses. Adverse events not
in this list, but that show a clinically meaningful between-treatment difference may be included.
For benefit-risk analyses, between-treatment differences will be shown with absolute rate or other
difference measures and corresponding 95% CIs. Both continuous and dichotomized versions of
continuous endpoints will be shown. Results will be displayed in tabular and forest plot form.

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Additional details on the benefit-risk assessment will be provided in a separate benefit-risk
Statistical Analysis Plan.
11.12. Interim Analysis
Two interim analyses for PFS are planned for this study. The first interim analysis will be
performed when approximately 143 PFS events have occurred (corresponds to 50% of the total
planned PFS events). The second interim analysis for PFS will be performed when approximately
185 PFS events have occurred (corresponds to 65% of the total planned PFS events). The
significance level for superiority and futility (non-binding) at the interim analyses for PFS will be
determined based on the observed number of PFS events at each interim analysis, using the
Hwang-Shih-DeCani alpha/beta spending function with gamma parameter  -2.5. The 2-sided
alpha to be spent at the first interim, second interim and final PFS analyses are 0.0112, 0.0126,
and 0.0414, respectively.
Descriptive analysis of OS was performed at the time of the first PFS interim analysis. After the
superiority of PFS has been established at the first PFS analysis, 2 formal interim OS analyses will
be conducted. The first interim OS analysis will be performed when approximately 285 PFS events
(approximately 170 OS events; 55% of the total planned OS events) have occurred. The second
interim OS analysis will be performed when approximately 233 OS events have occurred (75% of
the total planned OS events). The final OS analysis will be at the end of the study or after
approximately 310 deaths have been observed. A Pocock alpha spending function will be used to
determine the OS stopping boundary at each interim analysis based on the observed number of
deaths at that time.
11.13. Independent Data Monitoring Committee
An IDMC, consisting of 2 clinicians and 1 statistician who are independent experts not otherwise
participating in the study, will be established to review safety results after approximately
100 subjects have completed the induction phase (ie, Cycle 1 through Cycle 4) plus stem cell
mobilization and again after approximately 100 subjects have completed the consolidation phase
(ie, Cycle 5 and Cycle 6). In addition, the IDMC will review cumulative safety data on a regular
basis before the primary PFS analysis. After each of these reviews, the IDMC will make
recommendations regarding the continuation of the study. The details will be provided in a separate
IDMC charter. At the first interim analysis of PFS, the primary endpoint was met, and the study
data were unblinded. No new safety signals were observed. No further IDMC meetings will be
scheduled after the primary endpoint was met. Safety data will continue to be reviewed by the
sponsor. The medical monitors will remain blinded regarding OS.

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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 AE is any untoward medical occurrence in a clinical study subject administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Conference on
Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All
Adverse Events, for time of last AE recording).
Serious Adverse Event
A SAE 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

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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 AE occurs for which there is evidence suggesting a causal relationship
between the study drug 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).
Adverse Event Associated With the Use of the Drug
An AE 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.
12.1.2. 
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Related
An adverse event that might be due to the use of the drug.
12.1.3. 
Severity Criteria
The severity assessment for an AE or SAE should be completed using the NCI-CTCAE Version
5. Any AE or SAE not listed in the NCI-CTCAE will be graded according to investigator clinical
judgment by using the standard grading as outlined in the CTCAE version 5.
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. No maximum tolerated dose has been reached for
daratumumab. However, if the dose exceeds the maximum tested dose of 2000 mg, then it
will be considered as an overdose in this study.
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 eCRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the serious adverse event page of the eCRF.

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12.3. Procedures
12.3.1. 
All Adverse Events
All AEs 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 final dose of study treatment with
the exception of the transplant period (see Section 9.1.3.5 for specific AEs to be reported). The
only exception is 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 final dose of any component of the treatment regimen. For subjects who
have received additional treatment with therapeutic intent for multiple myeloma during the AE
reporting period, only AEs that are considered to be related to the study drug or any part of the
backbone treatment regimen must be reported (unless the subject has been withdrawn from the
study).
SAEs, including those spontaneously reported to the investigator within 30 days after the last dose
of study drug, and those that are considered related to study drug within the 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.
Death should not be recorded as an AE or SAE, but as the outcome of an AE. The event that
resulted in the death should be reported as a SAE.
All events that meet the definition of a SAE will be reported as SAEs, regardless of whether they
are protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be
recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as “upper respiratory
infection”). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs 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:

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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
12.3.2. 
Serious Adverse Events
All SAEs 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 SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the eCRF, which must be completed and reviewed by a physician
from the study site and transmitted to the sponsor within 24 hours. The initial and follow-up reports
of a SAE should be transmitted electronically or by facsimile (fax).
All SAEs 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 SAE.
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 SAE, except hospitalizations
for the following:
If the subject has not experienced a significant medical event but is hospitalized overnight
only for observation following injection of study drug, then the hospitalization should not be
reported as a SAE.
Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending
placement in long-term care facility).
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be

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considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.
For convenience the investigator may choose to hospitalize the subject for the duration of the
treatment period.
Expected progression of disease should not be considered an AE (or SAE). However, if determined
by the investigator to be more likely related to the study treatment than the underlying disease, the
clinical signs or symptoms of progression and the possibility that the study treatment is enhancing
disease progression, should be reported per the usual reporting requirements (see Section 12).
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 SAEs and
must be reported using the Serious Adverse Event Form. Any subject who becomes pregnant or
experiences a positive pregnancy test during the study must discontinue lenalidomide study
treatment. Discontinuation of all study treatment is also acceptable if mandated by local
regulations. Because the effect of the study treatment on sperm is unknown, pregnancies in
partners of male subjects included in the study will be reported as noted above. Investigators should
follow the local label for guidance on subject education and ensure that all subjects adhere to the
lenalidomide Global Pregnancy Prevention Plan. 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 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.

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If the defect is combined with a SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE 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. Contact Information 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
120 mg/mL in a vial. It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator’s Brochure for a list of excipients.
14.2. Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 120 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
All study drug vials must be stored in the original carton in a refrigerator ranging from 2°C to 8°C
and must not be utilized after the expiry date printed on the label. The product must be protected
from light and must not be frozen. Daratumumab does not contain preservatives; therefore, any
unused portion remaining in the vial must be discarded.
Refer to the IPPI and Pharmacy Manual for details regarding dose preparation, storage, and handling
of diluted solutions.
14.5. Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The study drug administered to the subject must be
documented on the drug accountability form. All study drug will be stored and disposed of
according to the sponsor’s instructions. Study-site personnel must not combine contents of the
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and must
be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drug must be available for verification by the sponsor's
study-site monitor during on-site monitoring visits. The return to the sponsor of unused study drug

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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.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
Study Protocol
Investigator’s Brochure
Site Investigator Product Procedures Manual (sIPPM)
Investigational Product Preparation Instructions (IPPI)
Laboratory manual and laboratory kits
Electronic data capture (eDC) Manual
Sample ICF Trial Center File, and corresponding site-specific documentation
Subject study tools, emergency ID card etc, (as applicable per country)
Investigator study tools and quick reference cards, as required
NCI-CTCAE Version 5
PRO questionnaires and user manuals: PRO questionnaires will include the EORTC
QLQ-C30, EORTC QLQ-MY20, and the EQ-5D-5L. Sample questionnaires are provided in
Attachment 10, Attachment 11, and Attachment 12, but should not be used for collection of
subject data
IWRS Manual
16. 
ETHICAL ASPECTS
16.1. Study-specific Design Considerations
Despite significant progress in the treatment of patients with multiple myeloma, it still remains
uncured, indicating the need for new therapeutic strategies for these patients. Daratumumab has
already shown marked activity as a monotherapy in heavily pre-treated patients. Its approval by
the FDA in 2016, when used in combination with lenalidomide and dexamethasone, or bortezomib

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and dexamethasone, highlights the potential clinical benefit of daratumumab as a backbone therapy
for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.
Further, the approval by the FDA in 2018 of daratumumab in combination with bortezomib,
melphalan, and dexamethasone for the treatment of patients with newly diagnosed multiple
myeloma, highlights the potential benefit of daratumumab in combination with backbone therapy
for the treatment of newly diagnosed patients. The combination of daratumumab with bortezomib,
lenalidomide, and dexamethasone, is also likely to provide clinical benefits to patients with newly
diagnosed multiple myeloma.
Several other protein therapeutics are approved for SC administration in combination with
rHuPH20. Dara-SC is given as an injection over approximately 3 to 5 minutes as compared with
the 4 to 7-hour IV infusion time for Dara-IV. Further, Dara-SC is given in a volume of 15 mL vs
500-1000 mL infusion volume for Dara-IV. Study MMY1004 provided preliminary safety and
efficacy data which suggest that, in patients with multiple myeloma, SC administration of
daratumumab may enable similar or better response rates compared with Dara-IV. Furthermore,
to date, the rate of IRRs with Dara-SC administration has been substantially lower than the rate
reported with Dara-IV administration. Dara-SC, which will be used in Study MMY3014, will offer
several tangible benefits for both patients and health care providers, as described above.
An IDMC will be established to review safety data on a regular basis throughout the duration of
the study as well as at 2 planned PFS interim analyses. Based on the data presented in Section 1.2,
the addition of daratumumab to VRd is anticipated to provide benefit to subjects in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may
be withdrawn at any time with no reason given and without penalty or loss of benefits to which
they would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits,
and potential AEs of the study, and provide their consent voluntarily will be enrolled. Note that as
specified in Section 16.2.3, a legally acceptable representative may provide consent on behalf of
the subject.
Blood volumes drawn for all phases of the study are provided in Section 9.1.1. The total blood
volume to be collected is considered to be acceptable for subjects participating in a cancer clinical
study and reasonable over the time frame of the study.
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.
GCP 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

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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
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 AEs that are serious, unlisted/unexpected, and associated with the study drug

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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 that choosing
not to participate will not affect the care the subject will receive or 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

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treatments, if needed. The physician may also recontact the subject for the purpose of obtaining
consent to collect information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and
the opportunity to ask questions. After this explanation and before entry into the study, consent
should be appropriately recorded by means of either the subject’s or his or her legally acceptable
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject’s legally acceptable representative
is not available, enrollment procedures should be described in the protocol with documented
approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-being of the
subject and to ensure compliance with applicable regulatory requirements. The subject or legally
acceptable representative must be informed about the study as soon as possible and give consent
to continue.
16.2.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study. These data must be collected
and processed with adequate precautions to ensure confidentiality and compliance with applicable
data privacy protection laws and regulations. Appropriate technical and organizational measures
to protect the personal data against unauthorized disclosures or access, accidental or unlawful
destruction, or accidental loss or alteration must be put in place. Sponsor personnel whose
responsibilities require access to personal data agree to keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative)
includes information about, and where required per applicable regulations, 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, or make requests
concerning his or her personal data in accordance with applicable data protection law. 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.

