A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy
Phase: PHASE3
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 20 July 2021
Janssen Research & Development *
Clinical Protocol
A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs
Lenalidomide and Dexamethasone (Rd) in Subjects with Previously Untreated Multiple
Myeloma who are Ineligible for High Dose Therapy
Protocol 54767414MMY3008; Phase 3
AMENDMENT 9
JNJ-54767414 (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
EudraCT NUMBER: 2014-002273-11
Status: 
Approved
Date: 
20 July 2021
Prepared by: Janssen Research & Development, LLC 
EDMS number: 
EDMS-ERI-85965381; 12.0
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.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Approved, Date: 20 July 2021
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 7
SYNOPSIS.................................................................................................................................................. 41
TIME AND EVENTS SCHEDULE OVERVIEW.......................................................................................... 47
TIME AND EVENTS SCHEDULE, DOSE ADMINISTRATION.................................................................. 51
ABBREVIATIONS...................................................................................................................................... 53
1. 
INTRODUCTION................................................................................................................................ 56
1.1. 
Background.................................................................................................................................... 56
1.1.1. 
Multiple Myeloma........................................................................................................................ 56
1.1.2. 
Treatment Options for Multiple Myeloma.................................................................................... 56
1.1.3. 
Transplant-ineligible Population ................................................................................................. 57
1.2. 
Daratumumab ................................................................................................................................ 57
1.2.1. 
Nonclinical Studies ..................................................................................................................... 57
1.2.2. 
Clinical Studies ........................................................................................................................... 58
1.2.2.1. 
Single-Agent Daratumumab Studies (GEN501 and MMY2002)............................................. 58
1.2.2.2. 
Combination Daratumumab Studies ....................................................................................... 59
1.2.2.3 Daratumumab Subcutaneous ......................................................................................................... 60
1.3. 
Lenalidomide.................................................................................................................................. 61
1.4. 
Lenalidomide and Daratumumab................................................................................................... 62
1.5. 
Overall Rationale for the Study...................................................................................................... 63
2. 
OBJECTIVES AND HYPOTHESIS................................................................................................... 63
2.1. 
Objectives ...................................................................................................................................... 63
2.2. 
Hypothesis ..................................................................................................................................... 64
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 65
3.1. 
Overview of Study Design.............................................................................................................. 65
3.2. 
Study Design Rationale.................................................................................................................. 68
4. 
SUBJECT POPULATION.................................................................................................................. 70
4.1. 
Inclusion Criteria ............................................................................................................................ 71
4.2. 
Exclusion Criteria ........................................................................................................................... 73
4.3. 
Prohibitions and Restrictions ......................................................................................................... 75
5. 
TREATMENT ALLOCATION AND BLINDING................................................................................. 77
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 77
6.1. 
Daratumumab (Arm B Only).......................................................................................................... 78
6.1.1. 
Daratumumab Preparation ......................................................................................................... 78
6.1.2. 
Daratumumab IV Administration................................................................................................. 78
6.1.3. 
Daratumumab SC Administration ............................................................................................... 79
6.1.4. 
Prevention of Infusion -Related and Injection-Site Reactions .................................................... 79
6.1.4.1. 
Pre-dose Medication................................................................................................................ 79
6.1.4.2. 
Post-dose Medication .............................................................................................................. 80
6.1.5. 
Management of Infusion-related Reactions................................................................................ 80
6.1.5.1. 
Infusion-Related Events of Grade 1 or Grade 2...................................................................... 81
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
6.1.5.2. 
Infusion-Related Reactions of Grade 3 or Higher ................................................................... 81
6.1.5.3. 
Injection-Site Reactions........................................................................................................... 82
6.2. 
Lenalidomide (Arm A and Arm B).................................................................................................. 82
6.3. 
Dexamethasone (Arm A and Arm B)............................................................................................. 82
6.4. 
Dose Delays and Dose Modification.............................................................................................. 82
6.4.1. 
Daratumumab Dose Modification ............................................................................................... 83
6.4.1.1. 
Daratumumab-Related Toxicity Management......................................................................... 83
6.4.1.2. 
Daratumumab Interruption or Missed Doses........................................................................... 84
6.4.2. 
Lenalidomide Dose Reductions.................................................................................................. 84
6.4.2.1. 
Thrombocytopenia................................................................................................................... 84
6.4.2.2. 
Neutropenia ............................................................................................................................. 84
6.4.2.3. 
Renal Impairment .................................................................................................................... 85
6.4.2.4. 
Other Adverse Events ............................................................................................................. 85
6.4.3. 
Dexamethasone Dose Modifications.......................................................................................... 85
7. 
TREATMENT COMPLIANCE............................................................................................................ 86
8. 
CONCOMITANT THERAPY.............................................................................................................. 86
8.1. 
Recommended Therapies.............................................................................................................. 87
8.1.1. 
Prevention of Deep Vein Thrombosis and Pulmonary Embolism............................................... 87
8.1.2. 
Bisphosphonate Therapy............................................................................................................ 87
8.1.3. 
Therapy for Tumor Lysis Syndrome ........................................................................................... 88
8.1.4. 
Prophylaxis for Pneumocystis carinii.......................................................................................... 88
8.1.5. 
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 88
8.1.6. 
Prevention of Steroid Induced Gastritis...................................................................................... 88
8.1.7. 
Management of Hepatitis B Virus Reactivation .......................................................................... 88
8.2. 
Permitted Therapies....................................................................................................................... 88
8.3. 
Prohibited Therapies...................................................................................................................... 89
8.4. 
Subsequent Therapies................................................................................................................... 89
9. 
STUDY EVALUATIONS.................................................................................................................... 90
9.1. 
Study Procedures........................................................................................................................... 90
9.1.1. 
Overview..................................................................................................................................... 90
9.1.2. 
Screening Phase ........................................................................................................................ 91
9.1.3. 
Treatment Phase ........................................................................................................................ 91
9.1.4. 
Follow-up Phase......................................................................................................................... 92
9.1.5. 
Assessments Following the Positive Second Interim Analysis of PFS ...................................... 93
9.1.6. 
Assessments Following Implementation of Amendment 8......................................................... 93
9.1.7. 
Assessments Following the Interim OS Analysis ....................................................................... 93
9.1.8. 
Final CSR Analysis and Long-term Survival Follow-up.............................................................. 94
9.1.9. 
Final OS analysis Until End of Study.......................................................................................... 94
9.2. 
Efficacy........................................................................................................................................... 94
9.2.1. 
Evaluations ................................................................................................................................. 94
9.2.1.1. 
Response Categories.............................................................................................................. 94
9.2.1.2. 
Myeloma Protein Measurements in Serum and Urine ............................................................ 96
9.2.1.3. 
Serum Calcium Corrected for Albumin.................................................................................... 97
9.2.1.4. 
β2-microglobulin and Albumin.................................................................................................. 98
9.2.1.5. 
Bone Marrow Examination ...................................................................................................... 98
9.2.1.6. 
Minimal Residual Disease Assessment .................................................................................. 99
9.2.1.7. 
Assessment of Lytic Disease................................................................................................... 99
9.2.1.8. 
Documentation of Extramedullary Plasmacytomas............................................................... 100
9.2.2. 
Endpoints.................................................................................................................................. 100
9.3. 
Pharmacokinetics and Immunogenicity ....................................................................................... 102
9.3.1. 
Evaluations ............................................................................................................................... 102
9.3.2. 
Analytical Procedures............................................................................................................... 103
9.3.3. 
Pharmacokinetic Parameters ................................................................................................... 103
9.3.4. 
Immunogenicity Assessments (Antibodies to daratumumab and rHuPH20)........................... 103
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 104
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Approved, Date: 20 July 2021
9.5. 
Biomarkers................................................................................................................................... 104
9.6. 
Medical Resource Utilization........................................................................................................ 105
9.7. 
Patient Reported Outcomes......................................................................................................... 105
9.8. 
Safety Evaluations ....................................................................................................................... 106
9.9. 
Sample Collection and Handling.................................................................................................. 109
10. SUBJECT COMPLETION/WITHDRAWAL..................................................................................... 110
10.1. 
Completion ................................................................................................................................... 110
10.2. 
Discontinuation of Study Treatment............................................................................................. 110
10.3. 
Withdrawal From the Study.......................................................................................................... 111
11. STATISTICAL METHODS............................................................................................................... 112
11.1. 
Subject Information ...................................................................................................................... 112
11.2. 
Sample Size Determination ......................................................................................................... 112
11.3. 
Efficacy Analyses......................................................................................................................... 112
11.4. 
Pharmacokinetic Analyses........................................................................................................... 113
11.5. 
Immunogenicity Analyses ............................................................................................................ 114
11.6. 
Pharmacokinetic/Pharmacodynamic Analyses............................................................................ 114
11.7. 
Biomarker Analyses ..................................................................................................................... 114
11.8. 
Patient Reported Outcomes......................................................................................................... 115
11.9. 
Safety Analyses ........................................................................................................................... 115
11.10. Interim Analysis............................................................................................................................ 116
11.11. Data Monitoring Committee ......................................................................................................... 116
12. ADVERSE EVENT REPORTING .................................................................................................... 116
12.1. 
Definitions .................................................................................................................................... 117
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 117
12.1.2. 
Attribution Definitions................................................................................................................ 118
12.1.3. 
Severity Criteria ........................................................................................................................ 119
12.2. 
Special Reporting Situations........................................................................................................ 119
12.3. 
Procedures................................................................................................................................... 119
12.3.1. 
All Adverse Events.................................................................................................................... 119
12.3.2. 
Serious Adverse Events ........................................................................................................... 121
12.3.3. 
Suspected Unexpected Serious Adverse Reactions................................................................ 122
12.3.4. 
Pregnancy................................................................................................................................. 122
12.4. 
Contacting Sponsor Regarding Safety......................................................................................... 122
13. PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 122
13.1. 
Procedures................................................................................................................................... 123
13.2. 
Contacting Sponsor Regarding Product Quality.......................................................................... 123
14. STUDY DRUG INFORMATION....................................................................................................... 123
14.1. 
Physical Description of Study Drug.............................................................................................. 123
14.2. 
Packaging .................................................................................................................................... 123
14.3. 
Labeling........................................................................................................................................ 124
14.4. 
Preparation, Handling, and Storage............................................................................................. 124
14.5. 
Drug Accountability...................................................................................................................... 124
15. STUDY-SPECIFIC MATERIALS..................................................................................................... 125
16. ETHICAL ASPECTS....................................................................................................................... 125
16.1. 
Study-Specific Design Considerations......................................................................................... 125
16.2. 
Regulatory Ethics Compliance..................................................................................................... 126
16.2.1. 
Investigator Responsibilities..................................................................................................... 126
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................. 126
16.2.3. 
Informed Consent ..................................................................................................................... 127
16.2.4. 
Privacy of Personal Data .......................................................................................................... 128
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 129
16.2.6. 
Country Selection ..................................................................................................................... 129
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
17. ADMINISTRATIVE REQUIREMENTS............................................................................................ 130
17.1. 
Protocol Amendments.................................................................................................................. 130
17.2. 
Regulatory Documentation .......................................................................................................... 130
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 130
17.2.2. 
Required Prestudy Documentation........................................................................................... 130
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 131
17.4. 
Source Documentation................................................................................................................. 131
17.5. 
Case Report Form Completion .................................................................................................... 132
17.6. 
Data Quality Assurance/Quality Control ...................................................................................... 133
17.7. 
Record Retention ......................................................................................................................... 133
17.8. 
Monitoring .................................................................................................................................... 134
17.9. 
Study Completion/Termination..................................................................................................... 134
17.9.1. 
Final OS Analysis/End of Study................................................................................................ 134
17.9.2. 
Study Termination..................................................................................................................... 135
17.10. On-Site Audits.............................................................................................................................. 135
17.11. Use of Information and Publication .............................................................................................. 136
REFERENCES.......................................................................................................................................... 138
INVESTIGATOR AGREEMENT............................................................................................................... 165
LIST OF ATTACHMENTS
Attachment 1: 
Modified IMWG Diagnostic Criteria for Multiple Myeloma........................................ 141
Attachment 2: 
ECOG Performance Status Scale............................................................................ 142
Attachment 3: 
Calculated and Measured Creatinine Clearance ..................................................... 143
Attachment 4: 
Serum Calcium Corrected for Albumin..................................................................... 144
Attachment 5: 
Lenalidomide Global Pregnancy Prevention Plan.................................................... 145
Attachment 6: 
Conversion Table for Glucocorticosteroid Dose....................................................... 154
Attachment 7: 
Asthma Guidelines ................................................................................................... 155
Attachment 8: 
International Staging system .................................................................................... 158
Attachment 9: 
The Family of antihistamine medications ................................................................. 159
Attachment 10: 
Anticipated Adverse Events...................................................................................... 160
Attachment 11: 
Long-term Survival Follow-up –After Final CSR Analysis Until Final OS
Analysis .................................................................................................................... 161
Attachment 12: 
Final OS Analysis Until End of Study....................................................................... 163
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Daratumumab Single-Agent Studies GEN501 and MMY2002................................................. 58
Table 2: 
Daratumumab Combination Studies GEN503 and MMY1001 ................................................. 59
Table 3: 
Daratumumab-Related Toxicity Management.......................................................................... 83
Table 4: 
Lenalidomide Dose Adjustment for Thrombocytopenia............................................................ 84
Table 5: 
Lenalidomide Dose Adjustment for Neutropenia...................................................................... 85
Table 6: 
Lenalidomide Dose Adjustment for Renal Impairment............................................................. 85
Table 7: 
Recommended Dose Reduction for Dexamethasone .............................................................. 86
Table 8: 
International Uniform Response Criteria Consensus Recommendations ................................ 95
Table 9: 
Bone Marrow Testing................................................................................................................ 99
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Approved, Date: 20 July 2021
FIGURES
Figure 1: Improvement of Daratumumab-induced Antibody-dependent Cell-mediated
Cytotoxicity by Lenalidomide in Bone Marrow Mononuclear Cells from Patients with
Multiple Myeloma...................................................................................................................... 62
Figure 2: Schematic Overview of the Study............................................................................................. 65
Figure 3: Daratumumab Maximal Target Suppression ............................................................................ 69
Figure 4: Schematic Overview Study Treatment Administration ............................................................. 78
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Approved, Date: 20 July 2021
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol 
14 July 2014
Amendment INT-1 
29 October 2014
Amendment INT-2 
26 August 2015
Amendment INT-3 
2 November 2016
Amendment INT-4 
22 May 2017
Amendment 5 
15 January 2019
Amendment 6 
12 June 2019
Amendment 7 
17 January 2020
Amendment 8 
3 April 2020
Amendment 9 
20 July 2021
Amendments below are listed beginning with the most recent amendment.
Amendment 9(20 July 2021)
The overall reason for the amendment: To define the clinical cut-off for the final CSR analysis. This cut-off will
mark the start of the long-term survival follow-up during which subjects will continue to receive study treatment
and will be followed for overall survival (OS). Additionally, this amendment revises the end of study definition
and defines the timing of the final overall survival (OS)analysis cut-off. This amendment also provides clarification
that subjects who are benefiting from study treatment will be able to continue to receive study treatment from the
final OS analysis until the end of study when alternative access to daratumumab is not available.
Applicable Section(s) 
Description of Change(s)
Rationale: To define the timing ofthe following: the final CSR, the transition to long-term survival follow-up,
and the final OS analysis.
Synopsis Overview of Study Design; 
3.1 Overview of Study Design; 
10.1 Completion; 11.2 Sample Size 
Determination; 11.3 Efficacy Analysis; 
17.9.1 Final OS Analysis/End of study  
3.1 Overview of Study Design  
Text was revised to add the final CSR analysis, which will
provide updates to the primary CSR analysis for both efficacy
and safety. Text was added to include the final OS analysis. It
was specified that the clinical cut-off of the final OS analysis will
occur when approximately 390 deaths have occurred.
Text was added to specify that following the positive second
interim OS analysis, the study will have the final CSR analysis
and then will transition to long-term survival follow-up.
Throughout the protocol 
Reference to Section 9.1.8 was added to define the longterm
survival follow-up. Reference to Section 9.1.9 was added to
define the final OS analysis cut-off. Reference to Section 17.9.1
was added to define end of study.
Rationale: To clarify procedures after the final CSR analysis until final OS analysis
Time and Events Schedule Overview; Time 
and Events Schedule, Dose Administration; 
3.1 Overview of Study Design; 
9.1.3 Treatment Phase; 9.1.4 Follow-up
Phase; 9.2.1.1 Response Categories;
9.8 Safety Evaluations; 9.9 Sample
Collection and Handling; 12.3.1 All Adverse