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In the event ofa data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory PK 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 Samples in Future
Research).
16.2.6. 
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 16.1, Study-specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.

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During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate 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 eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
17.2. Regulatory Documentation
17.2.1. 
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
17.2.2. 
Required 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:

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Completed investigator financial disclosure forms from all subinvestigators
Documentation of subinvestigator qualifications (eg, curriculum vitae)
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and age at initial informed consent. In cases where the subject is not enrolled into the study, the
date seen and age at initial informed consent 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 AEs and follow-up of AEs; 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). The minimum source documentation requirements for Section 4.1,
Inclusion Criteria and Section 4.2, Exclusion Criteria that specify a need for documented medical
history are as follows:
Referral letter from treating physician or
Complete history of medical notes at the site
Discharge summaries

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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.
An electronic source system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. This data are electronically
extracted for use by the sponsor. If the electronic source system is utilized, references made to the
eCRF in the protocol include the electronic source system but information collected through the
electronic source system may not be limited to that found in the eCRF. Data in this system may be
considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF 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 eCRF are accurate and
correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, 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 eCRF. Any
such worksheets will become part of the subject’s source documents. Data must be entered into
the eCRF in English. The eCRF 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 an eCRF are needed after
the initial entry into the eCRF, this can be done in 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, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory 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 eCRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review the eCRF 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 eCRF
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. For trials performed under Regulation [EU] No. 536/2014, the sponsor
and the investigator shall archive the content of the clinical trial master file for at least 25 years
after the end of the clinical trial.
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 use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study. 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 eCRF 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 eCRF are known to the sponsor and study-site personnel and are accessible for verification by

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the sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose ofverifying
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. Central monitoring will take place for data identified by the sponsor as requiring
central review.
17.9. Study Completion/Termination
17.9.1. 
Study Completion/End of Study
The study is considered completed when 310 deaths have been observed or when the sponsor
decides to stop the study (whichever occurs earlier). The sponsor will ensure that subjects
benefiting from treatment with daratumumab will be able to continue receiving treatment after the
end of the study. The final data from the study site will be sent to the sponsor (or designee) after
completion of the final subject assessment at that study site, in the time frame specified in the
Clinical Trial Agreement.
17.9.2. 
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor’s procedures, or GCP guidelines
Inadequate recruitment of subjects by the investigator
Discontinuation of further study drug development

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17.10. On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Subject privacy must, however, be respected.
The investigator and study-site personnel are responsible for being present and available for
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor’s
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including biomarker research data, generated as a result of this
study, are considered confidential and remain the sole property of the sponsor. The study site and
investigator agree 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 study site and investigator understand 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 for the study. Results of 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

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site-specific data after the primary data are published. If an investigator wishes to publish
information from the study, a copy of the manuscript must be provided to the sponsor for review
at least 60 days before submission for publication or presentation. Expedited reviews will be
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the International Committee
of Medical Journal Editors (ICMJE) Recommendations for the Conduct, Reporting, Editing and
Publication of Scholarly Work in Medical Journals, which state that the named authors must have
made a significant contribution to the conception or design of the work; or the acquisition, analysis,
or interpretation of the data for the work; and drafted the work or revised it critically for important
intellectual content; and given final approval of the version to be published; and agreed to be
accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity
of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law.
The summary of the results from the PFS interim analysis 1, as described in Section 11.12, may
be submitted to the EU database within 1 year of the intermediate data analysis date.
The summary of the results from the OS interim analyses 1 and 2, as described in Section 11.12,
may be submitted to the EU database within 1 year of the intermediate data analysis date.
The disclosure of the study results will be performed after the end of study per local regulatory
requirements.

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18. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
18.1. Appendix 1: Protocol Amendment History
Amendment 4 (27 June 2022)
The overall reason for the amendment: The key reasons for this protocol amendment are to align study visits with
disease evaluation visits for both study arms, to include protocol text with respect to COVID-19 vaccines and guidance
during the COVID-19 pandemic or another natural disaster, to update protocol text to align with EU CTR requirements
including merging country-specific amendments into this Protocol Amendment 4, and to allow next-generation flow
(NGF) in the Maintenance phase for determination of minimal residual disease (MRD) status to guide
stopping/restarting of daratumumab. Other changes include minor corrections, additional clarifications, and
consistency updates.
Applicable Section(s) 
Description of Change(s)
Rationale: To align study and disease evaluations visits and for clarification purposes.
Table 1 (Time and Events 
Schedule) 
Added italicized text; removed strikethrough text for footnote “a”:
For subjects who discontinue treatment prior to C7D1 without confirmed PD,
Disease Evaluations should be performed every 4 weeks (±7 days)
relative to C1D1 until confirmed PD.
and ECOG PS (including PRO and Medical Resource Utilization)
should be performed every 12 weeks (±14 days) relative to C1D1 until
confirmed PD;
For subjects who discontinue treatment after C7D1 without confirmed PD,
Disease Evaluations should be performed every 4 weeks (±7 days) for
first year relative to C7D1 then every 8 weeks (±7 14 days) until
confirmed PD.
and ECOG PS (including PRO and Medical Resource Utilization)
should be performed every 12 weeks (±14 days) for first year relative
to C7D1, then every 16 weeks (±14 days) relative to C7D1 thereafter,
until confirmed PD.
Footnote “i” (new) added to Vital Signs, Weight, Hematology, Serum
Chemistry, and Medical Resource Utilization: After 24 months of maintenance
therapy, vital signs, weight, hematology, serum chemistry, and medical
resource utilization may be performed every 8 weeks for subjects who are not
receiving daratumumab.
Rationale: To incorporate the previously issued COVID-19 appendix. Text within the COVID-19 appendix and
within the body of the protocol was updated to mitigate the impact of the COVID-19 pandemic and natural disasters
on study conduct/procedures and to provide guidance on COVID-19 vaccinations.
8.2.Permitted Therapies 
Text updated to include COVID-19 vaccines permitted for study use. Updated
text clarifies live, attenuated vaccines or those with suspected replication
capabilities are not permitted. Also added text to clarify that COVID-19
vaccinations should not be administered on the same day as study treatment
administration.
8.3.Prohibited Therapies 
Italicized text added; strikethrough text removed:  Administration of
investigational, live attenuated, or replication competent viral vector vaccines
<4 weeks prior to the start ofduring study treatment, during study treatment,
or initiated within <90 days after last dose of study treatment are prohibited.
Attachment 13: COVID-19 and 
Natural Disaster Guidance on 
Study Conduct and COVID-19 
Vaccine Timing 
Attachment 13 (new) –incorporated the previously issued COVID-19
appendix and added guidance on study conduct during the COVID-19
pandemic or another natural disaster. This new attachment also includes
guidance on COVID-19 testing, COVID-19 vaccine timing, COVID-19
prevention and treatment, and COVID-19 resources.

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References 
Added Ariza-Heredia literature reference.
Rationale: To align with EU CTR requirements.
Synopsis; 1.5.Benefit-risk 
Assessment (new)
Added text for benefit/risk
16.2.4.Privacy of Personal Data 
Updated text to align with latest departmental template.
Rationale: Merge country-specific changes into global amendment; health authority request.
4.2.Exclusion Criteria 
Added text clarifying that HIV antibody testing at screening should be
performed per local health guidelines.
10.2.Discontinuation of Study 
Treatment/ Withdrawal From the 
Study; 12.3.3.Pregnancy
Added text clarifying that discontinuation of all study treatment in case of
pregnancy is acceptable if mandated by local regulations.
Rationale: To allow NGF for determination of MRD status in subjects who cannot use NGS
6.1.2.Daratumumab 
Administration  
Moved text related to definition of MRD-negative subjects. Also removed
reference to NGS for MRD-negativity threshold.
Added italicized text: For subjects in Arm B whose MRD negativity at 10-5
threshold cannot be determined by NGS (due to lack of MRD index clone or
non unique clone sequence), MRD by next generation flow (NGF) may be
used to guide daratumumab stopping and restarting in agreement with the
sponsor.
9.5.Biomarkers/EMN Correlatives Added italicized text; removed strikethrough text:
If baseline clonality is still not established or for subjects with non unique
clone sequence, no further bone marrow samples should be collected for
MRD assessments for patients subjects in the VRd arm, however subjects in
the D VRd arm without baseline clonality or with non unique clone sequence
may have MRD assessment by NGF for the purpose of determining
daratumumab continuation.
Rationale: To provide additional clarification and/or improve readability and/or align with protocol text.
Synopsis; 3.1.Overview of Study 
Design  
Added/modified text to clarify that subjects with a response of CR or better
(in Arm B) will stop daratumumab after sustained MRD negativity for 12
months and a minimum of 24 months of maintenance therapy.
3.1.Overview of Study Design  
Added text regarding evidence of IMWG-defined disease progression
3.1.Overview of Study Design  
Added PRO assessments to list of data collected/recorded.
3.2.Study Design Rationale 
Added italicized text; removed strikethrough text:
Daratumumab is planned to be discontinued during the maintenance phase in
subjects who achieve sustained MRD negativity (10-5) for at least 1 year 12
months and after receiving at least 2 years 24 months of maintenance
treatment.
Updated text with respect to recurrence of MRD and restarting daratumumab.
Figure 1 (Schematic Overview of 
the Study) 
Added text regarding monitoring for new malignancies, subsequent treatment
and PROs; spelled out 24 months (from 24 mos)