Events; 12.3.2 Serious Adverse Events;
17.5 Case Report Form Completion;
17.9.1 Final OS Analysis/End of Study
Reference to Attachment 11 was added (description of study
procedures for all subjects during the long-term survival follow-
up).
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
8 Concomitant Medications 
Text was updated to clarify the timeframe of collection of
concomitant medications.
Synopsis; 3.1 Overview of Study Design; 
8.4 Subsequent Therapies; 9.1.3 Treatment 
Phase
Text was updated to clarify that PD confirmation by sponsor will
not be required after the cut off date for the final CSR analysis.
8.4 Subsequent Therapies 
Text was added to clarify procedures during long-term survival
follow-up.
9.1.1 Overview  
Text was added to specify that during the long-term survival
follow-up, no blood will be collected, only local routine testing
will be performed per local institutional practice
9.1.3 Treatment Phase 
Text was added to clarify that for subjects continuing to receive
study treatment after the final CSR analysis, routine safety
monitoring should comply with local institution practice. Text
was added to specify that after the final CSR analysis, end of
treatment visits are no longer required.
9.1.4 Follow-up Phase 
Text was added to clarify that Follow-up Phase procedures will
be performed until the start of the long-term survival follow-up
and reference is made to Attachment 11 for the Follow-up
procedures after final CSR analysis.
9.1.7 Assessments Following the Interim OS 
Analysis; 
Text was revised to specify that subject monitoring will continue
as summarized until the cut-off for the final CSR analysis.
9.1.8 Final CSR Analysis and Long-term 
Survival Follow-up (new) 
A new section was added to describe assessments and data
collection following the final CSR analysis until the final OS
analysis.
9.2.1.1 Response Categories 
Text was added to clarify efficacy evaluation requirements for
subjects who continue to receive study treatment after the final
CSR analysis.
9.8 Safety Evaluations 
Text was added to clarify hepatitis B virus DNA testing
requirements for subjects who continue to receive study drug
after the final CSR analysis.
9.8 Safety Evaluations; 12.3.1 All Adverse 
Events; 12.3.2 Serious Adverse Events 
Text was added to specify that serious adverse event reporting
will continue for those subjects receiving study treatment after
the final CSR analysis.
9.9 Sample Collection and Handling 
Text was added to clarify the sample collection and handling
requirements after the final CSR analysis.
12.3.4 Pregnancy  
12.3.1 All adverse events 
Text was added to specify that pregnancy reporting will continue
after the final CSR analysis.
Clarification was added that Anticipated events will be no longer
be reported after the final CSR analysis.
Attachment 11 (new) 
Attachment 11 (new) was added to clarify the study procedures
and data collection all subjects during the long-term survival
follow-up.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Approved, Date: 20 July 2021
Rationale: The final OS analysis is distinct from the end of study, as such, the end of study definition was
amended for clarity and text was updated to align with these definitions.
Synopsis, Overview of Study Design; 
17.9.1 Final OS Analysis/End of Study  
Text was added to define the end of study (defined as when all
subjects who are still receiving daratumumab after the final OS
analysis have access to daratumumab through another source
such as commercial availability, continued access through a
dedicated long-term extension study, or a patient access program,
or when all subjects have discontinued daratumumab treatment,
or by 31 January 2026 , whichever occurs first).
3.1 Overview of Study Design; 9.1.8 Final 
CSR Analysis and Long-term Survival 
Follow Up; 10.1 Completion
9.1.9 Final OS analysis Until End of Study  
Text was updated from “end of the study” to “until the final OS
analysis”.
A new section was added to describe assessments and data
collection following the final OS analysis till end of study.
Rationale: To clarify access to daratumumab after the final OS analysis until the end of study for those subjects
who are benefiting from study treatment.
Synopsis; 3.1 Overview of Study Design; 
17.9.1 Final OS analysis/End of Study 
Text was updated to clarify that subjects benefiting from
treatment with daratumumab have the option to continue to
receive study treatment after the final OS analysis until the end of
study.
Rationale: To clarify study assessments and data reporting requirements in relation to the final OS analysis
cut-off until the end of study.
Attachment 12 (new) 
Time and Events Schedule Overview; 
Time and Events Schedule, Dose 
Administration; 9.1.9 Final OS Analysis
till End of Study; 9.2.1.1 Response
Categories; 9.8 Safety Evaluations; 12.3.2
Serious Adverse Events; 12.3.4 Pregnancy;
17.5 Case Report Form Completion;
17.9.1 Final OS analysis/End of Study
3.1 Overview of Study Design; Figure 2 
Attachment 12 added to clarify the study procedures for subjects
who continue to receive daratumumab after the final OS analysis
cut-off.
Reference to Attachment 12 was added (description of study
procedures for all subjects after the final OS analysis cut-off.
Footnote added to Figure 2 to clarify that after Study MMY3008
transitions to long-term survival follow-up, an end-of-treatment
visit is no longer required.
Rationale: To clarify permitted/prohibited vaccinations.
8.2 Permitted Therapies 
8.3 Prohibited Therapies
Text was added indicating vaccinations are allowed per local
guidelines with a reference to Section 8.3.
Text was added clarifying the restriction of live-attenuated and
replication-competent viral vector vaccines.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Approved, Date: 20 July 2021
Rationale: To incorporate changes from France and United Kingdom country-specific amendments into
MMY3008 global Amendment 9.
9.8 Safety Evaluations HBV Serology and 
DNA Testing 
10.2 Discontinuation of Study Treatment 
Text from Study MMY3008  France amendment added to specify
that if the hepatitis B serologic status of a subject in the DRd arm is
unknown, HBsAg, Anti-HBs, and Anti-HBc testing is
recommended if the subject is still receiving daratumumab (or is
within 6 months after the last dose).
Text revised to incorporate a country-specific requirement from
Study MMY3008 UK amendment to specify that a subject's study
treatment will should be discontinued if:
Rationale: To clarify the definition of medically important serious adverse events.
12.1.1 Adverse Event Definitions and 
Classifications
Second primary malignancies added to medically important events.
Rationale: Minor errors were noted.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Approved, Date: 20 July 2021
Amendment 8 (3 April 2020)
The overall reason for the amendment: The overall reason for the amendment is to provide flexibility for study
investigators to prioritize the safety of their patients during the global coronavirus (COVID-19) pandemic. 
To ensure continuity of study treatment, while limiting subjects’ time spent at the study center, subjects will be
given the option to switch from daratumumab IV (16 mg/kg) to daratumumab subcutaneous (Dara-SC 1800 mg),
at the discretion of the investigator.
Applicable Section(s) 
Description of Change(s)
Rationale: To allow subjects currently receiving Dara-IV the option to switch to Dara-SC, at the discretion of the
investigator.
Synopsis; 3.1 Overview of Study Design  
Text has been added to describe the option of daratumumab SC
administration for subjects receiving daratumumab IV.
1.2.2.3 (new) Daratumumab Subcutaneous; 
3.2 (new) Study Design Rationale for 
Daratumumab SC Dose Regimen  
The following sub-sections and text have been added to support
daratumumab SC dosing: background information regarding the
SC formulation of daratumumab, rationale for daratumumab SC
dose regimen, rationale for daratumumab fixed dose, and
daratumumab SC administration.
Synopsis; Time & Events Schedules; 
3.1 Overview of Study Design; 6 Dosage and 
Administration; 6.1.1 Daratumumab 
Preparation; 6.1.4.1 Pre-dose Medication;
6.1.4.2 Post-dose Medication;
6.1.5 Management of Infusion-related
Reactions; 6.1.5.1 Infusion-Related Events
of Grade 1 or Grade 2; 6.1.5.2 Infusion-
Related Reactions of Grade 3 or Higher;
6.2 Lenalidomide (Arm A and Arm B);
6.3 Dexamethasone (Arm A and Arm B);
6.4.3 Dexamethasone Dose
Modifications; 6.4.1.1 Daratumumab-
Related Toxicity Management;
8 Concomitant Therapy;
11.4 Pharmacokinetic Analyses;
12.3.2 Serious Adverse Events; 16.1 Study-
Specific Design Considerations;
Attachment 9 The Family of Antihistamine
Medications
Where text was specific to infusion(s) but applicable to both IV
and SC administration, text was amended to remove “infusion”
and/or add “dose” or “administration”.
Synopsis; Sec 6.1.3 (new) Daratumumab SC 
Administration; 6.1.4.2 Post-dose 
Medication; 6.4.1.2 Daratumumab
Interruption or Missed Doses; 9.1.1
Overview
Text has been added to describe daratumumab SC dose
administration.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Synopsis; Time & Events Schedules; 
3.2 Study Design Rationale; 6 Dosage and 
Administration; 6.1.2 Daratumumab IV 
Administration; 6.1.4.1 Pre-dose Medication; 
6.1.5 Management of Infusion-related
Reactions; 6.1.5.1 Infusion-Related Events
of Grade 1 or Grade 2; 6.1.5.2 Infusion-
Related Reactions of Grade 3 or Higher;
8.4 Subsequent Therapies;
9.3.4 Immunogenicity Assessments
(Antibodies to Daratumumab and rHuPH20)
Text has been added to clarify where text is applicable to both
daratumumab IV and SC or to differentiate between
daratumumab IV or SC administration, procedures, or
requirements.
Synopsis; Time & Events Schedule 
Overview; 3.1 Overview of Study Design; 
9.3.1 Evaluations; 9.3.4 Immunogenicity 
Assessments (Antibodies to daratumumab
and rHuPH20)
Text has been added for pharmacokinetic and immunogenicity
sampling requirements for subjects treated with daratumumab
SC.
Rationale: Infusion-related reactions are systemic reactions related to daratumumab administration, regardless of
route of administration.
6.1.5 Management of Infusion-related 
Reactions 
Text has been added to describe IRRs and the applicability to
both daratumumab IV or SC administration.
Rationale: Subcutaneous administration of daratumumab is associated with local injection site reactions.
6.1.4 Prevention of Infusion-Related and 
Injection-Site Reactions; 6.1.5.3 (new) 
Injection-Site Reactions
Text has been added to describe injection-site reactions and
management of such events.
Rationale: Daratumumab SC is co-formulated with rHuPH20 and sorbitol.
Synopsis; Time & Events Schedule 
Overview; 2.1 Objectives; 9.3.1 Evaluations; 
9.3.2 Analytical Procedures; 
9.3.4 Immunogenicity Assessments
(Antibodies to Daratumumab and rHuPH20);
11.5 Immunogenicity Analyses
Text has been added to include the immunogenicity collection for
analysis of rHuPH20 for those subjects treated with
daratumumab SC.
Synopsis; 3.1 Overview of Study Design  
Text has been added to specify that subjects with known
allergies/intolerance to sorbitol will not be allowed to switch
from daratumumab IV to daratumumab SC.
Rationale: Daratumumab IV has been shown to be safe and effective in patients with multiple myeloma, as such,
immunogenicity sampling requirements for subjects receiving daratumumab IV have been amended to reduce
patient and site burden.
Time & Events Schedule Overview  
Footnote added to T&E to clarify that pharmacokinetic and anti-
daratumumab antibody sampling is no longer required for
subjects in Treatment Arm B who remain on daratumumab IV
therapy.
Synopsis; 9.1.6 (new) Assessments 
Following Implementation of Amendment 8; 
9.3.1 Evaluations; 9.3.4 Immunogenicity 
Assessments (Antibodies to daratumumab
and rHuPH20)
Text has been updated to remove pharmacokinetic and
immunogenicity sampling for subjects who remain on
daratumumab IV.
Rationale: Revisions made for clarity that align with daratumumab-wide program language.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
6.1.5 Management of Infusion-related 
Reactions 
Bolded text was added: Trained study staff at the clinic should be
prepared to intervene in case of any infusion-related reactions
occurring, and resources necessary for resuscitation (eg, agents
such as epinephrine and aerosolized bronchodilator, also medical
equipment such as oxygen tanks, tracheostomy equipment, and
a defibrillator) must be available at the bedside.
8.2 Permitted Therapies 
New text was added: Other symptoms may be managed
according to institutional guidelines provided prohibited
therapies are not administered (see Section 8.3).
Rationale: Clarification of collection of laboratory samples.
9.1.6 (new) Assessments Following 
Implementation of Amendment 8; 
9.1.7 Assessments Following the Interim OS 
Analysis 
New section added to specify that following the implementation
of Amendment 8, disease evaluations are to be performed locally
per the site’s standard of care and quantitative immunoglobulin
testing will be removed.  rHuPH20 immunogenicity testing for
Dara-SC subjects was added and pharmacokinetic and
immunogenicity sampling for subjects who remain on
daratumumab IV was removed.
Rationale: To provide physical description  and guidance about packaging, labeling, preparation, handling, and
storage for daratumumab SC.
14.1 Physical Description of Study Drug; 
14.2 Packaging; 14.3 Labeling;
14.4 Preparation, Handling and Storage
New text added about daratumumab SC.
Rationale: To allow sites flexibility in offering virtual visits due to COVID-19 pandemic.
Time & Events Schedule; 9.1.1 Overview  
Text added to specify that site visits may be replaced with virtual
visits or other local arrangements in exceptional circumstances.
Rationale: Minor errors, editorial issues, or changes for clarity/consistency noted in the protocol were corrected.
Abbreviations 
Abbreviations for IPPI (Investigational Product Preparation
Instruction), IRR (infusion-related reaction), ISR (injection-site
reaction), and rHuPH20 (recombinant human hyaluronidase
PH20) have been added.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.
Amendment 7 (17 January 2020)
The overall reason for the amendment: The overall reason for the amendment is to provide clarifications to
study conduct and align with updates in all daratumumab protocols.
Applicable Section(s) 
Description of Change(s)
Rationale:  Clarification was added for the assessments performed after the interim overall survival (OS)
analysis.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
9.1.6 Assessments 
Following the Interim 
OS Analysis 
Text was added to specify quantitative immunoglobulin testing is no longer required.
Bold text added to clarify that confirmation of disease progression by sponsor is no
longer required, with the exception of subjects who progress on the Rd arm and then
request subsequent therapy with daratumumab.
Bold text added to clarify that all subjects must still meet IMWG criteria for
progression (see Table 8), prior to initiation of subsequent anti-myeloma therapy.
Text in strikethrough has been deleted: For subjects who are continuing to receive study
treatment at the time of the interim OS analysis, dosing data and safety information will
be collected. Safety information will include adverse events during treatment and within
30 days after last dose, concomitant medications associated with a serious adverse event,
and information on all second primary malignancies.
Rationale: Modified the list of anticipated events to remove any events that are known adverse drug reactions
(ADRs) of daratumumab. Clarification that after unblinding of aggregate safety data by the sponsor’s study team,
there is no need for independent Safety Asessment Committee (SAC) review of anticipated events. Additional
clarification of the reporting responsibilities for anticipated events to Health Authorities and IRBs/IECs. Changed
name of committee to be in alignment with company procedures.
Attachment 10 
Anticipated Adverse 
Events 
 Anemia, neutropenia, and thrombocytopenia were deleted from the anticipated
events list.
 The review and reporting requirements for anticipated events were clarified.
 Revised “Anticipated Event Review Committee” (ARC) to “Safety Assessment
Committee” (SAC).
Rationale: To eliminate the possibility of inconsistency between the NCI-CTCAE version numbering used in the
protocol and the standard grade descriptions included in the protocol.
12.1.3 Severity 
Criteria 
Removed definitions of severity criteria as they are specified in NCI-CTCAE
Version 4.03.
Revised NCI-CTCAE version to 4.03.
Rationale: To further clarify the measures to mitigate the risk of embryo fetotoxicity associated with
lenalidomide.
4.3 Prohibitions and 
Restrictions
9.8 Safety 
Evaluations 
10.2 Discontinuation
of Study Treatment
12.3.4. Pregnancy
Attachment 5
Lenalidomide Global
Pregnancy Prevention
Plan
Additional text regarding the pregnancy prevention plan for lenalidomide was added.
Text regarding requirement of pregnancy test for women with regular and irregular
menstrual cycles after last dose of lenalidomide was added.
Rationale: Minor errors were noted.
9.5 Biomarkers 
Abbreviations 
Bold text added to clarify testing on biomarker samples: Samples for biomarker
evaluations will be collected as specified in the Time and Events Schedule  and may be
used for additional biomarker testing that may arise at a later time point (see
Section 16.2.5).
Abbreviation for Safety Assessment Committee (SAC ) has been added.
Amendment 6 (12 June 2019)
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
15
Approved, Date: 20 July 2021
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).
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).
Time and Events Schedule – 
Overview  
Added HBV DNA assessment at every 3 months during treatment ± 1 month
until 6 months after last dose of daratumumab with the note ‘Arm B subjects
with known history of hepatitis B infection or positive hepatitis B serologies
(HBsAg, Anti-HBc and/or Anti-HBs with exception of serologic findings
suggestive of HBV vaccination [Anti-HBs positivity as the only serologic
marker] and a known history of prior HBV vaccination)’.
8.1.7 Management of Hepatitis B 
Virus Reactivation  
Added a new section for information for the management of HBV
reactivation.
9.8 Safety Evaluations 
Added information detailing the conduct of HBV serology and updated DNA
tests
Rationale: To clarify the mode of subject monitoring post end-of-treatment (EOT).
Time and Events Schedule – 
Overview (Disease Evaluations) 
The following details clarifying subject monitoring post EOT were added –
‘After EOT, subjects in both treatment arms prior to disease progression (PD)
will continue to return for disease evaluations. After PD is documented,
subjects will be followed for survival, time from randomization to progression
on the next line of therapy or death, whichever comes first (PFS2), second
primary malignancies, and subsequent anti-myeloma therapy. After the
primary clinical cut-off date (24 September 2018), subject monitoring will be
conducted as per Section 9.1.5. After the second interim OS analysis has
occurred and the mPFS for DRd group has been confirmed, subject
monitoring will be conducted according to Section 9.1.7’
Rationale: To provide a window for the 6-monthly collection of Eastern Cooperative Oncology Group (ECOG)
and patient-reported outcome (PRO) assessments.
Time and Events Schedule – 
Overview; 9.1.5: Assessments 
Following the Positive Second
Interim Analysis of PFS
Added ‘±14 days’ to the 6-monthly collection of ECOG and PRO assessments
after completing the first year for these procedures.
Rationale: To clarify the guidance for delay in treatment.
6.4.1.2 Daratumumab 
Interruption or Missed Doses 
Text in bold added:
A daratumumab dose that is held for more than the permitted time (Table 3)
from the per-protocol administration date for any reason other than toxicities
suspected to be related to daratumumab should be brought to the attention of
the Sponsor at the earliest possible time. Subjects whose dose was delayed for
more than 4 weeks (Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and
beyond) should have study treatment discontinued, unless, upon consultation
with the sponsor and the review of safety and efficacy, continuation is agreed
upon. Infusion-related reactions may occur upon re-initiation of
daratumumab after a prolonged delay in treatment.
Rationale: To provide additional details regarding the provision of daratumumab by the sponsor for subjects
randomized to Arm A (Rd) who are receiving any subsequent line of therapy.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
16
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
8.4. Subsequent Therapies 
Added the sentence ‘For these subjects, daratumumab should not be added to
an ongoing subsequent therapy regimen until the subject has progressed on
that regimen’ and mentioned that safety management for and during the
administration of daratumumab must be in accordance with local prescribing
information and local regulations. Also clarified that second primary
malignancy reporting should continue to end of study.
Rationale: To clarify the timing when disease evaluation will switch to local laboratories.
9.1.6 Assessments Following the 
Interim OS Analysis 
Text in strikethrough has been deleted, text in bold has been added:
Once the interim overall survival (OS) analysis has occurred and when
the median progression free survival (PFS) is reached in the DRd arm,
the sponsor will notify the investigators that from that point onward,
disease evaluations are to For subjects without disease progression at the
time of the interim OS analysis, disease assessments will continue but will be
performed locally per the site’s standard of care.
Rationale: Minor errors were noted
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.
Amendment 5 (15 January 2019)
The overall reason for the amendment: Following review of data from the second interim analysis by the
Independent Data Monitoring Committee (IDMC), the study is being amended to allow subjects in Arm A
(lenalidomide and dexamethasone [Rd] alone) access to daratumumab after sponsor confirmation of disease
progression (PD) per International Myeloma Working Group (IMWG) criteria.
Applicable Section(s) 
Description of Change(s)
Rationale: Subjects randomized to Arm A (Rd) who have sponsor-confirmed disease progression may have the
option to receive daratumumab provided by the sponsor (in any subsequent line of therapy) in the Follow-up
phase, if recommended by the investigator. Eligibility for and administration of daratumumab must be in
accordance with local prescribing information and local regulations.
8.4. Subsequent 
Therapies
A new section has been added.
Rationale: To update the protocol following positive second interim analysis results.
Synopsis, Overview 
of Study Design;
Synopsis, Statistical
Methods;
3.1. Overview of
Study Design;
11.10. Interim
Analysis
Details of IDMC reviews and planned interim analyses have been revised.
Synopsis, Overview 
of Study Design; 
Synopsis, Statistical 
Methods;
3.1. Overview of
Study Design;
9.2.2. Endpoints;
It is explained that the interim PFS analysis will function as the primary PFS analysis of
this endpoint, as the superiority of daratumumab plus Rd (DRd) over Rd alone was
established at the second interim analysis.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
11.10. Interim
Analysis
Synopsis, Overview 
of Study Design; 
Time and Events 
Schedule, Overview; 
3.1. Overview of
Study Design
Removed text which referred to reduced data collection as described in Section 9.1.4.
Where appropriate, added references to subject monitoring as described in the new
Sections 9.1.5 (following positive second interim analysis of PFS) and 9.1.6 (following
interim overall survival [OS] analysis).
Synopsis, Overview 
of Study Design; 
3.1. Overview of 
Study Design;
11.10. Interim
Analysis
Described that the second interim OS will now occur when approximately 260 deaths
have occurred which will be about the same time the primary PFS analysis would have
taken place.
9.1.4. Follow-up 
Phase
Removed the following text:
A clinical cut-off will be established after the primary PFS analysis (390 PFS
events). Following the clinical cut-off date, disease assessments will no longer be
required and data collection will be limited to the following:
• For subjects still receiving study treatment: study treatment administration,
adverse events, SAEs, laboratory data associated with SAEs
• For all subjects: all subsequent anticancer treatment, PFS2 (based on investigator
judgment), second primary malignancies, and survival follow-up
9.1.5. Assessments 
Following the
Positive Second
Interim Analysis of
PFS
A new section has been added.
9.1.6. Assessments 
Following the Interim
OS Analysis
A new section has been added.
11.3. Efficacy 
Analyses 
Described that the analysis of OS may be confounded by subjects from Arm A receiving
daratumumab after disease progression. Exploratory analysis may be performed to
adjust for the effect daratumumab exposure may have on OS for the subjects who were
randomized to Arm A (Rd).
11.3. Efficacy 
Analyses 
Text describing secondary endpoints was revised to align with the secondary endpoints
which were planned to be sequentially tested at the second interim analysis.
Rationale: To clarify/emphasize the requirement to wait until confirmed PD prior to starting subsequent
anti-myeloma therapy.
Synopsis, Overview 
of Study Design; 
3.1. Overview of 
Study Design
It is emphasized that for both Arm A (Rd) and Arm B (DRd), subjects entering the
Follow-up Phase should not be started on subsequent anti-myeloma therapy ‘until
confirmed disease progression’.
8.3. Prohibited 
Therapies 
Clarified that the prohibition on concomitant administration of any other antineoplastic
therapy for the intention of treating multiple myeloma applies prior to confirmation of
disease progression.
Text in strikethrough has been deleted, text in bold has been added:
and other cancers not defined in the study protocol is prohibited
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
18
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
For management of second primary malignancies please see Section 10.2.
Synopsis, Overview 
of Study Design;
3.1. Overview of
Study Design;
9.1.4. Follow-up
Phase;
9.2.1.1. Response
Categories
Cross-references to the new Section 8.4 Subsequent Therapies have been added.
Rationale: Clarification of the IDMC’s role in data review following the interim PFS analysis.
Synopsis, Overview 
of Study Design; 
Synopsis, Statistical
Methods;
3.1. Overview of
Study Design;
11.11. Data
Monitoring
Committee
It is noted that the IDMC will no longer review study data after the interim PFS analysis
has been completed.
Rationale: To clarify the daratumumab pharmacokinetics (PK) and immunogenicity assessments specific to
Arm B (DRd).
Synopsis, 
Pharmacokinetic and 
Immunogenicity 
Evaluations;
9.3.1. Evaluations;
9.3.4.
Immunogenicity
Assessments
(Antibodies to
daratumumab)
Added text stating that in the Follow-up Phase, for all subjects in Arm B (DRd), samples
for PK and immunogenicity assessments are to be collected 8 weeks after the last dose
of daratumumab, regardless of whether there has been confirmed disease progression.
Time and Events 
Schedule, Overview  
Within the rows describing daratumumab PK and immunogenicity assessments, text has
been added to emphasize that these assessments apply only to subjects in Arm B.
Rationale: Clarification of visit time points to ensure consistent timing of assessments for both ECOG and ePRO
and align with other daratumumab protocols.
Time and Events 
Schedule, Overview  
Text in strikethrough has been deleted, text in bold has been added:
Within the ECOG and PRO rows:
‘D1 of Cycle 3, 6, 9, 12 for year 1; every 6th month cycle thereafter until EOT (PD)’
Rationale: Additional timepoints for MRD monitoring added to allow for MRD durability assessment.
Time and Events 
Schedule, Overview  
Text in strikethrough has been deleted, text in bold has been added:
Within the bone marrow aspirate/biopsy row:
‘To confirm CR/sCR, assess MRD, and evaluate PD (if feasible). Samples are requested
at time of suspected CR/sCR and at 12, 18, 24, and 30, 36, 48, and 60 months post
C1D1 (+/-1 month).’
9.2.1.5. Bone Marrow 
Examination, Table 9 
Text has been revised in the Bone Marrow Testing Table:
During Treatment
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
1. Central Testing: A portion of bone marrow aspirates collected at time of
suspected CR/sCR, and 12, 18, 24, and 30, 36, 48, and 60 (+/-1) months post
C1D1, will be analyzed for MRD*.
Footnote: **Immunohistochemistry or immunofluorescence (both require kappa/lambda
ratio from analysis of >100 plasma cells) or 2- to 4-color flow cytometry are acceptable
methods to evaluate plasma cell clonality.
Rationale: To clarify visit time points for quantitative immunoglobulin (Ig) assessments.
Time and Events 
Schedule, Overview  
Text in strikethrough has been deleted, text in bold has been added:
Within the quantitative Ig row, for ‘Day 1 of each cycle (28-day cycles):
every 16 weeks 3 months
9.2.1.2. Myeloma 
Protein 
Measurements in
Serum and Urine
 