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6.1.2.Daratumumab
Administration
Added italicized text; removed strikethrough text:
All subjects who stop daratumumab due to sustained MRD-negativitye
subjects are defined as those who achieve CR or better and achieve MRD
negativity (based on the NGS 10 5). These subjects will be monitored for loss
of CR (Table 7) by urine and serum M protein by central laboratories or
development of ≥5% plasma cells in the bone marrow by local laboratories as
outlined in the Time and Events Schedule (Table 1) and IMWG criteria as well
as MRD status via bone marrow aspirate by central laboratories as per Table 1
and Table 8. Upon confirmed loss of CR or loss recurrence of MRD negative
status (at 10-4) or higher, subjects must restart daratumumab with the following
treatment regimen until disease progression or unacceptable toxicity.
Added text regarding stopping of lenalidomide due to toxicity, subjects will
stop daratumumab and continue study assessments per treatment phase
requirements.
Added italicized text:
As this is a restart of daratumumab, subjects will receive pre-administration
medications and post-administration medications as outlined in Section 6.1.3
to prevent the reoccurrence of infusion related reactions.
NOTE: Once treatment with lenalidomide is stopped due to toxicity, it cannot
be restarted.
Added bullets to text regarding re-initiation of daratumumab treatment.
8.3.Prohibited Therapies 
Added italicized text; removed strikethrough text:
Systemic corticosteroids (>10 mg prednisone dexamethasone per day or
equivalent or a total maximum dose of 140 mg dexamethasone or equivalent in
14 days) other than those given for IRRs as described in Section 6.2.2 is
prohibited  .
8.4.Subsequent Therapies 
Added text to clarify that local laboratory can be used for additional testing
following confirmation of disease progression.
9.1.5.Posttreatment Phase 
(Follow-up) 
Added italicized text; removed strikethrough text:
For subjects who discontinue study treatment without disease progression prior
to transplant, disease evaluations at the central lab should continue to be
performed as specified in the Time and Events Schedule (Table 1) until
documented disease progression, even if subject initiates subsequent anti
cancer therapy. Subsequent antimyeloma therapy must not start until after
disease progression is confirmed per IMWG criteria (see Table 6) and
approved in the IWRS system (see Table 6) and approved in the IWRS system.
Subsequent anticancer treatment and the associated response to treatment by
local laboratories, including date of subsequent progression (PFS2) will be
recorded and survival status will be obtained.
Added text indicating survival status will be obtained every 16 weeks.
Added note indicating subjects who stop daratumumab due to sustained MRD-
negativity should continue study assessments/stay on study (Arm B).

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Added italicized text; removed strikethrough text:
For all subjects who complete or discontinue study drug without disease
progression, disease evaluations by central laboratory should continue to be
performed as specified in the Time and Events Schedule (Table 1) until
documented disease progression.
9.2.2.Myeloma Protein 
Measurements in Serum and 
Urine
Added clarification that daratumumab interference on serum IFE is applicable
to subjects in Arm B.
Rationale: To align protocol text with recent label updates.
4.3.Prohibitions and Restrictions 
Added italicized text; removed strikethrough text:
Subjects must not donate blood during therapy and for at least 4 weeks 3
months following discontinuation of lenalidomide all study treatment.
Rationale: To consolidate bone marrow assessments and assessments to confirm sCR; clarification.
Table 1 (Time and Events 
Schedule) 
Added italicized text: Bone marrow samples will be collected in subjects with
VGPR or better at the time of suspected CR/sCR to confirm CR/sCR. See
Table 8 for details.
Rationale: To provide additional clarification with respect to the collection of bone marrow samples.
Table 1 (Time and Events 
Schedule) 
Added text to footnote “g” to clarify that when baseline clonality is not
established, no further bone marrow is to be collected for Arm A. Also, added
text to clarify that when there is no baseline clonality or there is a non-unique
clone sequence, subjects in Arm B can continue to have bone marrow
collected for MRD for the determination of daratumumab continuation.
Rationale: To correct protocol text.
Table 1 (Time and Events 
Schedule); 3.1.Overview of Study
Design; 10.2.Discontinuation of
Study Treatment/ Withdrawal
From the Study
Changed “second primary malignancy” to “new malignancy”
Table 6 (IMWG Consensus 
Recommendations for Multiple 
Myeloma Treatment Response
Criteria)
Removed text regarding bone marrow plasma cell percentage under
Progressive Disease Response category
1.1.3.VRd as Backbone Therapy 
Throughout Treatment;
References
Literature reference updated: Rosinol 2017 updated to Rosinol 2019.
Rationale: General updates.
Title page 
Updated confidentiality statement.
All pages 
Added FOIA Exemption footer.
Rationale: Minor grammatical, formatting, or spelling changes were made.

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Throughout the protocol 
Synopsis –added italicized text:
After stopping daratumumab therapy, subjects with sustained MRD negativity
should restart therapy with daratumumab if there is a recurrence of MRD at
10-4 or higher or a confirmed loss of CR without disease progression, as
evidenced by the reappearance of serum or urine monoclonal protein
(M-protein) or increase to ≥5% plasma cells in bone marrow.
Table 1 –added italicized text; removed strikethrough text:
Every 4 months (EQ-5D-5L only), at sStart of subsequent therapy and 4 weeks
after start of subsequent therapy
Synopsis (abbreviations updated)

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Amendment 3 (20 March 2020)
The overall reason for the amendment: to remove language related to anticipated adverse events and align text
with the daratumumab program standard language.
Applicable Section(s) 
Description of Change(s)
Rationale: To provide clarity on sampling requirements for MRD evaluations.
Table 1 
Separate line items were created/text was updated to distinguish unique MRD
sampling requirements for whole blood and bone marrow aspirates.
Rationale: Language related to anticipated adverse events is being removed from the protocol since this refers to a
Janssen procedure which is not being utilized in this study. EMN, as the sponsor of the study, has been and will
continue to determine the regulatory reporting of SAEs per health authority regulatory guidance as per their
standard process.
12.1.1.Adverse Event 
Definitions and
Classifications; 12.3.1.All
Adverse Events;
Attachment 13
(Anticipated Events)
Removed text and attachment related to anticipated adverse events.
Rationale: To eliminate the possibility of inconsistency between the NCI-CTCAE version number referenced in the
protocol and the standard AE grade description included in the protocol.
12.1.3.Severity Criteria 
Removed definitions of severity criteria as they are specific in NCI-CTCAE v5.
Rationale: To ensure extramedullary plasmacytoma assessment occurs per protocol. Text was also modified for
additional clarity.
Table 1 
Additional clarification was added for extramedullary plasmacytoma assessment
requirements when performed by physical exam or by radiologic exam.
9.2.8.Documentation of 
Extramedullary 
Plasmacytomas 
Text was added to further clarify that extramedullary plasmacytoma assessments are
required every 12 weeks starting from Cycle 1 Day 1 until disappearance of the
plasmacytoma or confirmed disease progression. Also, text was modified to better
clarify sampling requirements following the disappearance of plasmacytoma.
Rationale: To allow for archival samples to be submitted for subjects whose baseline clone was not established and
when calibration continues to fail, no further bone marrow samples should be collected for MRD assessments.
9.2.5.Bone Marrow 
Examination; 
9.5.Biomarkers/EMN 
Correlatives; Table 1 
Text was added to specify that archived samples will not be accepted for MRD or
cytogenetic evaluation at screening and may be requested to be sent to the central
laboratory, if available, in cases in which there is difficulty establishing baseline
clonality for MRD. If baseline clonality is still not established, no further bone marrow
samples should be collected for MRD assessments.
Rationale: Text was updated to align with the daratumumab program standard protocol text, where applicable.
6.1.2.Daratumumab 
Administration; 16.1.Study- 
specific Design 
Considerations
Bolded text was added: Daratumumab (1800 mg) will be administered by SC injection
by manual push over approximately 3 to 5 minutes in the abdominal SC tissues in
left/right locations, alternating between individual doses.
9.8.Safety Evaluations; 
10.2.Discontinuation of Study 
Treatment/ Withdrawal From
the Study; 12.3.3.Pregnancy
Modified text to align with daratumumab program standard protocol text related to
pregnancy.

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Applicable Section(s) 
Description of Change(s)
10.2.Discontinuation of Study 
Treatment/ Withdrawal From 
the Study  
Bolded text was added:
The subject experiences a second primary malignancy that cannot be treated by
surgery alone (however, a subject who develops a malignancy that can be cured
surgically may continue to receive the assigned study treatment and should continue to
be followed for subsequent progression of multiple myeloma). Subjects who require
radiation therapy for treatment of second primary malignancy must have study
treatment discontinued unless, upon consultation with the sponsor’s medical
monitor and review of data, continuation is agreed upon. Subjects who require
systemic treatment of a new malignancy must end study treatment but should
continue to be followed for PFS2 and OS.
Rationale: Text was modified throughout for alignment with other protocol sections and/or for improved
readability/clarity.
Synopsis 
Bolded text was added; strikethrough text was removed: Subjects will then start
maintenance therapy (Cycle 7+), during which they will receive lenalidomide 10 mg
daily PO on Days 1 to 28 (continuously) of each 28 day cycle until disease progression
or unacceptable toxicity.Dexamethasone will be administered PO at 40 mg on Days 1-
4 and 9-12 during Cycles 1-6 as part of the VRd backbone regimen.
Table 1; 9.1.3.7.Post- 
consolidation Efficacy 
Assessment
Clarification of subjects with a response of VGPR or better was added to Section
9.1.3.7.
Table 1 
Text was updated for whole blood MRD evaluations: bolded text was added;
strikethrough text was removed: For subjects who achieve CR/sCR and are still
remain on the study, additional samples will be collected every 3 months (±1 month
of another collection) from 12 months to 36 months post-C1D1 and then yearly
thereafter.
Also, bolded text was added; strikethrough text was removed: It is recommended
that PRO measures should beare completed before any other study procedures are
performed on the day of the visit. It is advised that PRO measures are completed
before any conversation on status with the health care provider.
Text was added advising sites to recalculate the bortezomib dose when a subject’s
weight has changed ±10% from baseline.
Footnote a was updated to include assessment windows and text was added which
clarifies follow-up requirements for subjects who decline any further follow-up except
survival status.
An assessment window was added to the ECOG performance status maintenance
phase Day 1.
Footnote e was modified to clarify sampling to occur prior to C7D1 study drug
administration.
Footnote g was added which provides clarification on the use of archived samples for
establishing baseline clonality for MRD.
Footnote h was added which provides clarification that all subjects will have EMN
correlative completed post-consolidation and at disease progression.
Table 2 
Text in footnote a –“study drug” was changed to “daratumumab”.
1.2.1.Intravenous 
Daratumumab Administration 
in Combination Therapy 
Studies
Non-applicable text was removed “results of this study are not yet available”. Also,
text was corrected to include bortezomib for summary of Study MMY3006. Also, the
abbreviation of “VTd” was correct to “D-VTd”.
2.1.2.Endpoints 
The definition of duration of response was updated to include text clarifying the
calculation should also include the timepoint until death due to PD.