Serum quantitative immunoglobulins (QIgs)
 
All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD at Screening.
Every 16 weeks 3 months during treatment and at the EOT visit, subjects with
IgD or IgE disease will be evaluated for IgG, IgA, IgM, IgE, and IgD and
subjects with IgG, IgA, or IgM disease will be evaluated for IgG, IgA, and
IgM.
Rationale: Widening of window for collection of visit time points for hematology and clinical chemistry
assessments.
Time and Events 
Schedule, Dose 
Administration 
Text in strikethrough has been deleted, text in bold has been added:
Within the hematology and clinical chemistry rows:
‘For Cycle 1 Day 1, no need to repeat tests if they have been performed within the past 5
days. Testing may be performed up to 3 2 days before other infusion days.’
Rationale: Additional text added to include Arm A cycle delays.
6. Dosage and 
Administration  
Text in bold has been added:
Subjects whose study treatment is delayed for more than 4 weeks (Cycle 1 to
Cycle 6) or more than 6 weeks (Cycle 7 and beyond) should have study treatment
discontinued, unless, upon consultation with the sponsor and the review of safety
and efficacy, continuation is agreed upon.
Rationale: Clarification that lenalidomide and dexamethasone doses can be re-escalated at the investigator’s
discretion.
6.4.2. Lenalidomide 
Dose Reductions 
Text in bold has been added:
In the event of a dose adjustment, lenalidomide doses maybe re-escalated at the
investigator’s discretion.
6.4.3. Dexamethasone 
Dose Modifications 
In the event of a dose adjustment, dexamethasone doses maybe re-escalated at the
investigator’s discretion.
Rationale: To clarify that Eastern Cooperative Oncology Group (ECOG) and patient-reported outcomes (PRO)
assessments that occur at Week 8 and Week 16 post-PD should be scheduled relative to the date of laboratory
confirmed disease progression.
9.1.4. Follow-up 
Phase 
Text in bold has been added:
‘Every 16-week follow-up contacts, as well as Week 8 and Week 16 post-PD ECOG
and ePRO assessments, should be scheduled from the date of confirmed progression
(ie, the date of the confirmatory laboratory assessment, not the date of
confirmation by the sponsor).’
Rationale: Removed text that was not pertinent to subjects who achieved a partial response (PR) or disease
progression (PD).
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
9.2.1.1. Response 
Categories, Table 8 
Text has been deleted from the International Uniform Response Criteria Consensus
Recommendations Table:
Partial response (PR)
 
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%
Progressive disease (PD)†
 
Only in subjects without measurable serum and urine M-protein levels and without
measurable disease by FLC levels, bone marrow PC percentage (absolute
percentage must be ≥10%)
 
Bone marrow plasma cell percentage: the absolute percentage must be >10%
Abbreviations 
EBMT has been deleted from the list of abbreviations
Rationale: Replaced time qualifier of ‘1-3 weeks later’ because in urgent situations, a repeat investigation may
be needed sooner. ‘At least 1 day later’ is used to make clear that the confirmatory test cannot happen on the
same day as the initial test.
9.2.1.2. Myeloma 
Protein 
Measurements in 
Serum and Urine
Text in strikethrough has been deleted, text in bold has been added:
‘Disease progression based on 1 of the laboratory tests alone must be confirmed by at
least 1 repeat investigation performed at least 1 day 1 to 3 weeks later’.
Rationale: To clarify definitions for study end.
10.1. Completion  
Text added that the study end is defined as when 330 deaths have occurred or 7 years
after the last subject is randomized, whichever comes first.
Rationale: Alignment of text with recent protocol template changes.
Title page 
Added ‘Janssen Pharmaceutica NV’ to the list of legal entities.
12.3.1. All Adverse 
Events 
Revised the text for expected disease progression not being recorded as an adverse event
or a serious adverse event term. Noted that ‘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 12.1’.
17.3. Subject 
Identification, 
Enrollment, and 
Screening Logs 
Text in strikethrough has been deleted, text in bold has been added:
All reports and communications relating to the study will identify subjects by subject
identification and age at initial informed consent date of birth. In cases where the
subject is not randomized into the study, the date seen and age at initial informed
consent date of birth will be used.
17.11. Use of 
Information and 
Publication 
Text in strikethrough has been deleted, text in bold has been added:
‘key assessment parameters of the study will be used to determine a coordinating
investigator for the study’.
Changed the time for submitting combined results from the completed study for
publication
‘within 18 months after study end date 12 months of the availability of the final data
(tables, listings, graphs)’
Revised the text beginning ‘Authorship of publications...’
Abbreviations 
ICMJE has been added to the list of abbreviations.
Rationale: Minor errors were noted
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Throughout the 
protocol
‘anticancer’ has been replaced with ‘anti-myeloma’
Synopsis, Overview 
of Study Design; 
3.1. Overview of 
Study Design  
Text in bold has been added:
Subjects who discontinue study treatment for reasons other than disease progression
must continue to have disease evaluations according to the Time and Events Schedule
until confirmed disease progression (PD) (see Section 8.4, Subsequent Therapies).
9.1.4. Follow-up 
Phase 
Text in bold has been added:
Subjects who discontinue study treatment before disease progression must continue to
have disease evaluations.
10.3. Withdrawal 
from the Study  
‘When a subject withdraws before completing the study’ has been revised to ‘When a
subject withdraws from the study’.
12.3.4. Pregnancy  
Text in strikethrough has been deleted:
Any subject who becomes pregnant during the study must discontinue further study
treatment and promptly be withdrawn from the study.
Redundant text in strikethrough has been deleted:
Follow up information regarding the outcome of the pregnancy and any postnatal
sequelae in the infant will be required.
Amendment INT-4 (22 May 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: To allow subjects in Arm B (daratumumab + lenalidomide and
dexamethasone [DRd]) to continue treatment with lenalidomide and dexamethasone (Rd) beyond the current
protocol-specified 2 years.
Applicable Section(s) 
Description of Change(s)
Rationale: Subjects in Arm B will continue treatment with lenalidomide and dexamethasone (Rd) until disease
progression or unacceptable toxicity. Based on data from the FIRST study, lenalidomide treatment until disease
progression is emerging as the standard of care and is also consistent with the approved lenalidomide package
insert.
Synopsis; Time and 
Events Schedule, 
Dose Administration;
3.1. Overview of
Study Design; 6.2.
Lenalidomide (Arm
A and Arm B); 6.3.
Dexamethasone
(Arm A and Arm B)
6.2. Lenalidomide
(Arm A and Arm B);
Subjects in both treatment arms will continue lenalidomide and dexamethasone (Rd)
until disease progression or unacceptable toxicity.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
6.3. Dexamethasone 
(Arm A and Arm B) 
3.2. Study Design
Rationale
The following text is added to manage the implementation of this amendment: Subjects
in Arm B who discontinued treatment with Rd at 24 months may re-start treatment
with Rd as per Amendment INT-4.
Text is added to support the modification of lenalidomide and dexamethasone dosing in
Arm B.
Rationale: With the anticipated improved survival for subjects in Arm B (daratumumab, lenalidomide, and
dexamethasone [DRd]), who with this amendment will receive continuous lenalidomide and dexamethasone (Rd)
regimen, the end of study and long-term survival Follow-up Phase are extended from 5 to 7 years in order to
reach 330 deaths as originally planned.
Synopsis; 3.1. 
Overview of Study
Design; 9.1.4.
Follow-up Phase;
11.2. Sample Size
Determination;
17.9.1. Study
Completion
Text is changed from 5 to 7 years.
Rationale: Most infusion-related reactions will occur with the first infusion. Because antihistamines have side
effects in the elderly population, the benefit-risk ratio of continued prophylaxis with antihistamines during
subsequent infusions should be considered.
6.1.3.1. Preinfusion 
Medication 
The following text is added: After Cycle 6, if a subject has not developed an
infusion-related reaction and is intolerant to antihistamines, modifications are acceptable
as per investigator discretion.
Rationale: Clarify steroid administration.
8.3. Prohibited 
Therapies 
Clarify that steroids given for adverse events may exceed >10 mg prednisone if no other
treatment options are available.
Rationale: Clarify the permitted treatments for second primary malignancies and follow up requirements.
10.2. Discontinuation 
of Study Treatment 
The following text regarding second primary malignancies was edited and modified: A
subject who experiences a second primary malignancy that cannot be treated by surgery
alone must be withdrawn from the study. However, a subject who develops a
malignancy that can be cured surgically may continue to receive the assigned study
treatment and the subject 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 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: Update the recommended course of action regarding lenalidomide dose adjustment to treat
thrombocytopenia and neutropenia to be more consistent with the current package insert.
6.4.2.1. 
Thrombocytopenia 
(Table 4); 
Thrombocytopenia (Table 4):
Platelet Count: When count returns to ≥30 x 109/L after first fall to <30 x 109/L;
Recommended Course of Action:  Resume lenalidomide at 15 mg the next lower dose
Platelet Count: When count returns to ≥30 x 109/L for each subsequent drop in count to
<30 x 109/L; Recommended Course of Action:  Resume lenalidomide at the next lower
dose. level (10 mg or 5 mg) once daily. Do not decrease dose below 5 mg once daily.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
6.4.2.2. Neutropenia 
(Table 5) 
Neutropenia (Table 5):
Neutrophil Count: When count first falls to <1.0 x 109/L; Recommended Course of
Action: Interrupt lenalidomide treatment, start consider G-CSF treatment, follow
complete blood count weekly; Neutrophil Count: When count returns to ≥1.0 x 109/L
and neutropenia is the only observed toxicity; Recommended Course of Action:  Resume
lenalidomide at 25 mg once daily or initial starting dose
Neutrophil Count: When count returns to ≥1.0 x 109/L and dose-dependent
hematological toxicities other than neutropenia are observed; Recommended Course of
Action:  Resume lenalidomide at 15 mg once daily the next lower dose
Neutrophil Count: When count returns to ≥1.0 x 109/L for each subsequent drop in count
to <1.0 x 109/L; Recommended Course of Action: Resume lenalidomide at the next
lower dose level (15 mg, 10 mg, or 5 mg) once daily. Do not decrease dose below 5 mg
once daily.
Rationale: Clarify that preinfusion medications are required.
6.1.3. Prevention of 
Infusion Reactions 
Remove ‘guidelines’ from Section 6.1.3 header to clarify that preinfusion medications
are required.
Rationale: Align text with Amendment INT-3 which removed the whole blood sample for MRD assessment.
Synopsis; 3.1. 
Overview of Study 
Design; 9.5. 
Biomarkers 
The following text is modified: An assessment of MRD will be conducted on whole
blood and bone marrow samples.
The following text is modified: In addition to planned bone marrow aspirate assessments,
a whole blood sample will be collected from subjects as outlined in the Time and Events
Schedule for assessment of MRD and for processing to plasma and PBMCs.
Rationale: Clarify the requirements to meet the primary endpoint of progression-free survival.
9.1.3. Treatment 
Phase 
Text is added: If disease progression has not occurred at the time of the End-of-
Treatment visit, disease evaluations must continue until disease progression is
confirmed. Subsequent anti-myeloma treatment will not be started until after disease
progression is confirmed by the Sponsor.
Rationale: Clarify MRU procedures.
Time and Events 
Schedule Overview; 
9.6. Medical 
Resource Utilization  
MRU is added to the Disease Evaluation portion of the Time and Events Schedule
Overview.
Text is modified: Medical resource utilization (MRU) data, principally number of
hospitalizations, will be derived from data collected in the eCRF for all subjects
throughout the study. Medical resource utilization (MRU) data, including primary
non-protocol driven hospitalizations, outpatient visits, and emergency room visits,
should be collected in the eCRF (Hospitalization/Outpatient Visits CRF) by the
Investigator and study-site personnel for all subjects throughout the study. Please
see CRF completion guidelines.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Approved, Date: 20 July 2021
Amendment INT-3 (2 November 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The International Myeloma Working Group (IMWG) has recently
defined new categories of minimal residual disease (MRD)–negativity and has clarified several aspects of disease
response assessment along with clinical trial endpoints (Kumar, 201616). In order to align with the new categories
of MRD-negativity, the timepoints for collection of bone marrow and whole blood for MRD assessment are
revised.
Applicable Section(s) 
Description of Change(s)
Rationale: Revision of the timepoints for the assessment of MRD-negativity required to align with newly defined
IMWG categories
Time & Events Schedule 
(Bone marrow 
aspirate/biopsy; Blood 
sample for MRD) 
9.2.1.5 Bone Marrow 
Examination (Table 9); 
9.2.1.6 Minimal 
Residual Disease
Assessment; 9.2.2 
Endpoints 
Text is revised and added to clarify sample timing for MRD assessment: To confirm
CR/sCR, assess MRD, and evaluate PD (if feasible).
Samples are requested at time of suspected CR/sCR and at 12, 18, 24 and 30 months
post C1D1 (+/-1 month). If one of these time points occurs within 1 month of
suspected CR, a repeat bone marrow will not be requested. These bone marrow tests
will only be required if patient’s response is near CR or better by blood and urine
evaluations. See Section 9.2.1.5 for additional information including timepoints.
The whole blood sample for MRD assessment is removed from the protocol; text is
deleted to align with other daratumumab protocols.
The following text is modified in Section 9.2.1.5:
Additional bone marrow aspirates or biopsies (or both) will be performed to confirm
sCR and CR, or relapse from CR (only one analysis is required, with either IHC or
immunofluorescence or 2- to 4- color flow cytometry included in the analysis) and to
monitor for MRD at time points detailed in Table 9. An additional bone marrow
aspirate will be obtained 6, 12, and 18 months +/ 1 month after the achievement of
CR to monitor for MRD.
Rationale: Secondary objectives modified for consistency with other daratumumab protocols.
Synopsis; 
2. Objectives and 
Hypothesis; 9.2.2 
Endpoints; 11.3 Efficacy 
Analyses 
Time to response is added to objectives and endpoints.
This objective is modified: To assess the minimal residual disease (MRD) negative rate
after treatment Changed to: MRD negativity rate
This corresponding endpoint is added: To assess MRD negativity rate, defined as the
proportion of subjects assessed as MRD negative, at any timepoint after the date of
randomization.
Durability of MRD negativity is added to exploratory objectives and endpoints.
The order of secondary objectives and efficacy endpoints has been modified for
consistency with other daratumumab protocols
Rationale: Criteria modified for the timing of contraception, sperm donation, pregnancy, and fathering a child
for consistency across daratumumab protocols.
4.1 Inclusion Criteria; 
4.2 Exclusion Criteria; 
4.3 Prohibitions and 
Restrictions 
Inclusion criterion 6: Contraception must continue for 3 months after the last dose of
daratumumab.
Inclusion criterion 7: Men must not donate sperm for 3 months after the last dose of
daratumumab.
Exclusion criterion 15: Revised pregnancy timing and for men not to father a child
for 3 months after last dose of daratumumab.
The change to 3 months is also revised in Prohibition and Restriction 1 and 3.
Rationale: Minor clarification regarding use of dexamethasone.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
4.2 Exclusion Criteria 
Exclusion criterion 3: the following text is revised: (equivalent of dexamethasone
40 mg/day for a maximum 4 days)
Rationale: Clarifications in the Dosage and Administration section
6. Dosage and 
Administration 
In Figure 4 Schematic Overview Study Treatment Administration, the parenthetical
phrase is deleted for dexamethasone “For 1 yr, 20 mg thereafter” is removed from
dexamethasone to align figure with text.
6.1.3.1 Preinfusion 
Medication 
Text in the third bullet regarding dexamethasone is revised:
Dexamethasone 40 mg IV (preferred) or PO (only if IV is not available),
approximately 1 hour or less prior to daratumumab infusion. For subjects older than
75 years or underweight (body mass index [BMI] <18.5), dexamethasone 20 mg may
be administered as appropriate (see Section 6.3). An equivalent intermediate-acting
or long-acting corticosteroid may substitute (see Attachment 6 for conversion table).
On days when subjects receive this dose of dexamethasone in the clinic,
dexamethasone will not be self-administered at home. If weekly dexamethasone
dosing has been reduced below 10 mg due to adverse events during study, a
minimum of dexamethasone 10 mg IV should continue to be administered prior
to daratumumab infusions.
6.2 Lenalidomide (Arm 
A and Arm B) 
The following text is modified: On daratumumab infusion days, it is recommended
that lenalidomide should be administered either prior to or at the same time
(preferred) as the premedications. The daratumumab infusion should begin
approximately 1 hour after the lenalidomide administration.
6.4.1.1 Daratumumab- 
Related Toxicity 
Management 
The following text is modified: Other than on Day 1 of a cycle, if a daratumumab
administration does not commence within the prespecified window (Table 3) of the
scheduled administration date, then the dose will be considered a missed dose.
Day 1 of a cycle should not be skipped; however, IfDay 1 of a cycle is may be
delayed, and Day 1 of subsequent cycles should be adjusted accordingly to maintain
the 28-day cycle duration.
6.4.2 Lenalidomide 
Dose Reductions 
The following text is added: After initiation of lenalidomide, subsequent
lenalidomide dose adjustment is based on individual subject treatment tolerance. If
the investigator determines that an adverse event may be related to lenalidomide,
dose adjustment can be done even if not specified in this protocol.
6.4.2.3 Renal 
Impairment (Table 6, 
footnote a);
Attachment 3 Calculated
and Measured Creatinine
Clearance
Text is added to specify that calculation of CrCl should be adjusted for body weight in
subjects with a body mass index >30 kg/m2. 
6.4.2.4 Other Grade 3 or 
4 Adverse Events 
Heading is modified to remove “Grade 3 or 4” and the following text is added: Note
that the dose modifications above are suggested, but physician discretion and clinical
judgment should prevail.
6.4.3 Dexamethasone 
Dose Modifications 
The following text is added: For other Grade 3 or 4 non-hematologic and non-renal
toxicities judged by the investigator to be related to dexamethasone alone, treatment
with dexamethasone should be interrupted and restarted at the next lower dose level
once the toxicity has resolved to Grade 2 or less. Treatment with daratumumab and
lenalidomide may continue. For complete details on dexamethasone, refer to the most
current local product prescribing information.
If weekly dexamethasone dosing has been reduced below 10 mg due to adverse
events during study, a minimum of dexamethasone 10 mg IV should continue to be
administered prior to daratumumab infusions.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Rationale: Text is added to clarify timing of urine collection for M-protein analysis.
9.2.1.2 Myeloma Protein 
Measurements in Serum 
and Urine 
The following text is added: If the 24-h urine collection (UPEP) began before
informed consent was obtained as part of routine patient care, the sample can be used
in this study as long as it was sent to the central lab for analysis after the informed
consent was obtained.
Rationale: Text is modified to clarify imaging assessments for lytic disease.
9.2.1.7 Assessment of 
Lytic Disease 
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest,
humeri, femora, and any other bones for which the investigator suspects involvement
by disease) is to be performed and evaluated by the locally laboratory by X-ray
roentgenography or the local standard of care imaging, eg, or low-dose CT during the
Screening Phase.
Magnetic resonance imaging (MRI) may be included as an additional assessment at
the discretion of the investigator; however, focal lesions identified by MRI alone
cannot be counted as lytic disease.
Rationale: A list of anticipated events is added, consistent with other daratumumab studies.
12.3.1 All Adverse 
Events; 
Attachment 10
Anticipated Adverse
Events
Standard text on reporting of anticipated adverse events is added.
The list of events is added to Attachment 10.
Rationale: Clarifications regarding CRAB criteria eligibility
Attachment 1 Modified 
IMWG Diagnostic 
Criteria for Multiple 
Myeloma 
The following text is added:
Note: Subjects only meeting SLiM CRAB are not eligible.
c) Hemoglobin measurement performed as part of standard of care within 42 days
before randomization is acceptable for screening for CRAB criteria; but must be
performed within 21 days before randomization for other eligibility requirements.
Rationale: Additional minor clarifications.
Time & Events 
Schedule; 
9.1.4 Follow-up Phase 
In Follow-up, a window of ±2 weeks is added for after PD (Q16 wks).
The following text is added to the first paragraph in 9.1.4: Every 16-week follow-up
contacts should be scheduled from the date of confirmed progression. In subjects for
whom disease progression will not be documented (eg, received subsequent
anticancer treatment or refused disease evaluations, but agreed to follow-up contacts),
the every 16-week follow-up should be scheduled from the date of the End of
Treatment Visit.
8.1.5 Prophylaxis for 
Herpes Zoster 
Reactivation  
Standard text for herpes zoster reactivation text is added.
The following is revised: Prophylaxis for herpes zoster reactivation is recommended
during the Treatment Phase, as per institutional guidelines may be used at the
discretion of the investigator.
9.2.1.1 Response 
Categories 
The following text is added: For patients with measurable disease by SPEP or UPEP
at baseline, increases in serum free light chains (FLC) or the FLC ratio alone do not
meet criteria for progressive disease
9.8 Safety Evaluations 
Minor changes in the serum chemistry panel:
-blood urea nitrogen (BUN) or urea
-total; direct bilirubin (not required except in case of congenital bilirubinemia,
such as Gilbert disease)
New footnote: *Sodium and potassium assessment were added in Protocol
Amendment 2; however, collection of sodium and potassium results will be done
retrospectively from the date of subject consent for the duration of the study, if
collected as part of routine care
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
9.8 Safety Evaluations; 
11.9 Safety Analyses; 
Time & Events Schedule 
Text is modified to clarify vital signs:  Descriptive statistics of baseline temperature,
pulse/heart rate, and blood pressure (systolic and diastolic) values and changes from
baseline will be summarized.
17.5 Case Report Form 
Completion
Template text is revised based on the current Janssen global protocol template.
References 
New references are added:
Chapuy 2016
Kumar 2016
Attachment 7 Asthma 
Guidelines
Typo corrected for Persistent, Mild: >2 days/week but not daily.
Attachment 8 
International Staging 
System
Typo corrected for Stage III: Serum ß2 microglobulin ≥5.5 mg/L
Typo corrected for Note 2: Serum ß2 microglobulin 3.5 –5.4 mg/L
Title page 
Janssen Sciences Ireland UC is added and Janssen Infectious Diseases BVBA is
removed per the protocol template.
Abbreviations 
SLiM is defined
Rationale: Minor errors were noted.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-2 (26 August 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To incorporate Indirect Antiglobulin (Coombs) Testing (IAT) during
the Screening Phase due to the risk of daratumumab interference with blood typing, as well as make updates
throughout the protocol to align with the other daratumumab Phase 3 protocols and to incorporate regulatory
agency feedback.
Applicable Section(s) 
Description of Change(s)
Rationale: Due to risk of daratumumab interference with IAT testing, in addition to blood typing, subjects must
also have IAT performed at screening.
Time and Events 
Schedule Overview; 
Blood type assessment (ABO, Rh) and IAT must be performed at screening and at
C1D1 predose in Arm B only.
4.3 Prohibitions and 
Restrictions, Criterion 
#7
Removed the text pertaining to blood typing from here as this information is provided
in Section 9.8 Safety Evaluations.
9.8 Safety Evaluations 
Updated the requirement for blood typing and IAT results to align with other Phase 3
daratumumab protocols.
Rationale: Updated inclusion and exclusion criteria for clarity, to align with IMWG criteria, and to align with
other Phase 3 daratumumab protocols.
4.1 Inclusion Criteria 
Criterion #2, bullet 2.1 
Criterion modified as per Amendment INT-2:
2.1 Subject must have documented multiple myeloma satisfying the CRAB (calcium
elevation, renal insufficiency, anemia and bone abnormalities) criteria (see
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
28
Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Attachment 1), monoclonal plasma cells in the bone marrow ≥10% or presence of
a biopsy proven plasmacytoma, and measurable disease.
 