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Applicable Section(s) 
Description of Change(s)
6.Dosage and Administration 
Text was added to clarify treatment cycles are 28 days. Also, dexamethasone was
added to the dosing window previously described for bortezomib only.
6.1.2.Daratumumab 
Administration  
Table cross-references were added.
Text was added to clarify that daratumumab doses will remain constant throughout the
study.
Also bolded text was added; strikethrough text was removed: These subjects will be
monitored for loss of CR (Table 7) by urine and serum or development of ≥5%
plasma cells in the bone marrow as outlined in the Time and Events Schedule (Table
1) and IMWG criteria as well as MRD status via bone marrow aspirate as per Table
1 and Table 8.
Bolded text was added: Subjects in Arm B who have a post-ASCT recovery period
that requires greater than 12 weeks off daratumumab and skip consolidation should
restart therapy on the following schedule: daratumumab dosing every 2 weeks for 4
doses (Cycles 7-8 of maintenance therapy) then continue every 4 weeks, thereafter (for
Cycles 9+).
Strikethrough text was removed since details are summarized in other sections in the
protocol: Every effort should be made to keep subjects on the planned dosing
schedule. However, doses given within 3 days of the scheduled Day 1 dose are
permitted. All treatment cycles are 28 days.
6.1.3.2.Daratumumab Post- 
administration Medication
The text “VRd” was added.
6.2.2.3.Recurrent Infusion- 
related Reactions 
Text was added to clarify that long daratumumab dose interruptions could result in
reoccurrence of infusion-related reactions.
6.3.2.Lenalidomide 
Administration  
Text was updated: bolded text was added; strikethrough text was removed:
Lenalidomide will be administered PO at 25 mg on Days 1 to 21 in Cycles 1-6; four
28-day induction cycles and two 28-day consolidation cycles. Following
consolidation, sSubjects will then start maintenance therapy, during which they will
receive lenalidomideat 10 mg daily PO on Days 1 to 28 (continuously) of each 28-day
cycle until disease progression or unacceptable toxicity.
6.3.3.Dexamethasone 
Administration
The text “as part of the VRd backbone regimen” was added.
6.4.1.Cycle Delay  
Strikethrough text was removed: During the cycle delay, daratumumab, bortezomib,
dexamethasone and lenalidomide, (all applicable) must be held.
6.4.2.1.2.Daratumumab- 
related Toxicity Management 
Text was updated to reflect daratumumab dose holds exceeding 28 days will require
consultation with the sponsor to determine continuation of dosing (changed from
requiring permanent discontinuation of daratumumab).
8.4.Subsequent Therapies 
Text was updated to include additional data collection requirements for subsequent
therapy for multiple myeloma treatment.

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Applicable Section(s) 
Description of Change(s)
9.1.3.2.Mobilization and 
Harvesting Stem Cells 
Bolded text was added: Stem cell mobilization should be performed within 6 weeks
after completion of Cycle 4 using local standard of care.
Also, additional guidance was added regarding plerixafor treatment for suspected
inadequate mobilization.
Also, bolded text was added; strikethrough text was removed: The use of a second
mobilization as per local standard of care or alternatively a bone marrow harvest is
permitted should occur to ensure adequate stem cell yield as per institutional
practice, if the stem cell yield is deemed to be sub-optimal per investigator discretion.
9.1.3.3.Conditioning 
(Melphalan off Study as per 
Standard of Care) 
Bolded text was added; strikethrough text was removed: Subjects should proceed to
conditioning within 2 weeks after stem cell mobilization. Subjects will receive
melphalan 200 mg/m2 as conditioning therapy over a period of 24 to 48 hours prior to
ASCT. Melphalan may be given at a lower dose of 140mg/m2, per institutional
standards, if the subject has (ie, renal insufficiency).
9.1.3.4.Transplant (as per 
Standard of Care) 
Bolded text was added; strikethrough text was removed: Autologous stem cell
transplant should be completed within approximately 6 weeks after stem cell
mobilization/harvest. There should be approximately no more than 12 weeks between
end of induction and transplant.
9.1.3.5.Engraftment/ 
Recovery  
Bolded text was added; strikethrough text was removed: Subjects will be monitored
for successful engraftment by means of hematopoietic reconstitution (ie,defined as
ANC ≥0.5 x 109/L and platelet count ≥20 x 109/L). Also, text was updated to include
additional data collection requirements and to updated text from “at the start of
consolidation” to “during this period”.
9.1.3.6.Consolidation (Cycles 
5-6) 
Bolded text was added; strikethrough text was removed: Consolidation therapy
mayshould commence within 12 weeks of transplant when engraftment is complete
(defined as ANC ≥0.5 x 109/L and platelet count ≥20 x 109/L) and when in the opinion
of the investigator the subject is fit enough to tolerate subsequent systemic therapy (30-
60 days post ASCT). In addition, subjects also need to and meets the consolidation
start criteria in Section 6.4.1. Subjects will receive two 28-day cycles of VRd as
described in Section 6.3. Subjects assigned to Arm B will receive daratumumab as
described in Section 6.1.2. For subjects who are unable to initiate consolidation therapy
due to delayedachieve immunehematopoietic reconstitution (ie, ANC ≥0.5 x 109/L and
platelet count ≥20 x 109/L) exceeding>12 weeks after ASCT, should discuss, subjects
may proceed to maintenance therapy upon discussion continuation to consolidation
versus maintenance therapy with the sponsor’s medical monitor. Efficacy will be
assessed at the start of each cycle.
9.1.5.Posttreatment Phase 
(Follow-up) 
Bolded text was added; strikethrough text was removed: After documented disease
progression, follow-up information will be obtained every 16 weeks (±14 days). The
every 16-week follow-up contacts should be scheduled from the date of confirmed
disease progression. Thereafter sSubsequent anticancer treatment and response to
treatment including date of subsequent progression (PFS2) will be recorded and survival
status will be obtained.
9.2.1.Response Categories 
Text was added which clarifies that subjects who meet criteria for discontinuation of
daratumumab  in Arm B will be followed for loss of CR; subjects who meet criteria for
loss of CR without disease progression will restart daratumumab as per protocol. Also,
text was added to specify that the criteria for loss of CR without disease progression
only applies to subjects in Arm B who meet the criteria as per protocol.

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Applicable Section(s) 
Description of Change(s)
Table 6 
Text was updated to remove MR response and footnote updated to align with IMWG
criteria used for this protocol. Also, normal ranges for FLC ratio were removed since
testing is performed by a central laboratory.
Table 7 
Table title was updated to specify applicability to Arm B. Also, bolded text was added:
Reappearance of serum M-protein by immunofixation or electrophoresis (any value
without confirmed PD); Reappearance of urine M-protein by immunofixation or
electrophoresis (any value without confirmed PD).
Table 8 
For clarity, text was restructured/text was bulleted/bolded and text for bone marrow
testing during treatment was updated to include applicability during follow-up. Also,
bolded text was added; strikethrough text was removed:
During post-consolidationb in subjects with VGPR or better.
Additional bone marrow aspirates will be collected at the time of suspect
CR/sCR and
For subjects who achieve CR/sCR, have not progressed, and remain on the
study, additional bone marrow aspirate will be obtained at 12, 18, 24, 30, and
36 months post Cycle 1 Day 1 (±1 month) and yearly thereafter (±1 month).c
A portion of the bone marrow may be used for additional biomarker
assessments EMN correlative studies: Bone marrow aspirates will be
collected: -If feasible, for all subjects during post-consolidation and at
disease progression.
Also, text was added to clarify that archived samples may be requested/used when the
MRD index clone is not identified at screening.
Footnote c was updated to clarify applicability for MRD sampling.
9.2.6.Minimal Residual 
Disease Assessment; 
11.6.Biomarker Analyses 
Text was updated to clarify both bone marrow and whole blood samples are collected
for MRD assessments.  Also, a note was added to Section 9.2.6 to clarify bone marrow
and whole blood sampling requirements for subjects who achieve CR/sCR.
9.7. Patient-reported 
Outcomes 
The following sentence was added: PRO measures should be completed before any
conversation on status with the health care provider.
9.8.Safety Evaluations 
Bolded text was added: For subjects who receive ASCT, record number of CD34+
cells collected and transplanted, agents used for mobilization, and hematopoietic
engraftment information.
10.2.Discontinuation of Study 
Treatment/ Withdrawal From 
the Study  
The following text was removed to align with other sections of the protocol: The
subject’s dose is held for more than 28 days, or if 3 consecutive planned doses of
daratumumab are missed for reasons other than toxicity unless, upon consultation with
the sponsor and the review of safety and efficacy, continuation is agreed upon.
12.3.1.All Adverse Events 
Bolded text was added; strikethrough text was removed: All AEs 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 final dose of study drug treatment with
the exception of the transplant period (see Section 9.1.3.5 for specific AEs to be
reported).
Rationale: Throughout the protocol, minor edits were applied.
Table 1 
Abbreviation added (BM=bone marrow) and bolded text was added to ECOG
performance status at maintenance phase (Day 1): C7D1 then every 12 weeks.

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Applicable Section(s) 
Description of Change(s)
5.Treatment Allocation and 
Blinding; 6.4.1.Cycle Delay;
6.4.2.Dose Modification
Guidelines;
9.1.3.6.Consolidation (Cycles
5-6)
For consistency, the word “sponsor’s” was added prior to “medical monitor”
6.1.3.1.Daratumumab Predose 
Medication;
6.1.3.2.Daratumumab Post-
administration Medication;
6.2.1.Daratumumab Local
Injection-Site Reactions;
6.2.2.Daratumumab Infusion-
related Reactions
Title headings were updated to include “Daratumumab”
6.3.2.Lenalidomide 
Administration
The text “should be” was changed to “is”.
6.4.1.Cycle Delay  
In 2 instances, “must” was changed to “should”. Also, a cross reference to Table 5 was
added.
6.4.2.1.1.Daratumumab Dose 
Modification  
Strikethrough text was removed: Individual dose modification of daratumumab is not
permitted, but dose delay is recommended as the primary method for managing
daratumumab-related toxicities.
9.5.Biomarkers/EMN 
Correlatives
FACs was updated to FACS
Attachment 6 
Strikethrough text was removed: 1Intermediate-Acting

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Amendment 2 (09 April 2019)
The overall reason for the amendment: The overall reason for the amendment is in response to identification of
a new important risk (hepatitis B virus [HBV] reactivation). Additionally, revisions and clarifications were made
to considerations for lenalidomide use, secondary endpoints, dosing, as well as other measurement parameters
throughout the Protocol. Revisions noted below are representative of the changes; new text is displayed in bold
font, and deleted text is noted with strikethrough.
Applicable Section(s) 
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the
potential for HBV reactivation was added or modified in response to identification of a new important risk (HBV
reactivation).
Table 1 Time and 
Events Schedule 
Added row for HBV serology, modified text for HBV DNA test, and identified the
timepoints at which HBV serology and HBV DNA test would be conducted.
4.2 Exclusion Criteria 
(Criterion 9) 
Clarified language to exclude subjects who are seropositive for hepatitis B and
hepatitis C.
8.1.7 Management of 
Hepatitis B Virus 
Reactivation
Added a new section providing information for the management of hepatitis B virus
(HBV) reactivation.
9.8 Safety Evaluations 
Added and revised information detailing the conduct ofhepatitis B virus serology and
DNA tests.
9.1.1 Overview  
Modified the total blood volume collected for the study to 95 mL.
References 
Removed reference: Drafting Committee for Hepatitis Management Guidelines and the
Japan Society of Hepatology (JSH). Guidelines for the Management of Hepatitis B
Virus Infection. Hepatol Res. 2014;44 Suppl S1:1-58.
Rationale: Modification was made to the Secondary Endpoints.
2.1.2 Endpoints 
Post-consolidation secondary endpoints were removed to eliminate duplication with
previous endpoint: Post consolidation ORR, rate of VGPR or better rate of CR or
better, and rate of sCR, defined as the proportions of subjects who achieved PR or
better (or VGPR or better, or CR or better, or sCR) by the end of consolidation per the
IMWG criteria.
Rationale: Clarification was provided regarding contraception and the prohibition of treatment with lenalidomide
during known pregnancy or potential for pregnancy.
Table 1 Time and 
Events Schedule 
Table 1 (Urine or serum pregnancy test) was updated to include pregnancy testing at
the End-of-Treatment Visit, for consistency with Section 4.3.
4.1 Inclusion Criteria 
(Criterion 7)
The text of the Criterion was modified for clarity and readability.

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Applicable Section(s) 
Description of Change(s)
4.3 Prohibitions and 
Restrictions 
Modification to Restriction 1: Contraception must begin 4 weeks before initiating
treatment in the study with daratumumab, and continue during the Treatment Phase,
during dose interruptions and continuing for 4 weeks after the last dose of
lenalidomide and 3 months following of the last dose of daratumumab.
Modification to Restriction 3: All Investigators will comply with the respective
Celgene country-specific Revlimid Risk Minimization Program (ie, pregnancy
prevention program) as implemented in the post-marketing setting. All subjects
must adhere to the local lenalidomide Risk Evaluation and Mitigation Strategy
(REMS) program (when lenalidomide is supplied locally), or the lenalidomide Global
Pregnancy Prevention Plan (when lenalidomide is supplied centrally and no local
lenalidomide REMS program exists).
Modification to Restriction 4: Additional pregnancy tests may be required, as specified
in the Celgene country-specific Revlimid Risk Minimization Program (ie,
pregnancy prevention program). local lenalidomide REMS (where lenalidomide is
supplied locally) or the Lenalidomide Global Pregnancy Prevention Plan (where
lenalidomide is supplied centrally and no local lenalidomide REMS program exists).
9.8 Safety Evaluations 
Modified language for Serum Pregnancy Test: If pregnancy does occur, then
lenalidomide study treatment should must be discontinued immediately
12.3.3 Pregnancy  
Modified sentence for clarity: Any subject who becomes pregnant during the study
must be promptly withdrawn from the study and discontinue further discontinue
lenalidomide study treatment.
Rationale: Modifications, clarifications, and corrections were made to screening, laboratory, and disease
assessments.
Table 1 Time and 
Events Schedule 
Revised timing for ECOG performance status (Maintenance): C7D1 then every 12
weeks Q4W for the first year of maintenance and Q8W thereafter until PD
Table 1 Time and 
Events Schedule; 9.8 
Safety Evaluations
Revised notes for Spirometry test: Required for all subjects >65 years old; if < 65
years old, only required if Subjects with known or suspected to have COPD only.
Revised instructions for Pulmonary Function Test: All subjects with known or
suspected COPD or asthma must have a FEV1 test during Screening. Additionally, all
subjects ≥65 years old must have FEV1 and DLCO assessment at Screening for
confirmation of eligibility.
Synopsis; Table 1 
Time and Events 
Schedule; 9.1.2
Screening Phase; 9.8 
Safety Evaluations 
Added assessment and associated notes: Echocardiogram (ECHO)/Multigated
Acquisition (MUGA) Scan (only required for subjects >65 years old).
Added to Safety Evaluations: Echocardiogram (ECHO)/ Multigated Acquisition
(MUGA) scan: All subjects ≥65 years old will have an ECHO or MUGA scan
performed to assess left ventricular ejection fraction (LVEF) for confirmation of
eligibility in Screening.
Table 1 Time and 
Events Schedule; 9.1.2 
Screening Phase
Added assessment and associated notes: Diffusing Capacity of the Lung for Carbon
Monoxide (DLCO) (only required for subjects >65 years old).
Table 1 Time and 
Events Schedule
Revised timing for EMN Correlatives (Post PD) to indicate At PD.

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Applicable Section(s) 
Description of Change(s)
Table 1 Time and 
Events Schedule 
Added note to Disease Evaluations heading: Every effort should be made to conduct
disease evaluations as per schedule (window +7 days).
Revised notes for SPEP and SIFE, UPEP and UIFE to indicate repeat measurement on
C1D1 only if screening is done >14 days prior to C1D1.
For Assessment of lytic lesion and Extramedullary plasmacytoma, added clarifications
to indicate specific tests to be performed, and cross-references to applicable sections.
Revised timing of Patient reported outcome assessments (Maintenance treatment):
C7D1 then every third cycle 12 weeks until PD
Text was modified to replace the terms Q4W and Q8W with every 4 weeks and every
8 weeks, respectively.
The text of footnote a of Table 1 (for Follow-up Phase, Prior to PD) was revised for
clarity and timing.
9.1.5 Posttreatment 
Phase (Follow-up) 
Added clarification: For subjects who discontinue study treatment without disease
progression prior to transplant, disease evaluations at the central lab should
continue to be performed as specified in the Time and Events Schedule (Table 1)
until documented disease progression, even if subject initiates subsequent anti-
cancer therapy.
Rationale: Clarifications were made to dosing of the components of study treatment.
Table 1 Time and 
Events Schedule 
Clarification was added for dexamethasone administration: Administer 1-3 hours
before the daratumumab administration. Dexamethasone 20 mg IV or PO prior
to the first 2 doses and 10 mg for all subsequent doses (must have absence of IRR
adverse events for 2 doses prior to decreasing dose).
On daratumumab administration days, backbone therapy substitutes for the pre-
medication dexamethasone.  Accordingly, 40 mg dexamethasone will be
administered PO or IV prior to daratumumab in Cycles 1-6. On daratumumab
dosing days in C1 C6, dexamethasone should only be given once as pre administration
medication 1 3 hours before the daratumumab SC administration.
6.1.3.1 Predose 
Medication  
Clarification was added for dexamethasone administration: Backbone therapy
substitutes for the pre-medication dexamethasone. Accordingly, 40 mg
dexamethasone will be administered PO or IV prior to daratumumab in Cycles 1-
6.
6.3.3 Dexamethasone 
Administration  
Text was revised for clarity: On daratumumab administration days, during
induction/consolidation, dexamethasone may dexamethasone backbone therapy
substitutes for the pre-medication dexamethasone. Accordingly, 40 mg
dexamethasone will be administered PO or IV intravenously 1-3 hours before the
daratumumab administration.
6.4 Dose Delays and 
Dose Modifications 
Added instructions that subjects who discontinue a component of study treatment may
continue to receive the other components according to individual drug SmPC
recommendations.
6.4.2.2.1 Dose 
Adjustments of 
Lenalidomide; Table 5 
Instructions for dose adjustments of lenalidomide were revised to align with dose
reduction steps outlined in the lenalidomide SmPC (Nov 2018) for lenalidomide
maintenance in subjects who have undergone ASCT.

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Applicable Section(s) 
Description of Change(s)
Rationale: Clarification was made to prohibited therapies.
8.3 Prohibited 
Therapies 
Instructions were clarified: The sponsor must be notified in advance (or as soon as
possible thereafter) of any instances in which prohibited therapies are administered.
Investigators should refer to the local bortezomib, lenalidomide and
dexamethasone updated summary of product characteristics (SmPC) for drugs
prohibited or to be used with precautions. Use of the treatments listed below is
prohibited during the study
Clarification for live attenuated vaccines was added: Administration of live
attenuated vaccine during study treatment or within 90 days after last dose of
study treatment.
Rationale: Clarifications were made to instructions for transplant therapy.
9.1.3.2 Mobilization 
and Harvesting Stem 
Cells
Text was modified to clarify timing and methods for stem cell mobilization according
to standard of care.
9.1.3.4 Transplant (as 
per Standard of Care) 
Text was added for clarity: Autologous stem cell transplant should be completed
within approximately 6 weeks after stem cell mobilization/harvest. There should
be approximately 12 weeks between end of induction and transplant.
9.1.3.5 Engraftment/ 
Recovery  
Text was modified for clarity: Only the following AEs and only concomitant
medications associated with these AEs have to be recorded in the eCRF at the start of
consolidation (Cycle 5 Day 1):
Rationale: Minor changes and clarifications were made throughout.
4.1 Inclusion Criteria 
Criterion 12 was modified: Signed an informed consent form (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.
Subjects in emergency situations that do not allow for collection of informed
consent are excluded.
4.2 Exclusion Criteria 
Criterion 4 was modified for clarity: Radiation therapy for treatment of
plasmacytoma within 14 days of randomization (palliative radiation for pain
control secondary to lytic lesion is allowed within 14 days of randomization).
Criterion 7 was re-worded for clarity.
Criterion 11b was modified for clarity: uncontrolled cardiac arrhythmia or clinically
significant electrocardiogram (ECG) abnormalities
Criterion 11c was modified for consistency: screening 12-lead ECG showing a
baseline QT interval >470 msec (exception: subjects with pacemaker)
Criterion 11d was re-worded for clarity.
Criterion 13 was updated to include lenalidomide or its excipients.
Criterion 14 was modified to encompass additional situations: Subject is taking any
prohibited medications as per Section 8.3. Subject is deprived of their freedom by
a judicial or administrative decision, or subject is in psychiatric care. Subject is
subjected to a legal protection measure or unable to provide their consent.
Criterion 17 was modified to provide further clarity regarding the time since the use of
a prior investigational drug or invasive investigational medical device.