Measurable disease, as assessed by central laboratory, defined by any of the
following:
 
IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL
or urine M-protein level ≥200 mg/24 hours; or
 
IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL
or urine M-protein level ≥200 mg/24 hours; or
 
Light chain multiple myeloma without measurable disease in serum or
urine: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal
serum immunoglobulin kappa lambda free light chain ratio.
Criterion #5, bullet g1 
Creatinine clearance ≥30 mL/min (for lenalidomide dose adjustment for subjects with
creatinine clearance 30-50 mL/min, refer to Section 6.2). Creatinine clearance can be
calculated using the Cockcroft-Gault formula provided in Attachment 3; or for
subjects with over- or underweight, creatinine clearance may be measured from
a 24-hours urine collection using the formula provided in Attachment 3;--
Criterion #5, bullet h1 
Criterion #6, bullet 6.1
corrected serum calcium ≤14 mg/dL (≤3.5 mM/L); or free ionized calcium
≤6.5 mg/dL (≤1.6 mM/L) (Attachment 4)
Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse or to use 2 methods of reliable birth control
simultaneously. This includes one highly effective form of contraception (tubal
ligation, intrauterine device [IUD], hormonal [progesterone-only birth control
pills or injections or partner’s vasectomy) and one additional effective contraceptive
method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception
must begin 4 weeks prior to dosing and must continue for 4 months after 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. (Also
see Attachment 5: Lenalidomide Global Pregnancy Prevention Plan).
4.2 Exclusion Criteria 
Criterion #8.1a and 
Criterion #8. 1b  
Modified the criteria pertaining to subjects with COPD and severe persistent asthma
to align with other Phase 3 daratumumab protocols.
8.1a) Subject has known chronic obstructive pulmonary disease (COPD) with a
Forced Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note
that FEV1 testing is required for subjects suspected of having COPD and
subjects must be excluded if FEV1 <50% of predicted normal.
8.1b) Subject has had known moderate or severe persistent asthma within the
last 2 years (see Attachment 7), 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).
Attachment 7: Asthma Guidelines was added.
Criterion #9.1 
Subject is known to be seropositive for human immunodeficiency virus (HIV) or
hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or
antibodies to hepatitis B surface and core antigens [anti-HBs and anti-HBc,
respectively]) or hepatitis C (anti-HCV antibody positive or HCV-RNA
quantitation positive).
Rationale: Clarified that the visit window is not intended for all study visits, only intended for the start of a
treatment cycle
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Time and Events 
Schedule Overview  
Modified the second sentence: Study treatment should be initiated within 72 hours
after randomization. Day 1 of each cycle Each study visit may occur ±3 days of the
scheduled day in order to accommodate the schedule of the site or subject.
Rationale: Clarified that if a full chest CT has been done, it is not necessary to perform an additional chest X-ray
Time and Events 
Schedule Overview
9.1.2 Screening
Modified Procedures: Chest X-ray (or full chest CT scan)
Rationale: To clarify the timing of daratumumab PK sample collection on infusion days.
Time and Events 
Schedule Overview  
6.1.2 Daratumumab 
Administration
Modified Laboratory Assessments for Daratumumab PK sampling:
Arm B only. On dara infusion days, 1 sample to be collected before infusion start
(window -2 hrs) and 1 sample to be collected after end of infusion (window +2
hrs).infusion
As noted in the Time and Events Schedule, vital signs should be monitored
extensively on Cycle 1 Day 1 before, during, and after the first infusion of
daratumumab. For all other infusions, vital signs should be measured before the start
of infusion and at the end of the infusion. If a subject experiences any significant
medical event, then the investigator should assess whether the subject should stay
overnight for observation.
Rationale: To clarify that vital signs 2 hours post end of infusion are not necessary
Time and Events 
Schedule, Dose 
Administration 
Modified Vital Signs Notes: On Cycle 1 Day 1: Immediately before the start of dara
infusion; at 0.5, 1, 1.5, 2, 3.5 hrs after the start of the infusion; at end of infusion; and
0.5, and 1 hr after end of infusion.
Rationale: To allow for flexibility if preinfusion medications are administered orally.
6.1.3.1 Time and Events 
Schedule, Dose 
Administration, Pre- 
infusion medications 
 
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but
avoid IV use of promethazine) approximately 1 hour prior to infusion (see
Attachment 9 for list of antihistamines that may be used)
Added the sentence: If necessary, all PO preinfusion medications may be
administered outside of the clinic on the day of the infusion, provided they are
taken within 3 hours before the infusion.
Rationale: Removed the requirement that tracheostomy equipment needs to be available in case of infusion-
related reactions.
6.1.4 Management of 
Infusion Related 
Reactions 
Trained study staff at the clinic should be prepared to intervene in case of any
infusion reactions occurring, and resources necessary for resuscitation (eg, agents
such as epinephrine and aerosolized bronchodilator, also medical equipment such as
oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at the
bedside. Attention to staffing should be considered when multiple subjects will be
dosed at the same time.
Rationale: To reflect current practice, updated management of infusion-related reactions section to indicate that
the infusion will be paused (not interrupted or slowed down) if an infusion-related reaction occurs.
6.1.4 Management of 
Infusion Related 
Reactions
If an infusion-related reaction develops, then the infusion should be paused
temporarily interrupted or slowed down.
If an infusion is paused or the infusion rate is decreased, then a longer-than-
anticipated infusion time may occur.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Rationale: FEV1 measurement is not relevant for asthma assessment.
Time and Events 
Schedule Overview;
9.8 Safety Evaluations
For subjects with COPD and/or asthma, FEV1 should be measured at baseline.
6.1.3.2 Postinfusion 
Medications 
For subjects with higher risk of respiratory complications (ie, subjects with mild
asthma, or subjects with COPD who have a FEV1 <80%), the following
postinfusion medications should be considered.
Rationale: Updated protocol to align with Revlimid US Package Insert and EU SmPC
1.3 Lenalidomide 
6.2 Lenalidomide (Arm 
A and Arm B) 
6.4.2.3 Renal 
Impairment
Added: REVLIMID® (lenalidomide) in combination with dexamethasone was
approved by both U.S. Food and Drug Administration and the European
Commission for the treatment of adult patients with previously untreated multiple
myeloma who are not eligible for transplant, on 18 February 2015 and
20 February 2015, respectively.
Lenalidomide will be self-administered at a dose of 25 mg PO each day on Days 1
through 21 of each 28 day cycle for subjects with creatinine clearance >50 mL/min. If
creatinine clearance is between 30 and 50 mL/min, the dose of lenalidomide will be
10 mg every 24 hours. Once the creatinine clearance is >50 mL/min during the course
of the treatment, lenalidomide can be increased to 25 mg.
Lenalidomide dose adjustment should be instituted for subjects with a creatinine
clearance of 50 mL/minute or less. The recommended doses for subjects with multiple
myeloma and renal impairment are shown in Table 6.
Table 6: 
Lenalidomide Dose Adjustment for Renal Impairment
Category  
Renal Function 
Dose
Moderate renal 
impairment
CrCl 30-50 mL/min  
10 mg every 24 hours
Severe renal 
impairment 
CrCl <30 mL/min (not 
requiring dialysis)
15 mg every 48 hours
Rationale: To provide guidance on management of missed lenalidomide doses
6.2 Lenalidomide (Arm 
A and Arm B) 
Added the following 3rd paragraph:
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.
Rationale: Aligned language to be consistent with criteria in other Phase 3 protocols.
6.4.1.1 Daratumumab- 
Related Toxicity 
Management 
The criteria for dose delay due to hematologic toxicity have been revised.
 
Grade 4 hematologic toxicity thrombocytopenia or
 
Grade 3 thrombocytopenia with bleeding
 
Grade 4 neutropenia, if this is the second occurrence despite growth factor
support
 
Febrile neutropenia of any grade -----
----A missed dose will not be made up.---
---Doses of daratumumab may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up to
6 weeks (Cycle 7 and beyond). If Day 1 of a cycle is delayed, Day 1 of subsequent
cycles should be adjusted accordingly to maintain the 28-day cycle duration. 
However, if a within-cycle dose is delayed, then the dates of the subsequent
within-cycle doses should not be adjusted.  Any adverse event deemed to be related
to daratumumab that requires a dose hold of more than 4 weeks (Cycle 1 to Cycle
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Applicable Section(s) 
Description of Change(s)
6) or more than 6 weeks (Cycle 7 and beyond) will result in permanent
discontinuation of daratumumab.----
6.4.1.2 Daratumumab 
Interruption or Missed 
Doses 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 6) or
more than 6 weeks (Cycle 7 and beyond) should have study treatment discontinued,
unless, upon consultation with the sponsor and the review of safety and efficacy,
continuation is agreed upon.
Rationale: Changed per Irish Regulatory Authority request (aligned with lenalidomide SmPC and US Package
Insert
6.4.2.2. Neutropenia 
Modified Table 5 as below:
Neutrophil Count 
Recommended Course of Action
 
When count first 
falls to <1.0 109/L 
 
When count returns
to 1.0 109/L and
neutropenia is the
only observed
toxicity
 
Interrupt lenalidomide treatment, start G-CSF
treatment, follow complete blood count weekly
 
Resume lenalidomide at 25 mg once daily
 
When count 
returns to
1.0 109/L and
dose-dependent
hematological 
toxicities other
than neutropenia
are observed
 
Resume lenalidomide at 15 mg once daily
 
For each 
subsequent drop in 
count to 
<1.0 109/L 
 
When count returns
to 1.0 109/L
 
Interrupt lenalidomide treatment
 
Resume lenalidomide at the next lower dose level
(15 mg, 10 mg, or 5 mg) once daily. Do not
decrease dose below 5 mg once daily
Rationale: Updated recommended therapies to prevent deep vein thrombosis and pulmonary embolism to align
with IMWG criteria.
8.1.1 Prevention of 
Deep Vein Thrombosis 
and Pulmonary 
Embolism  
Text in Section 8.1.1 reworded.
Lenalidomide has been associated with increased incidence of deep vein thrombosis
and pulmonary embolism. Therefore, prophylaxis of venous thromboembolism
(VTE) for all subjects is recommended according to IMWG guidelines as well as
at the investigator’s discretion (Palumbo 2008). Both individual and myeloma-
related risks of VTE should be taken into account in determining the type of
thromboprophylaxis. In summary:
 
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, low molecular weight heparin (LMWH)
(equivalent of enoxaparin 40 mg once daily) or full-dose warfarin,
international normalized ratio (INR) 2-3, is recommended
 
If any myeloma therapy-related risk factor is present, then LMWH
(equivalent of 40 mg enoxaparin once daily) or full-dose warfarin (target INR
2-3) is recommended
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
all subjects should be prophylactically treated with aspirin at a dose of 100 to 150 mg
PO daily. Subjects at increased risk of thromboembolic events (based on their medical
history) should be treated with enoxaparin at a dose of 40 mg subcutaneously daily
(or other low molecular heparin with equivalent dose and frequency for prophylaxis
indication). The injection should be handled according to local practice.
Rationale: Clarification of the use of bisphosphonate after Cycle 1
8.1.2 Bisphosphonate 
Therapy  
After Cycle 1, investigators should not prescribe bisphosphonates to subjects who
have not received it before, unless it has been discussed with sponsor and there is
no sign of disease progression.
Rationale: Modification of the dexamethasone dose in both treatment arms and provides guidance on management
of missed doses.
Synopsis: Dosage and 
Administration 
6.3 Dexamethasone 
(Arm A and Arm B) 
Added sentence:
If a weekly dexamethasone dose is missed, it may be taken if <4 days have
elapsed since the time that it should have been taken.  If the next dose is
scheduled to be taken within 3 days, the missed dexamethasone dose should be
skipped.
Rationale: Allows for flexibility in scheduling
6 Dosage and 
Administration; 
9.1.3 Treatment Phase 
Inserted following sentence in 1st paragraph:
In Cycles 1 through 6, weekly or bi-weekly daratumumab infusions may be given
within ±1 day of the scheduled day in order to accommodate the schedule of the
site or subject. In all cycles, weekly dexamethasone doses may be given within ±1
day of the scheduled day in order to accommodate the schedule of the site or
subject. Changes to within-cycle dosing should not impact Day 1 of the next
cycle.
Also inserted new Figure 4: Schematic Overview Study Treatment
Administration in Section 6
Rationale: Clarification of bone marrow examination requirements. Clinical staging must be done locally; no
option for this to be done centrally.
9.2.1.5 Bone Marrow 
Examination  
Bone marrow aspirate or biopsy will be performed at Screening for clinical
characterization (morphology, IHC or immunofluorescence or 2- to 4- color flow
cytometry, and cytogenetics), to establish baseline multiple myeloma clonality to
monitor for MRD and to perform molecular subtyping to monitor daratumumab
activity in high-risk molecular subgroups. Good quality slides are required for
morphological examination to determine plasma cell percentage in the bone marrow.
Assessment by flow cytometry alone is not sufficient. Bone marrow examination
for disease assessment Clinical staging may will be performed locally; however, a
portion of the bone marrow aspirate must be sent to the central laboratory for
analysis of MRD and molecular subtyping. A fresh bone marrow aspirate at screening
is required if at all possible, by exception non-decalcified diagnostic tissue (bone
marrow aspirate slides or FFPE tissue) may be supplied for MRD assessment instead. 
Additional bone marrow aspirates or biopsies (or both) will be performed to confirm
sCR, CR, or relapse from CR (only one analysis is required, with either IHC or
immunofluorescence or 2- to 4- color flow cytometry included in the analysis) and
to monitor for MRD. An additional bone marrow aspirate will be obtained 6, 12, and
18 months +/- 1 month after the achievement of CR to monitor for MRD. If feasible,
a bone marrow aspirate may be collected from subjects at disease progression to
evaluate mechanisms of daratumumab resistance.
Inserted Table 9. Bone Marrow Testing
Rationale: Description of Daratumumab interference with Indirect Antiglobulin Test (IAT) results.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
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Applicable Section(s) 
Description of Change(s)
9.8 Safety Evaluations 
Inserted the following:
Daratumumab Interference with Indirect Antiglobulin Test (IAT) results:
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a
routine pre-transfusion  test  performed  to identify a patient’s antibodies to
minor antigens so that suitable donor blood can be given for transfusion.
Daratumumab does not interfere with ABO/RhD typing.  CD38 is expressed at
very low levels on erythrocytes.  Daratumumab binds to the CD38 on
erythrocytes, which results in a positive IAT (Indirect Coombs Test).   This
positive result masks the detection of antibodies to minor antigens and may
prevent or delay blood banks from issuing donor blood for transfusion.  This
effect occurs during daratumumab treatment and for up to 6 months after
treatment ends.  Subjects will receive a patient identification wallet card for the
study that includes the blood profile (ABO, Rh, and IAT) determined before the
first infusion of daratumumab along with information on the IAT interference
for healthcare providers/blood banks.  Subjects are to carry this card
throughout the treatment period and for at least 6 months after treatment ends. 
Blood banks can eliminate the daratumumab IAT interference by treating
reagent RBCs with dithiothreitol (DTT) (Chapuy 2015).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects
receiving daratumumab include:
a)    Providing ABO/RhD compatible, phenotypically or genotypically matched units
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying
alloantibodies using dithiothreitol (DTT)-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if
transfusion is needed emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically
significant hemolysis has been observed in daratumumab studies. For additional
details, refer to the Daratumumab IB. Blood type assessment
CD38 is expressed on erythrocytes to a minor extent. Hemolysis could occur
following the infusion of daratumumab, which would confound the blood type
assessment. To be cautious and in case of urgent need for blood transfusion, the
subject’s blood type, including minor group, will be assessed before the first infusion
of daratumumab. Subjects in Arm B should at all times carry a card with their blood
type during the study.
Rationale: Inserted information per Irish Regulatory request
12.1.1 Adverse Event 
Definitions and 
Classifications 
12.3.3 Suspected 
Unexpected Serious
Adverse Reactions 
Inserted:
Suspected Unexpected Serious Adverse Reactions (SUSARs)
If a serious and unexpected adverse event occurs for which there is evidence
suggesting a causal relationship between the study treatment and the event (eg,
death from anaphylaxis), the event must be reported as a serious and unexpected
suspected adverse reaction even if it is a component of the study endpoint (eg,
all-cause mortality).  Refer to Section 12.3.3 for SUSAR Reporting
Requirements.
If a serious and unexpected adverse event occurs for which there is evidence
suggesting a causal relationship between the study treatment and the event (eg, death
from anaphylaxis), the event must be reported as a serious and unexpected suspected
adverse reaction even if it is a component of the study endpoint (eg, all cause
mortality).
Added Section. The sponsor assumes responsibility for appropriate reporting of
all Suspected Unexpected Serious Adverse Reactions (SUSAR) [serious adverse
events that are unlisted (unexpected) and associated with the use of the study
drug] to the regulatory authorities in accordance with GCP. The sponsor will
also report to the investigator (and the head of the investigational institute where
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JNJ-54767414  (daratumumab)
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
required) all serious adverse events that are unlisted (unexpected) and associated
with the use of the study drug. The investigator (or sponsor where required)
must report these events to the appropriate Independent Ethics
Committee/Institutional Review Board (IEC/IRB) that approved the protocol
unless otherwise required and documented by the IEC/IRB.
Rationale: Attachment 1 was updated to be consistent with other Daratumumab protocols
Attachment 1: Modified 
IMWG Diagnostic
Criteria for Multiple
Myeloma
Entire attachment updated to be consistent with other Daratumumab protocols
Rationale: Added for convenience by clinical operations (logistical purposes)
Time and Events 
Schedule, Overview: 
Blood sample for MRD
For subjects who maintain CR, whole blood sample will also be obtained at 6, 12, and
18 months ± 1 month after confirmed CR.
Rationale: Clarification of disease evaluation testing in Screening Phase
Time and Events 
Schedule, Overview: 
Added clarification on serum and urine disease evaluation at Screening in the Disease
Evaluation section:
Serum disease evaluations (SPEP):    X (Repeat on C1D1 if not within 14 days prior to
C1D1)
Urine disease evaluations (UPEP):      X (Repeat on C1D1 if not within 14 days prior to
C1D1)
Calcium, albumin, β2-microglobulin:  X (Repeat calcium and albumin on C1D1 if not
within 14 days  prior to C1D1); don’t repeat β2-microglobulin
Rationale: Miscellaneous updates for clarity.
Time and Events 
Schedule, Dose
Administration
Removed the requirement to measure vital signs 2 hours after the end of infusion.
6.1.3.1 Preinfusion 
Medication 
Change to bullet 3: An equivalent intermediate-acting or long-acting corticosteroid
may substitute (see Attachment 6 for conversion table).
6.1.3.2 Postinfusion 
Medication 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2
adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators
such as tiotropium or salbumatol salmeterol ± inhaled corticosteroids for subjects
with COPD)
8.3 Prohibited Therapies Concomitant administration of any other antineoplastic therapy for the intention of
treating multiple myeloma and other cancers not defined in the study protocol is
prohibited.
Nonsteroidal anti-inflammatory agents should be used with caution in order to
prevent myeloma-related kidney disease.
9.2.1.8 Documentation 
of Extramedullary 
Plasmacytomas 
To qualify for PR, the sum of products of the perpendicular diameters of the existing
extramedullary plasmacytomas must have decreased by at least 50% or 25%,
respectively, and new plasmacytomas must not have developed (see the disease
response criteria in Table 8).
9.5 Biomarkers 
Biomarker assessments will focus on 2 main objectives including evaluating the
ability of daratumumab + Rd to reduce MRD in subjects who achieve a complete
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JNJ-54767414  (daratumumab)
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Applicable Section(s) 
Description of Change(s)
response (compared to Rd alone) and to determine the clinical benefit (ORR, PFS,
and OS) of daratumumab + Rd in high-risk molecular subtypes (del17p, t(4;14),
t(14;16), specific gene signatures, specific mutations).
Attachment 3: 
Calculated and
Measured Creatinine
Clearance
5 Treatment Allocation 
and Blinding 
6.1.3.1 Preinfusion
Medication 
Added the formula to measure CrCL to the attachment:
Eligible subjects will be stratified by International Staging System (I vs II vs III
see Attachment 8), region (North America vs Other), and age (<75 vs ≥75) and then
randomized to treatment in a 1:1 ratio to either Treatment Arm A (Rd alone) or
Treatment Arm B (daratumumab+Rd [DRd]). A new Attachment 8 was added.
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid
IV use of promethazine) approximately 1 hour prior to infusion (see Attachment
9) for list of antihistamines that may be used). Added Attachment 9.
9.2.2 Endpoints, 
Secondary Endpoints 
12.3.1 All Adverse
Events
 