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Applicable Section(s) 
Description of Change(s)
6 Dosage and 
Administration  
Text was re-worded for clarity: In Cycles 1 and 2 with weekly daratumumab and
Cycles 3-6 with bi-weekly daratumumab, administrations may be given within ±1
day of the scheduled day to accommodate the schedule of the site or subject.
6.1.2 Daratumumab
Administration
Correction was made to MRD-negative status (revised to 10-4) 
6.2 Management of 
Injection-site and 
Infusion-related
Reactions
Modified section title and sub-section titles to indicate Injection Infusion-related
Reactions.
9.1.2 Screening Phase 
Modified text for consistency with Table 1: Screening procedures will be performed
within 28 days before randomization Cycle 1 Day 1;
9.1.3.6 Consolidation 
(Cycles 5-6) 
Correction made: For subjects who are unable to tolerate initiate consolidation therapy
due to delayed immune reconstitution
9.8 Safety Evaluations 
Added “ECHO or MUGA (only required for subjects ≥65 years old)”
Added “SC injection-site evaluations” for consistency
Modified elements in the Serum Chemistry Panel from “urea” to “BUN or urea”,
added clarification to measurement of bilirubin, and indicated the timing to be during
Screening and induction and consolidation.
Table 1 Time and 
Events Schedule; 9.2.2
Myeloma Protein
Measurements in
Serum and Urine
Added measurement of IgD.
9.5 Biomarkers/ EMN 
Correlatives
Section name updated to Biomarkers/EMN Correlatives.
Attachment 13 
Anticipated Events 
Reporting of Anticipated Events was revised with specific instructions on reporting to
US FDA.
Abbreviations 
Added and corrected abbreviated terms.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.

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Amendment 1 (04 Sept 2018)
The overall reason for the amendment: To add language describing hepatitis testing, which is now required
across daratumumab studies for subjects who are positive for anti-HBc or anti-HBs.
Applicable Section(s) 
Description of Change(s)
Rationale: Language regarding hepatitis testing for subjects who are positive for anti-HBc or anti-HBs has been
added.
Table 1: Time and Events 
Schedule; 
9.8 Safety Evaluations 
Requirements for HBV DNA monitoring at various timepoints during the study
have been added to the Time and Events Schedule.
Clarification has been made to the requirements for HBV DNA testing.
Rationale: Clarification to vital sign collection for subjects in Arm A versus Arm B has been made.
Table 1: Time and Events 
Schedule; 
9.8 Safety Evaluations 
Text added to specify that for Arm A, vital signs are required only on Day 1 of
every cycle.
Details on the requirements for the collection of vital signs have been added.
Rationale: Changes and clarifications were made to the timepoints for collection of pharmacokinetic and
immunogenicity samples.
Table 2: Pharmacokinetic 
and Immunogenicity 
Evaluations (Arm B Only) 
Posttreatment Week 4 collections have been deleted.  Clarification has been
made to specify that daratumumab and rHuPH20 immunogenicity are required
only at Cycle 7 Day 1 for subjects not receiving consolidation treatment (ie,
Cycles 5-6) after transplant.
Rationale: To update biomarker assessments to require a mandatory fresh bone marrow aspirate for cytogenetics
and to remove the option for archived sample for MRD at screening. Also, the description of the SEBIA
Hydrashift Interference Test has been added to the protocol.
Table 1: Time and Events 
Schedule 
Revised the line entry title for “Biomarkers” to “EMN Correlatives” and updated
timepoints for collection. Updated the MRD Evaluation row for clarity.
9.1.1 Overview  
To coincide with the revisions made to the biomarker assessments and provide
more granularity in the breakdown of the blood volumes for this study, the
estimated total blood volumes have been updated.
9.2.1 Response Categories; 
New Attachment 9: 
Interpretation of The SEBIA
Hydrashift 2/4 Daratumumab 
IFE Interference Test; 
9.2.2 Myeloma Protein
Measurements in Serum and
Urine
Added text to indicate that for subjects with suspected daratumumab interference
on SPEP and immunofixation, a reflex assay will be performed.
Included a description of the new SEBIA Hydrashift 2/4 Daratumumab IFE
Interference test that will be used to distinguish a positive SPEP/IFE.
9.2.5 Bone Marrow 
Examination; 
9.5 Biomarkers;
11.6 Biomarker Analyses
Clarified the requirements for a fresh bone marrow aspirate at screening and the
MRD assessment for cytogenetics evaluations.
 
Table 8: Bone Marrow 
Testing 
Clarified the process for how the bone marrow aspirate will be portioned out for
assessment.

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Applicable Section(s) 
Description of Change(s)
Rationale: To align with the causality options presented on the revised SAE reporting form, the AE attribution
definitions have been revised.
12.1.2 Attribution 
Definitions 
Revised the AE attribution definitions to limit to:
Not Related: An adverse event that is not related to the use of the drug
Related: An adverse event that might be due to the use of the drug
12.3.1 All Adverse Events 
To align with the revision to the AE attribution definitions, revised text as
follows: “For subjects who have received additional treatment with therapeutic
intent for multiple myeloma during the AE reporting period, only AEs that are
considered to be possibly, probably, or definitely related to the study drug or any
part of the backbone treatment regimen must be reported (unless the subject has
been withdrawn from the study).”
Rationale: Miscellaneous edits/clarifications have been made to the protocol.
Title page 
EudraCT number has been added: 2018-002992-16.
Table 1: Time and Events 
Schedule 
Clarified that hematology collection is required on Day 8 and Day 22 during
Cycles 1 and 2 only.  Added timepoints for body weight measurements.
To align with the study treatment visits, clarified that MRU is to be assessed on
D22 of Cycle 1 and Cycle 2 only and that MRU is not to be assessed in Follow-
up Post-PD.
Table 5: Dose Modification 
Guidelines for Bortezomib, 
Lenalidomide, and 
Dexamethasone
Revised footnote f to specify that creatinine clearance is calculated by the
Cockcroft-Gault formula and adjusted for body weight in subjects with a body
mass index >30 kg/m
2
and that the eGFR (MDRD) or CKD-epi formulas can also
be utilized to assess renal function.
9.2.3 Albumin and Serum 
Calcium Corrected for 
Albumin  
Revised text to specify that blood samples for calculating serum calcium
corrected for albumin are to be analyzed by the central laboratory rather than by
local laboratories.
11.12 Interim Analysis 
Clarified the wording relating to the interim OS analyses.
Deleted Section 12.4 
Reporting, Monitoring, and 
Review of Safety Events for 
the Subjects Enrolled at Sites
in Japan;
Deleted (old) Attachment 12:
Reporting, Monitoring, and
Evaluating Safety Events for
the Subjects Enrolled at Sites
in Japan
The section and attachment that described the procedures specific to reporting
adverse events in Japan have been removed as now no sites in Japan are planned
to participate in the study.
New Attachment 2: Modified 
Diet in Renal Disease 
Formula;
References 
A new attachment with the MDRD formula has been added, and a cross-
reference to it has been added to Inclusion Criterion #6.
A new citation for Levey 2006 has been added.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.

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Attachment 1: ECOG Performance Status Score 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 1982

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Attachment 2: Modified Diet in Renal Disease Formula
For creatinine in mg/dL, the estimated glomerular filtration rate (eGFR) for the modified diet in renal
disease (MDRD) formula is:
eGFR (MDRD) mL/min per 1.73m2= 175 × [serum creatinine (mg/dL)]-1.154  × [age]-0.203 × [1.212 if
black] × [0.742 if female]
For creatinine in µmol/L, the estimated glomerular filtration rate (eGFR) for the MDRD formula is:
eGFR (MDRD) mL/min per 1.73m2= 175 x [serum creatinine (µmol/L)/88.4]-1.154× [age]-0.203 × [1.212
if black] × [0.742 if female]
Source: Levey 2006

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Attachment 3: Serum Calcium Corrected for Albumin
If calcium is expressed in mg/dL and albumin is expressed in g/dL:
Corrected calcium (mg/dL) =
           serum calcium (mg/dL) + 0.8•(4 - serum albumin [g/dL])
If calcium is expressed in mM/L and albumin is expressed in g/L:
Corrected calcium (mM/L) =
           serum calcium (mM/L) + 0.02•(40 - serum albumin [g/L])
Source: Burtis 1998

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Attachment 4: Asthma Guidelines
Components of
Severity
Classification ofAsthma 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 :
8-19yr 85%
20-39yr 80%
40-59yr 75%
60-80yr 70%
Symptoms
≤2 days/week  
≥2 days/week but not daily  
Daily  
Throughout the day
Nighttime
awakenings 
0
≤2x/month  
1 2x/ 
month  
3 4x/month  
3 4x/ 
month  
>1x/week but not 
nightly 
>1x/
month  
Often 7x/week
SABA use for
symptom control (not
prevention
of EIB)
≤2 days/week  
≤2 days/week but not daily 
>2 days/
week but
not daily, 
and
not more
than 1x
on
any day
Daily  
Several time per day
Interference with
normal activity
None 
Minor limitation  
Some limitation  
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1
between
exacerbations
>80%
>85%
Normal FEV1
between
exacerbations
>80%
Normal
N/A  
>80%
>80%
>80%
Normal
N/A
60-80%
75-80%
60-80%
Reduced
5%
N/A  
<60%
<75%
<60%
Reduced
5%
Risk
Exacerbations
requiring oral
systemic
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral
steroids or >4 wheezing
episodes/1 year lasting >1
day andrisk factors for
persistent asthma
≥2/year 
Relative 
annual risk 
may be 
relatedto 
FEV1. 
≥2/year
Relative
annual risk
may be
relatedto
FEV1.
≥2 exacerbations in 6
months requiring oral
steroids or >4 wheezing
episodes/1 year lasting >1
day andrisk factors for
persistent asthma
≥2/year
Relative
annual risk
may be
relatedto
FEV1.
≥2/year
Relative
annual risk
may be
relatedto
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
relatedto
FEV1.
≥2/year
Relative
annual
risk
may be
related
to FEV1.
Considerseverity andinterval since last exacerbation. Frequency andseverity may fluctuate over time for patients in any severity category.

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Recommended
Step for
Initiating Treatment
Step 1 
Step 2 
Step 3and consider 
short course of oral 
steroids 
Step 3: 
medium  
dose ICS  
and 
consider 
short 
course of 
oral
steroids
Step 3and 
consider 
short course 
of oral 
steroids
Step 3and consider 
short course of oral 
steroids 
Step 3: 
medium dose 
CS 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 observedin 4-6weeks, stop treatment andconsider alternate diagnosis or adjusting therapy. 5-11 and12+ years: adjust therapy accordingly.

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Components of
Control
Classification of Asthma Control
Well Controlled 
Not Well Controlled 
Very Poorly Controlled
0-4 yrs 
5-11 yrs 
12+ yrs 
0-4 yrs 
5-11 yrs 
12+ yrs 
0-4 yrs 
5-11 yrs 
12+ yrs
Symptoms 
≤2 days/week but not 
more than once on each  
day  
≤2 days/ 
week  
>2 days/week or
multiple times on 
≤2 days/week  
>2 days/ 
week
Throughout the day
Impairment
Nighttime
awakenings 
≤1x/month  
≤2x/month  >1x/month  ≥2x/month  1-3x/week  
>1x/week  
≥2x/week  ≥4x/week
Interference with
normal activity  
None  
Some limitation  
Extremely limited
SABA use for symptom
control (not prevention of
EIB) 
≤2 days/week  
>2 days/week  
Several times per day
Lung function  
FEV1 or peak flow  
FEV1/FVC  
N/A  
>80% 
>80% 
>80% 
N/A  
60-80% 
75-80% 
60-80% 
N/A
<60% 
<75%
<60%
Validated questionnaires 
ATAQ  
ACQ
ACT
0 
≤0.75 
≥20 
1-2 
≥1.5 
16-19 
3-4
N/A
≤15
Risk
Exacerbations requiring 
oral systemic
corticosteroids 
0-1/year 
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/
Progressive loss of lung 
function
Evaluation requires long-term follow-up
• Maintain current step  
• Regular follow-up every 1- 
6 months 
Step up 1 
step  
Step up at 
least 1 
step  
• Step up 
1 step  
• Reevaluate 
• Consider short 
course of oral 
steroids 
• Step up 1-2 steps 
• Consider
short course
of oral
steroids

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Components of
Control
Classification of Asthma Control
Well Controlled 
Not Well Controlled 
Very Poorly Controlled
0-4 yrs 
5-11 yrs 
12+ yrs 
0-4 yrs 
5-11 yrs 
12+ yrs 
0-4 yrs 
5-11 yrs 
12+ yrs
Recommended Action for
Treatment
• Consider step down if well 
controlledfor at least 3 
months 
• Before step up: 
Review adherence to 
medication, inhaler 
technique, and 
environmental control. 
If alternative treatment 
was used, discontinue 
it and use preferred 
treatment for that step. 
• Reevaluate the level 
of asthma control in 
2-6 weeks to 
achieve control. 
0-4 years: If no clear 
benefit is observed in  
4-6 weeks, consider 
alternative diagnoses or 
adjusting therapy. 
5-11 years: Adjust 
therapy accordingly. 
• For side effects, 
consider alternative 
treatment options. 
in 2-6 
weeks 
• For side 
effects, 
consider 
alternative 
treatment 
options 
• Before step up: 
Review adherence to 
medication, inhaler 
technique, and 
environmental control. 
If alternative treatment 
was used, discontinue 
it and use preferred 
treatment for that step. 
• Reevaluate the level 
of asthma control in
2-6 weeks to
achieve control.
0-4 years: If no clear
benefit is observed in
4-6 weeks, consider
alternative diagnoses or
adjusting therapy.
5-11 years: Adjust
therapy accordingly.
• For side effects,
consider alternative
treatment options.
• Step up 1-
2 steps
• Reevaluate
in 2 weeks
• For side
effects,
consider
alternative
treatment
options

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Attachment 5: Antihistamines That may be Used Predose
The following antihistamines may be used predose, before Dara-SC injection (including, but not limited
to):
Diphenhydramine
Cetirizine
Fexofenadine
Loratadine
Clemastine
Dexchlorpheniramine
Promethazine*
* The IV use of promethazine should be avoided.

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Attachment 6: Conversion Table for Glucocorticosteroid Dose
Glucocorticoid 
Approximate Equivalent 
Dose (mg)
Half-life (Biologic) hours
Intermediate-Acting
Methylprednisolone 
4 
18-36
Prednisolone 
5 
18-36
Prednisone 
5 
18-36
Triamcinolone 
4 
18-36
Long-Acting
Betamethasone 
0.6 –0.75 
36-54
Dexamethasone 
0.75 
36-54

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Attachment 7: Body Surface Area Calculation
BSA should be calculated using the Mosteller Formula (shown below); however, the DuBois Formula can
be used as an alternative.

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Attachment 8: Individual and Myeloma-related Risk Factors
Source: Palumbo 2008.

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Attachment 9: Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE Interference Test
Background: Clinical response assessment in myeloma relies on serum protein electrophoresis (SPEP)
and immunofixation electrophoresis (IFE). As daratumumab is a monoclonal IgG kappa antibody, the
SPEP and IFE can be positive for daratumumab at the serum levels anticipated during this protocol.
Implementation: To mitigate this interference, the sponsor will use the SEBIA Hydrashift 2/4
Daratumumab IFE Interference test to distinguish a positive SPEP/IFE due to the presence of
daratumumab versus the presence of the underlying (endogenous) monoclonal protein.  The SEBIA
Hydrashift 2/4 Daratumumab IFE Interference test will be sent automatically to the central laboratory if a
subject with IgG kappa multiple myeloma has an SPEP at or below 0.2 g/dL on 2 or more consecutive
cycles. In addition, the SEBIA Hydrashift 2/4 Daratumumab IFE Interference test will be sent
automatically to the central laboratory if a subject has an SPEP of zero, but persistently positive IFE for
IgG kappa on 2 or more occasions.
Interpretation of results:
The results will be available to the investigator via the central laboratory interface and will be reported as
follows:
DARAHydra Impress1: result defined as “DARA detected”, “DARA not detected”, OR “DARA
indeterminate”
DARAHydra Impress2: result defined as “M-protein not detected” OR the specific protein detected
(i.e. “IgG,k” or “IgA”)
DARAHydra Impress3: result defined as “M-protein not detected” OR the specific protein detected
(i.e. “IgG,k” or “IgA”)
If Impress1 result is “DARA detected” and Impress2 and 3 results are “M-protein not detected,”
the patient may be in CR if the other criteria for CR (including negative bone marrow
aspirate/biopsy) are achieved.
If Impress1 result is “DARA not detected” or “DARA indeterminate”, the patient is still positive
for underlying (endogenous) monoclonal protein and Impress2 and 3 can inform as to the type of
endogenous protein still present. Therefore, this patient is not in a CR, because the CR response
criteria requires a negative SPEP and serum IFE.
If Impress1 result is “DARA detected” but there is also protein present and reported by Impress2
or 3, the patient is still positive for underlying (endogenous) monoclonal protein and Impress2
and 3 can inform as to the type of endogenous protein still present. Therefore, this patient is not
in a CR, because the CR response criteria requires a negative SPEP and serum IFE.

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Attachment 10: 
EORTC QLQ-C30

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During the past week: 
Not at 
A           Quite 
Very
All 
Little 
a Bit 
Much
47. 
Have you felt physically less attractive as a result
of your disease or treatment? 
1 
2 
3 
4
48. 
Have you been thinking about your illness? 
1 
2 
3 
4
49. 
Have you been worried about dying? 
1 
2 
3 
4
50. 
Have you worried about your health in the future? 1 
2 
3 
4

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Attachment 13: 
COVID-19 and Natural Disaster Guidance on Study Conduct and COVID-19
Vaccine Timing
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic or another natural
disaster may have an  impact on the conduct of this clinical study due to, for example, self-
isolation/quarantine by subjects and study-site personnel, travel restrictions/limited access to
public places (including hospitals), and study-site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for
study-related subject management in the event of disruption to the conduct of the study. This
guidance does not supersede any local or government requirements or the clinical judgment of
the investigatorto protect the healthand well-being ofsubjects, his- orherself, and site staff. If, at
any time, the investigator assesses that the risk of treatment may outweigh the benefit, study
treatment will be interrupted, and study follow-up will be conducted.
Scheduledvisits thatcannotbeconductedinpersonatthestudysite willbe performedto the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments
shouldbeperformedifrequiredandas feasible. Subjects willalso bequestionedregarding general
health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for subjects on study,
including follow-up. Modifications to protocol-required assessments may be permitted after
consultation between the subject and the investigator, and with agreement of the sponsor. Missed
assessments/visitswillbecapturedintheclinicaltrialmanagementsystemforprotocoldeviations.
Discontinuations of study treatments and withdrawal from the study due to the coronavirus
pandemic shouldbe documentedwiththe prefix“COVID-19-related” inthe electronic case report
form (eCRF), or “natural disaster-related”, when applicable.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changeswillbecommunicatedto thesitesandto thehealthauthorities accordingto localguidance.
If a subject has tested positive for COVID-19, the investigator should contact the European
Myeloma Network (EMN) Medical Monitor to discuss plans for study treatment and follow-up.
Modifications made to the study conduct as a result of the coronavirus pandemic should be
summarized in the Clinical Study Report.
For COVID-19: Testing for COVID-19 should be performed according to local guidance. If a
subject has tested positive for COVID-19, the following should be reported in the eCRF:
all cases of COVID-19, regardless of severity or causality (including asymptomatic
COVID-19).
all medications given to prevent (including vaccines) or treatments COVID-19.