Endpoints Overall response rate (ORR), defined as the proportion of subjects who
achieve PR or better, according to the IMWG criteria, during or after the study
treatment.
 
Duration of response, calculated from the date of initial documentation of a
response (PR or better) to the date of first documented evidence of progressive
disease, as defined in the IMWG criteria. For subjects who have not progressed,
data will be censored at the last disease evaluation before the start of any
subsequent anti-myeloma therapy.
Subjects (or their designees, if appropriate) will be provided with a "wallet (study)
card" and instructed to carry this card with them for the duration of the study and for
at least 6 months after treatment ends indicating the following: ---
Rationale: Hydrocortisone is not an adequate substitute for a glucocorticosteroid as it is a short acting
corticosteroid. Per request of Swedish HA, hydrocortisone has been replaced with betamethasone as an
acceptable substitute for pre-medication with dexamethasone, due to the short duration of action of
hydrocortisone.  Attachment 6 is modified accordingly.
Attachment 6: 
Conversion Table for 
Glucocorticosteroid 
Dose 
Removed hydrocortisone (20 mg) because it is short-acting and therefore not an
adequate substitution.
Generic Name 
Oral or Intravenous
Dose (mg)
Dexamethasone 
0.75
Hydrocortisone 
20
Methylprednisolone 
4
Prednisolone 
5
Prednisone 
5
Betamethasone 
0.6
Rationale: Minor errors were noted.
Throughout the protocol 
Minor grammatical, formatting, abbreviations or spelling changes were made.
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Amendment INT-1 (29 October 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: To incorporate investigator feedback into the protocol and to further
clarify MRD monitoring.
Applicable Section(s) 
Description of Change(s)
Rationale: To clarify that when a subject discontinues lenalidomide/dexamethasone study treatment on Arm B,
they would still continue to receive dexamethasone as premedication. 
Synopsis, Overview of 
Study Design; 
3.1 Overview of Study 
Design;
6.3 Dexamethasone
(Arm A and Arm B)
Text was added to indicate that subjects will continue to receive dexamethasone as a
premedication for daratumumab administration even after the
lenalidomide/dexamethasone treatment is discontinued.
Rationale: To allow for a bone marrow biopsy or aspirate (or both) to confirm CR. 
Time and Events 
Schedule Overview; 
9.2.1.5 Bone Marrow 
Examination 
Additional bone marrow aspirates or biopsies (or both) will be performed to confirm
sCR, CR, or relapse from CR (IHC or immunofluorescence) and to monitor for MRD.
Only 1 bone marrow sample is required, with either IHC or immunofluorescence
included in the analysis. For subjects who maintain CR, fresh aspirate will also be
obtained at 6 and 12 months +/- 1 month after confirmed CR to monitor for MRD. A
portion of all bone marrow tissues may be used for other biomarker assessments
Rationale: To allow for the possibility of stopping treatment ≥24 months based on MRD status, an additional
time point of 18 months was added for collection of fresh aspirate and a whole blood sample after confirmed CR
to monitor MRD. 
Synopsis, Efficacy 
Evaluations/Endpoints; 
Time and Events 
Schedule Overview;
9.2.1.5 Bone Marrow
Examination;
9.2.1.6 Minimal
Residual Disease
Assessment;
9.2.2 Endpoints
Text was added to indicate that for subjects with confirmed CR, an additional bone
marrow aspirate and whole blood sample will be obtained 6, 12, and 18 months +/-
1 month to monitor for MRD.
Rationale: To indicate that bone marrow aspirate or biopsy performed at Screening for clinical staging will be
analyzed for morphology and via cytogenetics, only.
9.2.1.5 Bone Marrow 
Examination 
Bone marrow aspirate or biopsy will be performed at Screening for clinical staging
(morphology and cytogenetics, and immunohistochemistry [IHC] or
immunofluorescence or flow cytometry) to establish baseline multiple myeloma
clonality, to monitor for MRD, and to perform molecular subtyping to monitor
daratumumab activity in high-risk molecular subgroups.
Rationale: To clarify that good quality slides are required for morphological examination to determine plasma
cell percentage in the bone marrow.
9.2.1.5 Bone Marrow 
Examination 
Good quality slides are required for morphological examination to determine plasma
cells percentage in the bone marrow. Assessment by flow cytometry alone is not
sufficient
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Rationale: To include clarithromycin as a prohibited therapy because it may have potential anti-multiple
myeloma effects when combined with lenalidomide and dexamethasone.
8.3 Prohibited 
Therapies
Added clarithromycin as a prohibited therapy.
Rationale: To exclude subjects with uncontrolled cardiac arrhythmias (thereby allowing participation of subjects
with controlled cardiac arrhythmias).
4.2 Exclusion Criteria 
Subject has clinically significant cardiac disease, including:
• myocardial infarction within 1 year before randomization, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III IV
• uncontrolled cardiac arrhythmia (NCI CTCAE Version 4 Grade ≥2) or clinically
significant ECG abnormalities
• screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s
formula (QTcF) >470 msec
Rationale: To clarify that the secondary objective and secondary endpoint is to assess the MRD negative rate.
Synopsis, Secondary 
Objectives;
2.1 Objectives
To assess the MRD negative rate after treatment
Synopsis, Efficacy  
Evaluations/Endpoints; 
9.2.2 Endpoints
Assess MRD negative rate, as measured in subjects who achieve CR/sCR, at 6 and
12 months after confirmed CR.
Rationale: To align PRO and ECOG performance status evaluations with study visits.
Time and Events 
Schedule Overview  
Evaluations will be conducted on D1 of Cycle 3, 6, 9, 12 for year 1; every 6th cycle
thereafter until EOT (PD). Post-PD evaluations will be collected at Weeks 8 and 16.
Rationale: Added a PRO evaluation at Screening which will allow the PRO assessment conducted during the
study to be compared with baseline.
Time and Events 
Schedule Overview  
Added an assessment during the Screening Phase for the PROs: EORTC-QLQ-30,
EQ-5D-5L.
Rationale: To clarify that all PRO measures will be collected via an electronic device (ePRO) and the mode of
data transfer.
Time and Events 
Schedule Overview;
9.7 Patient Reported
Outcomes
All PRO measures will be collected via an electronic device (ePRO).
17.6 Data Quality 
Assurance/Quality 
Control
PRO data will be transmitted to the ePRO vendor database and then to the sponsor’s
database.
Rationale: To clarify the administration schedule of daratumumab, in particular, starting at Cycle 7 and beyond,
treatment will be every 4 weeks rather than monthly.
Synopsis, Overview of 
Study Design; 
3.1 Overview of Study 
Design  
For subjects assigned to DRd, daratumumab will be administered weekly for the first
8 weeks (Cycles 1-2) of treatment and then every other week for 16 weeks (Cycles 3-
6), then every 4 weeks (from Cycle 7 and beyond) until disease progression or
unacceptable toxicity.
NCT02252172

JNJ-54767414  (daratumumab)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Rationale: To revise the inclusion criteria to align with the other protocols in the daratumumab program.
4.1 Inclusion Criteria 
total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such as
Gilbert syndrome (direct bilirubin ≤2.0 x ULN);
corrected serum calcium ≤14 mg/dL (≤3.5 mM/L); or free ionized calcium <6.5 mg/dL
(<1.6 mM/L)
Rationale: To align the creatinine clearance calculation with the other protocols in the daratumumab program.
4.1 Inclusion Criteria 
g) Creatinine clearance ≥30 mL/min (for lenalidomide dose adjustment for subjects
with creatinine clearance 30-60 mL/min, refer to Section 6.2). Creatinine clearance
may be calculated using the Cockcroft-Gault formula provided in Attachment 3
Attachment 3 
Added the Cockcroft-Gault formula for Calculated Creatinine Clearance.
Rationale: To align the criteria for a dose delay with the other protocols in the daratumumab program.
6.4.1.1 Daratumumab- 
Related Toxicity
Management
Grade 4 thrombocytopenia was added to the criteria for a dose delay.
Rationale: To further clarify procedures not considered to be major surgeries.
4.2 Exclusion Criteria 
Included vertebroplasty as a procedure that is not considered to be a major surgery.
Rationale: To specify the timing of lenalidomide administration and to align with other protocols in the
daratumumab program.
6.2 Lenalidomide 
(Arm A and Arm B) 
On daratumumab infusion days, lenalidomide will be administered at the same time as
the premedications. The daratumumab infusion should begin approximately 1 hour
after the lenalidomide administration.
Rationale: Fixed typographical errors whereby the sample size remained the same, but the assumptions were
corrected.
Synopsis, Statistical 
Methods; 
11.2 Sample Size 
Determination  
The sample size calculation is performed on the basis of the following assumption.
Based on the published data, the median PFS for Rd arm is assumed to be
approximately 24 6 months. Assuming that DRd can reduce the risk of the disease
progression or death by 25%, ie, assuming the hazard ratio (DRd vs Rd) of 0.75 0.724,
a total of 390 PFS events is needed to achieve a power of 80% 85% to detect this
hazard ratio with a log-rank test (two-sided alpha is 0.05). With a 21-month accrual
period and an additional 24-month follow-up, the total sample size needed for the study
is approximately 730 (365/arm) subjects. The sample size calculation has taken into
consideration an annual dropout rate of 5%.
Rationale: Because dexamethasone in IV formulation is not available in some countries, the PO administration
of dexamethasone is permitted (only when IV is not available).
Time and Events 
Schedule, Dose
Administration;
6.1.3.1 Preinfusion
Medication
Dexamethasone 40 mg IV or PO (only if IV is not available)
Rationale: To make the administration of drug medication more convenient for patients.
6.2 Lenalidomide 
(Arm A and Arm B) 
On daratumumab infusion days, lenalidomide will be administered either prior to or at
the same time (preferred) as the premedications.
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JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Approved, Date: 20 July 2021
Applicable Section(s) 
Description of Change(s)
Rationale: To align with other protocols in the daratumumab program.
14.4 Preparation, 
Handling, and Storage 
Clarified that daratumumab must be protected from light.
Clarified that daratumumab infusion solution prepared for administration does not need
to be stored in a refrigerator.
Clarified that the daratumumab infusion solution does not need to be kept at room
temperature for approximately 1 hour before the start of infusion and that the infusion
does not have to be completed within 24 hours of preparation.
Added that daratumumab will be diluted in a sterile, pyrogen-free physiological saline
solution (0.9%NaCl) prior to IV administration.
Included that additional guidance can be found in the Investigational Product
Preparation Instructions and Investigational Product Procedures Manual.
6.1.3.1 Preinfusion 
Medication 
Preinfusion medications for subjects receiving daratumumab will be administered as
described in the Time and Events Schedules. On daratumumab infusion days, subjects
will receive the following medications prior to infusion:
• Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1
hour or less prior to daratumumab infusion
• An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent)
approximately 12 hours prior and again approximately 1 hour prior to infusion on
Cycle 1 Day 1, for all subsequent infusions approximately 1 hour prior
• Dexamethasone 40 mg IV or PO, approximately1 hour or less prior to
daratumumab infusion. Dexamethasone 20 mg may be administered as appropriate [see
Section 6.3]. An equivalent long-acting corticosteroid may substitute [see Attachment 6
for conversion table]. On days when subjects receive this dose of dexamethasone in the
clinic, dexamethasone will not be self-administered at home.
Rationale: Miscellaneous grammatical, formatting, or spelling changes were made for consistency and
clarification.
Time and Events 
Schedule, Dose 
Administration; 
6.1.3.1 Preinfusion 
Medication 
For consistency with other parts of the protocol, added the below bolded text and
removed the text in strikeout.
Administer approximately 1 hour before daratumumab infusion.
• Dexamethasone 40 mg IV or PO (only if IV is not available). For subjects older
than 75 years or underweight (BMI <18.5), see Section 6.3. Substitutions for
dexamethasone allowed, see Attachment 6.
• An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent) on C1D1
administer 12 hours before infusion and again 1 hr before infusion
• Acetaminophen (paracetamol) 650-1000 mg IV or PO
Synopsis, Overview of 
Study Design; 
3.1 Overview of Study
Design;
5 Treatment Allocation
Amended the stratification factor wording to “International Scoring Staging System” to
be consistent with the proper nomenclature.
6.4.1.1 Daratumumab- 
Related Toxicity 
Management 
To emphasize the criteria when to stop daratumumab, bolded and underlined the
following sentence: ONLY if any of the following criteria are met, and the event
cannot be ascribed to lenalidomide, the daratumumab infusion must be held to
allow for recovery from toxicity.
Clarified that any adverse event deemed to be related to daratumumab and unrelated to
lenalidomide that requires a dose hold of more than 4 weeks will result in permanent
discontinuation of daratumumab.
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Applicable Section(s) 
Description of Change(s)
Time and Events 
Schedule Overview  
Clarified that both PRO questionnaires and ECOG performance status must be
administered and completed prior to any other study procedures or assessments for that
study visit.
Clarified that β2-microglobulin will be evaluated at screening only.
Clarified that EOT is part of the Treatment Phase of the study.
4.2 Exclusion Criteria 
Removed intolerance to lenalidomide from exclusion criteria 12 because subjects in
this study are newly diagnosed multiple myeloma patients and have never been
exposed to lenalidomide.
Synopsis, Overview of 
Study Design;
Time and Events
Schedule, Dose
Administration;
3.1 Overview of Study
Design;
6.1.3.1 Preinfusion
Medication
Provided the generic name for paracetamol (acetaminophen), as this is a global study
14.2 Physical 
Description of Study 
Drug
Clarified that the daratumumab supplied for this study is a colorless to slightly yellow
liquid and sterile concentrate of 20 mg/mL in a vial.
1.1.3 Transplant- 
ineligible Population; 
1.3 Lenalidomide; 
3.2 Study Design
Rationale
Updated the reference to the Frontline Investigation of Revlimid and Dexamethasone
versus Standard Thalidomide (FIRST) study (previously referred to in protocol as
MM-020 study), with citation to the recently published NEJM publication.
Synopsis, Overview of 
Study Design; 
Time and Events
Schedule, Dose
Administration;
3.1 Overview of Study
Design;
3.2 Study Design
Rationale;
6.2 6.2 Lenalidomide
(Arm A and Arm B);
6.3 Dexamethasone
(Arm A and Arm B)
To be consistent throughout the protocol, text was added that treatment would continue
until disease progression or unacceptable toxicity. 
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide
and Dexamethasone (Rd) in Subjects with Previously Untreated Multiple Myeloma who are Ineligible for
High Dose Therapy
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor
cells that express high levels of CD38, such as plasma cells from patients with multiple myeloma. This
target is distinct from those of other approved agents for multiple myeloma therapy.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to compare the efficacy of daratumumab when combined with lenalidomide and
dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free
survival (PFS) in subjects with newly diagnosed myeloma who are not candidates for high dose
chemotherapy and autologous stem cell transplant.
Secondary Objectives
The secondary objectives are:
 
To evaluate clinical outcomes including:
 
Time to disease progression (TTP)
 
CR rate
 
MRD negativity rate
 
PFS2 (defined as time from randomization to progression on the next line of therapy or death,
whichever comes first)
 
Overall survival
 
Time to next treatment
 
Stringent CR (sCR) rate
 
Overall response rate (partial response [PR] or better)
 
Proportion of subjects who achieve very good partial response (VGPR) or better
 
Time to response
 
Duration of response
 
To assess the safety and tolerability of daratumumab when administered in combination with Rd.
 