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GUIDANCE SPECIFIC TO THIS PROTOCOL:
These emergency provisions are meant to ensure subject safety on study while site capabilities are
compromised by COVID-19-related or other natural disaster-related restrictions. As restrictions
are lifted, sites should revert to study conduct as outlined in the current protocol as soon as feasible.
Subject Dosing Visits
Evaluate the feasibility for each subject to return for scheduled dosing visits based on the local
situation. For subjects who are unable to come to the site for scheduled visits and/or if site
capabilities are compromised by COVID-19-related or other natural disaster-related
restrictions, contact (eg, telephone, videoconference, or other channels) with the subject
should be made in advance, to collect information on the subject’s current health status and
any new or ongoing adverse events and concomitant medications. Normal study procedures
should be followed for the applicable visits as closely as possible even if lab assessments and
physical exams are performed locally. Where local laboratories are used, it is important to
ensure appropriate documentation of laboratory reference ranges. The remote contact with the
subject (as allowable per local regulations), should be documented in the subject source
record.
Continue with mobilization and ASCT after Cycle 4 as outlined in the protocol, iffeasible
based on local requirements. Consider mobilization of stem cells with granuloctye colony-
stimulating factor/Plerixafor without high-dose cyclophosphamide.
Should ASCT require postponement due to local requirements (ie, closure of hospital to
transplant procedures) due to the coronavirus pandemic, ensure to collect stem cells after
completion of Cycle 4 as per protocol. Then proceed with Cycles 5 and 6 first as extensional
induction treatment and perform the transplant procedure immediately following Cycle 6. The
pre-ASCT visit should occur within 2 weeks after completion of Cycle 6. Following recovery
from ASCT, proceed directly with maintenance therapy (ie, consolidation will be skipped as
the cycles of bortezomib, lenalidomide, and dexamethasone (VRd) or daratumumab in
combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) were given prior
to transplant and only 6 total cycles of VRd or D-VRd will be given to any subject in the
study). The post-consolidation bone marrow analysis for MRD should occur prior to initiation
of maintenance therapy.
Subjects who miss a scheduled dosing visit may be rescheduled to receive the missed dose at
the next appropriate opportunity. Evaluate the subject’s situation on a case-by-case basis and
contact the EMN Medical Monitor. Every effort should be made to keep subjects on treatment
if it is in their best interest and to maintain phone contact with subjects who are unable to
physically visit the hospital to monitor their safety and medication usage.
As subject safety and benefit is the priority, investigators may make the decision to provide
other available therapy to subjects on the study. This should be discussed with the EMN
Medical Monitor and recorded in source documents and the eCRF with the reason  for
administration.
The use of local laboratories for safety evaluations is permitted if access to the treating hospital
is limited. Allinformationshouldbe collectedregardingstandardvalues forthese laboratories.

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Subject Disease Evaluation Visits
Continue with central laboratory testing to the greatest extent possible. If central laboratory tests
cannot be performed, the use of a local laboratory will be allowed for efficacy evaluations during
the coronavirus pandemic. Central laboratory testing should be resumed as soon as conditions
permit.
Exposure to COVID-19
In the event a subject requires treatment for a coronavirus infection, refer to the protocol to
determine any requirements for dose hold, dose modifications, or other prohibitions and
considerations. Report the COVID-19 infection as an AE and any concomitant medications (CM)
used to treat it, to the sponsor following the usual CM and AE reporting requirements. Ensure any
AEs of COVID-19 include the term "COVID-19" and any serious adverse events (SAE) document
confirmed infection with coronavirus.
On-site Monitoring Visits
In the event on-site monitoring visits are not possible, as per institution policies, the sponsor’s site
managers may contact the investigator to arrange remote monitoring visits. Additional on-site
monitoring visits may be needed in the future to catch up on source data review and verification.
Study Drug Supply
Since daratumumab must be administered in the clinic and closely monitored by well-trained
health care providers, shipment of daratumumab to patients for at-home administration is not
permitted.
A direct-to-patient delivery of oral, self-administered medication will be allowed within
countries where this is appropriate (a list of countries will be provided). This decision was
made to allow study subjects access to oral trial treatments in the event they miss scheduled
dosing visits due to the pandemic. Therefore, if locally permitted, alternative solutions to
arrange direct-to-patient provision of oral lenalidomide or dexamethasone that are part of the
treatment regimen can be discussed with the EMN MedicalMonitor.
A caregiver or family member may pick up oral study drug on behalf of the subject if first
discussed with and agreed by the subject. The conversation with the subject must be
documented in the subject's source records. The subject must name the individual who will
pick up study drug on the subject’s behalf. This is necessary for site staff toconfirm the study
drug is provided to the appropriate individual, ensure proper chain of custody ofstudydrug,
and to maintain subject privacy. Identification of who will pick up the study drug must be
confirmed and documented in the subject's source record.
If locally permitted, alternative solutions to arrange bortezomib dosing on Cycle Day 1, 4, 8,
or 11 can be discussed with the EMN Medical Monitor.
Protocol Deviations
All deviations from the study protocol will be reported based on standard guidance. If related to
the coronavirus pandemic situation, these deviations will be recorded with  a as “COVID-19-
related” prefix or category.

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Guidance on COVID-19 Vaccine Timing and COVID-19 Prevention and Treatment
It is recommended that subjects receive prophylactic COVID-19 vaccination and boosters when
locally available, at the discretion of investigator judgment or institutional practice, and in
compliance with the study protocol and local labels for the vaccine. Below is general guidance for
consideration.
Many vaccines against COVID-19 are being developed with different technologies and platforms
and may have safety and efficacy profiles that are not fully characterized even after preliminary
health authority approval. However, the benefit-risk ratio of receiving a COVID-19 vaccine among
patients with multiple myeloma is considered to be positive and should be considered for
administration while in compliance with the study protocol and when not otherwise
contraindicated for use in the vaccine label.
Per protocol, live attenuated vaccines must be completed within 4 weeks of first study agent
administration (see Section 4.2) or >90 days after last dose of study treatment (see Section 8.2 and
Section 8.3). There are no specific timing restrictions for inactivated vaccines, such as vaccines
which use alternative technology like mRNA or replication-incompetent viral vectors, per protocol
(mRNA vaccines are recommended). Enrollment into an interventional clinical trial for an
experimental vaccine is prohibited during study. Any vaccination, including COVID-19
vaccinations, must be recorded on the Concomitant Medication page of the eCRF.
No data are currently available to suggest that COVID-19 vaccines pose specific or additional
safety risk beyond other vaccines for patients with multiple myeloma undergoing
treatment. Theoretically, a diminished immune response may occur in immunocompromised
patients, and therefore these patients may have reduced vaccine effectiveness.
Several organizations and journals have published recommendations for COVID-19 vaccine
administration in cancer patients, including:
Garassino, M. C. et al. The ESMO call to action on COVID-19 vaccinations and patients with
cancer: Vaccinate. Monitor. Educate. Ann. Oncol.
https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-
pandemic
Nature Reviews Clinical Oncology: COVID-19 vaccine guidance for patients with cancer
participating in oncology clinical trials Desai A, Gainor JF, Hegde A, et al. (March 15, 2021)
DOI: 10.1038/s41571-021-00487-z.
https://www.nature.com/articles/s41571-021-00487-z
European Society for Blood and Marrow Transplantation
https://www.ebmt.org/covid-19-and-bmt
American 
Society 
for 
Transplantation 
and 
Cellular 
Therapy 
(ASTCT):
https://www.hematology.org/covid-19/ash-astct-covid-19-vaccination-for-hct-and-car-t-cell-
recipients Centers for Disease Control and Prevention (CDC)
https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html

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National Comprehensive Cancer Network (NCCN)
https://www.nccn.org/docs/default-source/covid-19/2021 covid-
19_vaccination_guidance_v5-0.pdf?sfvrsn b483da2b_116
Based on guidance from the organizations listed above, the following measures should be
implemented to minimize subjects’ risk of severe COVID-19 infection:
Subjects should be reminded that the ongoing pandemic is still putting them at risk of
contracting COVID-19. Investigators should ask subject to continue to limit their risk of
exposure to infected individuals as much as possible and strictly adhere to prevention
measures such as proper masking, hand hygiene, social distancing, and avoiding travel and
public transportation to the extent possible.
Investigators should discuss with subjects the importance of COVID-19 vaccines in the
prevention of severe illness, hospitalization, and death from COVID-19. Subjects should
assume that any vaccination administered prior to receiving study treatment no longer
provides protection. For this reason, it is strongly recommended that all subjects receive a full
COVID-19 vaccination series (eg, a primary vaccine and boosters for mRNA vaccines) (Note:
mRNA vaccines are recommended). In addition, if not already vaccinated, caregivers, family,
and household contacts should be advised to receive COVID-19 vaccination as well.
Investigators should consider prophylaxis (eg, Evusheld, if available in the region) to reduce
subjects’ risk of severe/fatal COVID. It is critical that subjects understand that multiple
myeloma patients may not seroconvert until after the 3rd COVID-19 vaccine dose and as a
result they may remain at a very high risk of severe COVID-19 for at least 2 to 3 months after
starting vaccination.
Investigators should instruct subjects to notify them or study-site staff immediately if they are
diagnosed with COVID-19, even if asymptomatic, so that appropriate treatment measures can
be determined.
If available in the region, antivirals (eg, Paxlovid or other available agents) should be considered
early after COVID-19 diagnosis. Antiviral treatment with Paxlovid is highly recommended as soon
as possible, typically within the first 5 days after a COVID-19 diagnosis. Refer to the Paxlovid
prescribing information for any drug-drug interactions and contraindications. Subjects may remain
asymptomatic or have minimal symptoms for a period of time prior to deteriorating. Investigators
should make subjects aware that these drugs may potentially significantly lower
their risk of severe COVID-19.

Signature
User 
Date 
Reason
 
04-Mar-2024
09:08:26
(GMT)
Document Approval
PPD