To assess the pharmacokinetics of daratumumab in combination with Rd.
 
To assess the immunogenicity of daratumumab in Arm B subjects and the immunogenicity of
rHuPH20 in subjects receiving daratumumab SC.
 
To evaluate treatment effects on patient reported outcomes and heath economic/resource utilization
 
To evaluate the clinical efficacy of daratumumab combination with Rd in high-risk molecular
subgroups
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Exploratory Objectives
 
To explore biomarkers predictive of response or resistance to therapy
 
To assess durability of MRD negativity
Hypothesis
The primary hypothesis of this study is that daratumumab in combination with Rd will prolong PFS as
compared with Rd alone in subjects with newly diagnosed multiple myeloma who are ineligible for high
dose chemotherapy and autologous stem cell transplant.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, active controlled, parallel-group, multicenter study in subjects at least
18 years of age with newly diagnosed multiple myeloma who are not candidates for high dose
chemotherapy and ASCT. Approximately 730 subjects will be enrolled in this study with 365 subjects
planned per treatment arm.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. The
Screening Phase will be up to 21 days before Cycle 1, Day 1.  The Treatment Phase will extend from Day 1
of Cycle 1 until discontinuation of all study treatment. For subjects assigned to DRd, daratumumab will be
administered weekly for the first 8 weeks (Cycles 1-2) of treatment and then every other week for 16 weeks
(Cycles 3-6), then every 4 weeks (from Cycle 7 and beyond) until disease progression or unacceptable
toxicity. This will equate to 9 consecutive weeks of dosing at the start of the study and a total of 23 doses
in the first year. Lenalidomide will be administered at a dose of 25 mg orally (PO) on Days 1 through 21
of each 28-day cycle, and dexamethasone will be administered at a dose of 40 mg once a week. Subjects in
both treatment arms will continue lenalidomide and dexamethasone until disease progression or
unacceptable toxicity. Subjects in the DRd arm will continue on daratumumab until disease progression or
unacceptable toxicity. Randomization will be stratified by International Staging System (I vs II vs III),
region (North America vs Other), and age (<75 vs ≥75), using an equal allocation ratio of 1:1.
Measures to prevent infusion-related reactions will include pre-dose medication with dexamethasone,
acetaminophen (paracetamol), and an antihistamine before each daratumumab administration.
All subjects randomized to Treatment Arm B in this study initially received daratumumab IV formulation;
however, following implementation of protocol amendment 8, subjects still receiving treatment with
daratumumab IV will have the option to switch to daratumumab SC on Day 1 of any cycle, at the discretion
of the investigator. Subjects with a known allergy/intolerance to any of the components of the SC
formulation, including sorbitol, will not be eligible to switch to daratumumab SC. Note: throughout this
document, text has been added to highlight any differences between daratumumab IV and daratumumab
SC dosing, and where there is no clarification, it is implied that the descriptions are the same for
daratumumab IV and daratumumab SC.
The Follow-up Phase will begin once a subject discontinues all study treatments. Subjects who discontinue
study treatment for reasons other than disease progression must continue to have disease evaluations
according to the Time and Events Schedule until confirmed disease progression (PD) (see Section 8.4,
Subsequent Therapies). After PD is documented, follow-up will be obtained at least every 16 weeks.
Subsequent anti-myeloma therapy, PFS2 (per investigator judgment), second primary malignancies, and
survival will be recorded. The Follow-up Phase will continue until death, lost to follow up, consent
withdrawal, or study end, whichever occurs first.
Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety, will be
performed after a total of approximately 100 subjects have been treated for at least 8 weeks or discontinued
the study treatment. The second interim analysis will be performed when 234 PFS events, which are 60%
of the total planned events, have been accumulated. The purpose of this interim analysis is to evaluate
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cumulative interim safety and efficacy data. The significance level at this interim analysis to establish the
superiority of DRd over Rd with regard to PFS will be determined based on the observed number of PFS
events at the interim analysis, using the O’Brien-Fleming boundaries as implemented by the Lan-DeMets
alpha spending method. If the experimental arm (DRd) is numerically worse than the control arm in terms
of PFS (observed hazard ratio >1 favoring the control arm), then the study may be terminated for futility.
As the superiority of DRd over Rd alone with respect to PFS was established at the second interim analysis,
the interim PFS analysis will serve as the primary PFS analysis, which otherwise was to occur when
approximately 390 PFS events had been observed. The first interim OS analysis was performed at the
interim PFS analysis. The second interim OS analysis occurred when 273 deaths had occurred and
demonstrated superiority of DRd over Rd alone for OS. The median OS was not reached.
The date established for the primary PFS analysis (24 September 2018) will serve as the clinical cut-off
date, after which subject monitoring in the study will be conducted as per Section 9.1.5. After the second
interim OS analysis (19 February 2021) subject monitoring will be conducted according to Section 9.1.7.
Following the positive second interim OS analysis that established the superiority of DRd over Rd alone
for OS, the final CSR  analysis will be performed approximately 5 years after the last subject was
randomized. The final CSR analysis will provide updates to the primary CSR analysis for both efficacy and
safety. The sponsor will communicate the clinical cut-off date for the final CSR analysis to sites. At the
time of this clinical cut-off, the study will transition to long-term survival follow-up.
The clinical cut-off of the final OS analysis will occur when approximately 390 deaths have occurred. No
additional eCRF data will be collected after the final OS analysis. Data collected up to this timepoint will
be included in the final OS analysis and reported in a separate addendum to the clinical study report.
The sponsor will ensure that subjects who are benefiting from treatment with daratumumab can continue to
receive daratumumab after the final OS analysis through end of study. For these subjects, treatment with
daratumumab will be available through continued access within the current study until it is available
through another source such as commercial availability, continued access through a long-term extension
study, a patient access program, when all subjects have discontinued daratumumab treatment, or until
31 January 2026, whichever occurs first.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to review
efficacy and safety results at the planned interim analyses. After the interim review, they will make
recommendations regarding the continuation of the study. In addition, the IDMC may also review
cumulative safety data every 6 months besides the 2 interim analyses. The IDMC will no longer review
study data after the interim PFS analysis has been completed.
Assessment of tumor response and disease progression will be conducted in accordance with the
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be
conducted on bone marrow samples. Safety evaluations will include adverse event monitoring, physical
examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology and
chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance
status. Blood samples will be drawn for assessment of pharmacokinetic parameters.
Following the positive second interim analysis that established the superiority of DRd over Rd alone with
respect to the primary endpoint (PFS), the sponsor will provide access to daratumumab for subjects
randomized to Arm A (Rd) who have sponsor-confirmed disease progression (see Section 8.4, Subsequent
Therapies), if recommended by the investigator. After the cut-off for the final CSR, sponsor confirmation
of PD is no longer required and will be based on investigator assessment of PD.
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SUBJECT POPULATION
Key eligibility criteria include the following: subjects who are 18 years of age, have a confirmed diagnosis
of symptomatic multiple myeloma and measurable secretory disease, an ECOG performance status score
of 0, 1, or 2, must be newly diagnosed and not considered candidates for high-dose chemotherapy with stem
cell transplantation (SCT).
DOSAGE AND ADMINISTRATION
Daratumumab IV (16 mg/kg) or daratumumab SC (1800 mg fixed dose) will be administered to subjects
assigned to Arm B initially once every week for 8 weeks; then once every other week for 16 weeks;
thereafter once every 4 weeks until documented progression, unacceptable toxicity, or study end.
Lenalidomide will be self-administered at a dose of 25 mg PO each day on Days 1 through 21 of each
28-day cycle.
Dexamethasone (or equivalent in accordance with local standards; see Attachment 6 for conversion table)
will be administered at a total dose of 40 mg weekly.
EFFICACY EVALUATIONS/ENDPOINTS
Disease evaluations must be performed every 28 days for the first 2 years and then every 8 weeks until
disease progression (or other reasons as per Section 10). A window of ±7 days is allowed. If treatment has
been delayed for any reason, the disease evaluations must be performed according to schedule, regardless
of any changes to the dosing regimen.
The primary endpoint is PFS, which is defined as the duration from the date of randomization to either
progressive disease, or death, whichever occurs first. Disease progression will be determined according to
the IMWG criteria.
The secondary efficacy endpoints include:
 
Time to disease progression (TTP) is defined as the time from the date of randomization to the date of
first documented evidence of PD, as defined in the IMWG criteria. For subjects who have not
progressed, data will be censored at the date of the disease evaluation before the start of any subsequent
anti-myeloma therapy.
 
CR rate, defined as the percentage of subjects achieving CR, as defined:
 
Negative immunofixation of serum and urine, and
 
Disappearance of any soft tissue plasmacytomas, and
 
<5% plasma cells (PCs) in bone marrow
 
For those subjects with negative serum M-protein quantitation by electrophoresis (SPEP) and
suspected daratumumab interference on immunofixation, a reflex assay using anti-idiotype
antibody will be utilized to confirm daratumumab interference and rule out false positive
immunofixation. Patients who have confirmed daratumumab interference, but meet all other
clinical criteria for CR or sCR, will be considered CR/sCR.
 
MRD negativity rate, defined as the proportion of subjects assessed as MRD negative, at any timepoint
after the date of randomization.
 
Progression-free Survival on Next line of Therapy (PFS2), defined as the time from randomization to
progression on the next line of treatment or death, whichever comes first. Disease progression will be
based on investigator judgment. For those subjects who are still alive and not yet progressed on the
next line of treatment, they will be censored on the last date of follow-up.
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 
Overall survival (OS), measured from the date of randomization to the date of the subject’s death. If
the subject is alive or the vital status is unknown, then the subject’s data will be censored at the date
the subject was last known to be alive.
 
Time to next treatment, defined as the time from randomization to the start of the next-line treatment.
 
sCR rate, defined as the percentage of subjects achieving CR in addition to having a normal free light
chain (FLC) ratio and an absence of clonal cells in bone marrow by immunohistochemistry,
immunofluorescence, 2-4 color flow cytometry
 
Overall response rate (ORR), defined as the proportion of subjects who achieve PRor better, according
to the IMWG criteria, during or after the study treatment.
 
Proportion of subjects who achieve VGPR or better, defined as the proportion of subjects achieving
VGPR and CR (including sCR) according to the IMWG criteria during or after the study treatment at
the time of data cut-off.
 
Time to response, defined as the time between the randomization and the first efficacy evaluation that
the subject has met all criteria for PR or better. For subjects without response, data will be censored
either at the date of progressive disease or, in the absence of progressive disease, at the last disease
evaluation before the start of subsequent anti-myeloma therapy.
 
Duration of response, calculated from the date of initial documentation of a response (PR or better) to
the date of first documented evidence of progressive disease, as defined in the IMWG criteria. For
subjects who have not progressed, data will be censored at the last disease evaluation before the start
of any subsequent anti-myeloma therapy.
 
To evaluate clinical efficacy of DRd in high risk molecular subgroups compared to Rd alone.
 
To evaluate the impact of DRd compared to Rd on patient-reported perception of global health.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the generation of
antibodies to daratumumab and rHuPH20 (immunogenicity) will be obtained in the D-Rd group according
to the Time and Events Schedule. Following amendment 8, subjects in Treatment Arm B who continue to
receive daratumumab IV no longer require pharmacokinetic and immunogenicity sampling, however
subjects in Treatment Arm B who switch to daratumumab SC will require pharmacokinetic and
immunogenicity samples as specified in the Time and Events Schedule.
BIOMARKER EVALUATIONS
Bone marrow aspirates will be collected at screening and following treatment as outlined in the Time and
Events Schedule.  Baseline bone marrow aspirate samples will be subjected to DNA and RNA sequencing
in order to classify subjects into high-risk molecular subgroups and to establish the myeloma clone for
MRD monitoring.
In addition to planned bone marrow aspirate assessments, a whole blood sample will be collected from
subjects as outlined in the Time and Events Schedule for processing to plasma and PBMCs.
SAFETY EVALUATIONS
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign measurements, physical
examination findings, and assessment of ECOG performance status score.
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STATISTICAL METHODS
The sample size calculation is performed on the basis of the following assumption. Based on the published
data, the median PFS for Rd arm is assumed to be approximately 24 months. Assuming that DRd can reduce
the risk of the disease progression or death by 25%, ie, assuming the hazard ratio (DRd vs Rd) of 0.75, a
total of 390 PFS events is needed to achieve a power of 80% to detect this hazard ratio with a log-rank test
(two-sided alpha is 0.05). With a 21-month accrual period and an additional 24-month follow-up, the total
sample size needed for the study is approximately 730 (365/arm) subjects. The sample size calculation has
taken into consideration an annual dropout rate of 5%.
Long-term survival follow-up was originally planned to continue until 330 deaths had been observed or
7 years after the last subject was randomized. Therefore, this study would achieve approximately 80%
power to detect a 27% reduction in the risk of death (hazard ratio = 0.73) with a log-rank test (two-sided
alpha = 0.05). However, after reaching the statistical significance at the second interim OS, the long-term
survival follow-up will be extended to approximately 390 deaths when the median survival for the DRd
group has likely been reached.
Response to study treatment and progressive disease will be evaluated by a computer algorithm. For the
primary endpoint of PFS, the primary analysis will consist of a stratified log rank test for the comparison
of the PFS distribution between the 2 treatment arms. The Kaplan-Meier method will be used to estimate
the distribution of overall PFS for each treatment. The treatment effect (hazard ratio) and its two-sided 95%
confidence intervals are to be estimated using a stratified Cox regression model with treatment as the sole
explanatory variable.
Details of the 2 planned interim analyses are provided in the Synopsis, Overview of Study Design. After
each interim review, the IDMC will make recommendations regarding the continuation of the study. The
IDMC will no longer review study data after the interim PFS analysis has been completed.
As the superiority of daratumumab combined with Rd over Rd alone with respect to PFS was established
at the second interim analysis, the interim PFS analysis will serve as the primary PFS analysis, which
otherwise was to occur when approximately 390 PFS events had been observed.
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Notes 
Screening
Phase 
Treatment Phase 
Follow-up Phase
within 21 
days before 
randomization 
Day 1 of each cycle (28-day cycles) 
EOT
within 30 
days of 
last dose 
Prior to 
PD  
After PD
(Q16wks)
±2 wks
Abbreviations for Time and Events Tables:
AE=adverse event; Anti-HBc=antibodies to hepatitis B core antigen; Anti-HBs=antibodies to hepatitis B surface antigen; BMI=body mass index; C=cycle; COPD=chronic obstructive
pulmonary disease; CR=complete response; ECOG=Eastern Cooperative Oncology Group; D=day; Dara=daratumumab; DRd=daratumumab with lenalidomide plus low-dose
dexamethasone; ECG=electrocardiogram; EOT= End-of-Treatment; ePRO= electronic patient reported outcomes; FEV1= Forced Expiratory Volume (in 1 second); FFPE=formalin-
fixed paraffin embedded; FLC=free light chain; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; IAT= indirect antiglobulin test; ICF=informed consent form;
IFE=immunofixation; Ig=immunoglobulin; IV= intravenous; MRD=minimal residual disease; MRI=magnetic resonance imaging; MRU=medical resource utilization; OS=overall survival;
PBMC= peripheral blood mononuclear cell; PFT=pulmonary function test; PFS2= time from randomization to progression on the next line of therapy or death, whichever comes first;
PK=pharmacokinetics; PD= disease progression; PO= per oral; PRO=patient reported outcomes; Q(3)(6)mo=every (3)(6) months; Q16wk=every 16 weeks; SAE=serious adverse
event; sCR=stringent complete response; SIPPM= Site Investigational Product Procedures Manual (or equivalent document); SPEP=serum M-protein quantitation by electrophoresis;
UPEP=urine M-protein quantitation by electrophoresis;  Wk=week
aTreatment Arm B –Daratumumab pharmacokinetic and anti-daratumumab antibody sampling at EOT and 8 weeks after the last daratumumab SC dose are required for subjects who
switch from daratumumab IV to daratumumab SC treatment. After amendment 8 is implemented, daratumumab pharmacokinetic and anti-daratumumab antibody sampling at EOT and
8 weeks after the last daratumumab IV dose are NOT required for subjects who remain on daratumumab IV treatment.
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ABBREVIATIONS
ADCC  
antibody-dependent cell-mediated cytotoxicity
ADCP  
antibody-dependent cellular phagocytosis
ALT  
alanine aminotransferase
Anti-HBc 
antibodies to hepatitis B core antigen
Anti-HBs 
antibodies to hepatitis B surface antigen
ASCT  
autologous stem cell transplantation
AST  
aspartate aminotransferase
BMI 
body mass index
BUN  
blood urea nitrogen
CDC  
complement-dependent cytotoxicity
CL 
total systemic clearance
Cmax  
maximum observed concentration
Cmin  
minimum observed concentration
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CRAB  
calcium elevation, renal insufficiency, anemia and bone abnormalities
CrCl 
creatinine clearance
CT  
computed tomography
DLT  
dose limiting toxicity
DMC  
Data Monitoring Committee
DRd 
daratumumab with lenalidomide plus low-dose dexamethasone
DTT  
Dithiothreitol
ECG  
Electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EOT  
end of treatment
ePRO  
electronic patient-reported outcome(s)
EU  
European Union
FCBP  
females of childbearing potential
FEV  
forced expiratory volume
FFPE 
formalin fixed paraffin embedded
FISH  
fluorescence in situ hybridization
FLC  
free light chain
FOIA  
Freedom of Information Act
GCP  
Good Clinical Practice
G-CSF  
granulocyte colony stimulating factor
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HIV  
human immunodeficiency virus
HR  
hazard ratio
IAT  
indirect antiglobulin testing
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IFE 
Immunofixation
Ig 
Immunoglobulin
IHC  
immunohistochemistry
IMiD  
immunomodulatory agent
IMWG  
International Myeloma Working Group
INR  
international normalized ratio
IPPI 
Investigational Product Preparation Instructions
IRB  
IRR  
Institutional Review Board
infusion-related reaction
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ISR  
injection-site reaction
ITT  
intent-to-treat
IUD  
intrauterine device
IV  
Intravenous
IWRS  
interactive web response system
LDH  
lactic acid dehydrogenase
LMWH  
low molecular weight heparin
mAb 
monoclonal antibody
MedDRA  
Medical Dictionary for Regulatory Activities
MP  
melphalan-prednisone
MPT  
melphalan-prednisone-thalidomide
MRD  
minimal residual disease
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
MTD  
maximum tolerated dose
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS  
next generation sequencing
NK  
natural killer
OR  
overall response
ORR  
overall response rate
OS  
overall survival
PBMC  
peripheral blood mononuclear cell
PC 
plasma cell
PCP  
pneumocystis carinii pneumonia
PD 
disease progression
PFS  
progression free survival
PFS2 
time from randomization to progression on the next line of therapy or death, whichever comes first
PI 
proteasome inhibitor
PK 
Pharmacokinetics
PO 
per oral
POEMS  
polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes syndrome
PQC  
Product Quality Complaint
PR 
partial response
PRO  
patient-reported outcome(s)
QD 
once daily
QIg 
quantitative immunoglobulins
QTcF  
QT corrected according to Fridericia's formula
RBC  
red blood cell
Rd 
lenalidomide plus low-dose dexamethasone
rHuPH20 
recombinant human hyaluronidase PH20
REMS  
Risk Evaluation and Mitigation Strategy
SAC  
Safety Assessment Committee
SAE 
serious adverse event
sCR  
stringent complete response
SCT  
stem cell transplantation
SIPPM  
Site Investigational Product Procedures Manual (or equivalent document)
SLiM  
60% Plasmacytosis, Light chains >100, MRI 1 or more focal lesion
SPEP  
serum M-protein quantitation by electrophoresis
SUSAR  
Suspected Unexpected Serious Adverse Reactions
TTP  
time to disease progression
ULN  
upper limit of normal
UPEP  
urine M-protein quantitation by electrophoresis
US  
United States
V 
volume of distribution
VD  
VELCADE-dexamethasone
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VGPR  
very good partial response
VMP  
VELCADE-melphalan-prednisone
VTD  
VELCADE-thalidomide-dexamethasone
VTE 
venous thromboembolism
WHO  
World Health Organization
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1. 
INTRODUCTION
1.1. 
Background
1.1.1. 
Multiple Myeloma
Multiple myeloma is a malignant disorder of the plasma cells, characterized by uncontrolled and
progressive proliferation of a plasma cell clone. The disease leads to progressive morbidity and
eventual mortality by lowering resistance to infection and causing significant skeletal destruction
(with bone pain, pathological fractures, and hypercalcemia), anemia, renal failure, neurological
complications and hyperviscosity syndrome.
The majority of patients with multiple myeloma produce a monoclonal protein, also called
paraprotein, M-protein or M-component, which is an immunoglobulin (Ig) or a fragment of one
that has lost its function (Kyle 2009, Palumbo 2011).18,26 Normal immunoglobulin levels are
compromised, leading to susceptibility of infections. The proliferating multiple myeloma cells
displace the normal bone marrow leading to dysfunction in normal hematopoietic tissue and
destruction of the normal bone marrow architecture, which is reflected by clinical findings such as
anemia, paraprotein in serum or urine, and bone resorption seen as diffuse osteoporosis or lytic
lesions shown in radiographs (Kyle 2003).17 Furthermore, hypercalcemia, renal insufficiency or
failure, and neurological complications are frequently seen (Palumbo 2011).26 A small minority of
patients with multiple myeloma are non-secretory.
At the time of diagnosis, multiple myeloma is a heterogeneous disease, with a course that varies
on the basis of both disease- and host-related factors (eg, age, renal function, stage, chromosomal
abnormalities). Multiple myeloma causes significant morbidity and mortality. It accounts for
approximately 1% of all malignancies and 13% of hematologic cancers. Approximately 50,000
patients per year are diagnosed with multiple myeloma in the EU and US, and 30,000 patients per
year die due to multiple myeloma (ACS 2013, Ferlay 2010).1,10
1.1.2. 
Treatment Options for Multiple Myeloma
Treatment choices for multiple myeloma vary with age, performance status, comorbidity, the
aggressiveness of the disease, and related prognostic factors (Palumbo 2011).26 Newly diagnosed
patients with multiple myeloma are typically categorized into 2 subpopulations usually defined by
their age and suitability for the subsequent approach to treatment. Younger patients will typically
receive an induction regimen followed by consolidation treatment with high-dose chemotherapy
and autologous stem cell transplantation (ASCT). For those not considered suitable for high-dose
chemotherapy and ASCT, longer-term treatment with multi-agent combinations including
alkylators, high-dose steroids, and novel agents are currently considered as standards of care.
The availability of different efficacious multi-agent regimens has provided clinicians with the
opportunity of tailoring treatment for each patient. Selection is based on patients' comorbidities
and biologic age, while at the same time, taking into account the expected toxicity profiles of each
treatment regimen (Gay 2011).11
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1.1.3. 
Transplant-ineligible Population
In general, patients over the age of 65 or with significant comorbidities are usually not considered
eligible for more intensive forms of first line therapy, and as a result the treatment approach often
favors longer, less-intensive/toxic treatments (Gay 2011).11 Treatment traditionally consists of
systemic chemotherapy, with adjunctive use of radiation or surgery in selected cases associated
with extramedullary disease (NCCN 2013, Palumbo 2009, Smith 2005).23,29,34 For many years, the
oral combination melphalan-prednisone (MP) was considered the standard of care for patients with
multiple myeloma who were not eligible for ASCT (Gay 2011).11 The advent of
immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) has led to a multiplicity of
new treatment options for newly diagnosed patients not considered suitable for transplant based
therapy.
The results of the Frontline Investigation of Revlimid and Dexamethasone versus Standard
Thalidomide (FIRST) Study were presented at the American Society of Hematology Meeting in
December 2013 (Facon 2013),9 and most recently published in The New England Journal of
Medicine (Benboubker 2014).2 In this open-label Phase 3 study, non-transplant eligible patients
with newly diagnosed myeloma were randomized to either melphalan-prednisone-thalidomide
(MPT) or lenalidomide + low-dose dexamethasone (Rd). Patients who received Rd until disease
progression had an improved outcome compared to those randomized to MPT, with a 28%
reduction in the risk of progressive disease or death (median: 25.5 months, HR 0.72; p 0.00006).
Secondary endpoints including duration of response and overall response were superior in the Rd
cohorts. The safety profile of Rd was manageable, with reduced hematologic second primary
malignancies compared with MPT. In the oral presentation at ASH 2013, the authors indicated that
overall survival for patients who received Rd until disease progression was 59.4%, based on a
preliminary survival analysis at 4 years (Facon 2013, 2014).9
1.2. 
Daratumumab
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a
unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed
towards tumor cells that express high levels of CD38, such as plasma cells from patients with
multiple myeloma. This target is distinct from those of other approved agents for multiple
myeloma therapy.
For the most comprehensive nonclinical and clinical information as well as Reference Safety
Information regarding daratumumab, refer to the latest version of the Investigator's Brochure
(Daratumumab IB).13
1.2.1. 
Nonclinical Studies
Based on preclinical data, daratumumab may utilize multiple effector cell functions, resulting in
immune mediated killing of tumor cells. In ex vivo experiments utilizing human bone marrow
stromal cells co-cultured with primary multiple myeloma cells, complement-dependent
cytotoxicity (CDC) occurs rapidly and demonstrates maximal myeloma cell killing by
daratumumab within 1 hour of antibody-mediated activation of the complement proteins
(de Weers 2011).6 Daratumumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC)
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is slower in its action, with maximal ADCC by daratumumab observed at 4 hours in vitro
(de Weers 2011).6 Daratumumab has also been shown to induce antibody-dependent cellular
phagocytosis (ADCP) in the presence of macrophages within 4 hours in vitro (Overdijk 2013).25
The precise role of some or all of these effector functions in reducing tumor burden in patients is
unknown.
In toxicology studies in cynomolgus monkeys and chimpanzees, the major observed toxicities
were cytokine release syndrome and thrombocytopenia. A minor decrease in red blood parameters
was also observed. Cytokine release was seen only following the first dose and was markedly
reduced following implementation of a 10-mg predose of daratumumab. The effect on platelets
and red blood cells was reversible.
1.2.2. 
Clinical Studies
1.2.2.1. 
Single-Agent Daratumumab Studies (GEN501 and MMY2002)
Two single-agent studies with daratumumab are ongoing (Studies GEN501 and MMY2002), as
described in Table 1.
Table 1: 
Daratumumab Single-Agent Studies GEN501 and MMY2002
Study Number 
Study Design 
Number of subjects Treated/
Treatment Regimen
GEN501 
Open label, Phase 1/2, first in human,
single agent study in subjects with
multiple myeloma whose disease is
relapsed or refractory to at least 2 prior
lines of therapies
Population was heavily treated with
prior treatment, including ASCT,
chemotherapy based regimens, IMiDs,
and PIs
Part 1
n 32 total treated with daratumumab weekly
0.005 1 mg/kg (n 17)
2 mg/kg (n 3)
4 mg/kg (n 3)
8 mg/kg (n 3)
16 mg/kg (n 3)
24 mg/kg (n 3)
Part 2
n 51 total treated
8 mg/kg (n 30) 
Weekly for 8 weeks, 
followed by q2w for an 
additional 16 weeks, and 
monthly thereafter 
16 mg/kg (n 21)
First dose, followed by a 3
week resting period,
followed by weekly doses
for 7 weeks, then q2w for an
additional 14 weeks, and
monthly thereafter
MMY2002 
Open label, multicenter, 2 stage, Phase 
2 study of daratumumab for the
treatment of subjects with multiple 
myeloma who have received at least 3 
prior lines of therapy including a PI and 
an IMiD or whose disease is double 
refractory to both a PI and an IMiD
n 34 total treated in Stage 1
8 mg/kg (n 18) 
q4w  
16 mg/kg (n 16)
qw for 8 weeks, then q2w for
another 16 weeks, and then
q4w thereafter
ASCT  autologous stem cell transplantation; IMiD immunomodulatory agent; PI proteasome inhibitor; q2w every 2 weeks;
q4w every 4 weeks
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Among the 32 subjects treated in Part 1 of Study GEN501, the maximum tolerated dose (MTD)
was not reached following intravenous (IV) infusions up to 24 mg/kg. Two subjects experienced
dose-limiting toxicities (DLTs) in the lower dose cohorts (a subject in the 0.1-mg/kg group had
Grade 3 anemia and Grade 4 thrombocytopenia, and a subject in the 1.0-mg/kg group had Grade 3
aspartate aminotransferase increased).
Among the 51 subjects treated in Part 2 of Study GEN501, serious adverse events (SAEs) were
reported in 37% of subjects (43% of subjects in the 8-mg/kg group and 29% of subjects in the
16 mg/kg-group). The most frequently reported SAEs were pneumonia (6% subjects), and pyrexia
(4% of subjects).
Among the 34 subjects treated in Stage 1 of Study MMY2002, SAEs were reported in 27% of
subjects (33% of subjects in the 8 mg/kg group, and 19% of subjects in the 16 mg/kg group). The
most frequently reported SAE was renal failure acute (6% of subjects).
1.2.2.2. 
Combination Daratumumab Studies
One study of daratumumab in combination with lenalidomide and dexamethasone
(Study GEN503), and one study of daratumumab in combination with various backbone treatment
regimens (Study MMY1001) are ongoing (Table 2).
Table 2: 
Daratumumab Combination Studies GEN503 and MMY1001
Study
Number
Study Design 
Treatment Regimen
Status/Estimated
Start Date
Number of subjects
Treated/Planned
GEN503
Open label, Phase 1/2 multicenter, dose
escalating study investigating the safety
of daratumumab in combination with
lenalidomide and dexamethasone in
subjects with relapsed or refractory
multiple myeloma
Phase 1:
2 16 mg/kg daratumumab, in
combination with lenalidomide
(25 mg daily Days 1 21 of 28
days) and dexamethasone (40 mg
weekly)
Part 1: Ongoing (n 13
subjects treated)
2 mg/kg (n 3)
4 mg/kg (n 3)
8 mg/kg (n 4)
16 mg/kg (n 3)
Phase 2:
16 mg/kg daratumumab, in
combination with lenalidomide
(25 mg daily Days 1 21 of 28
days) and dexamethasone (40 mg
weekly)
Part 2:
n 18 subjects treated
approximately 30 subjects
planned
MMY1001 
Open label, non randomized,
multicenter, Phase 1b study to evaluate
the safety, tolerability, and dose regimen
of daratumumab in combination with
various backbone treatment regimens
for multiple myeloma in either newly
diagnosed or those who have received at
least 2 prior therapies, depending on
backbone treatment regimen
Daratumumab 16 mg/kg
(initially, with possibility to de
escalate, if necessary)
The backbone regimens to be
combined with daratumumab
include VELCADE
dexamethasone (VD), VMP,
VTD, and Pom dex
n 18 subjects treated1
VTD (n 6)
VMP (n 5)
VD (n 1)
Pom dex (n 6)
approximately 80 subjects
planned
1. 
As of 21May2014
Pom dex pomalidomide dexamethasone; VD VELCADE dexamethasone; VMP VELCADE melphalan prednisone;
VTD VELCADE thalidomide dexamethasone
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Based on preliminary efficacy data, 15 of 20 efficacy evaluable subjects in Study GEN503 have
achieved a PR or better following treatment with daratumumab in combination with lenalidomide
and dexamethasone.
The safety profile observed in Study GEN503 is consistent with historical safety data for
lenalidomide and dexamethasone. Doses ranged from 2 mg/kg to 16 mg/kg daratumumab, in
combination with the approved doses of lenalidomide (25 mg daily Days 1-21 of 28 days) and
dexamethasone (40 mg weekly). No dose-limiting toxicity (DLT) drug-related safety signals have
been observed in this heavily pre-treated population of subjects with advanced multiple myeloma.
The Part 2 daratumumab dose was determined to be 16 mg/kg. Across all dose cohorts in Part 1
and in the 16 mg/kg expansion cohort for Part 2, the most frequently reported Grade 3 or higher
adverse event was neutropenia (6 subjects), which is a known toxicity of lenalidomide. Eight SAEs
have been reported. All SAEs were assessed by the investigator as not related to daratumumab.
Four subjects experienced infusion-related reactions during the first infusion of daratumumab.
These events were determined by the investigator to be related to daratumumab. In all instances,
daratumumab was interrupted temporarily and restarted without complication or further incident.
Planned Phase 3 combination studies include a Phase 3 study (MMY3003) comparing
daratumumab, lenalidomide, and dexamethasone with Rd and a Phase 3 study (MMY3004)
comparing daratumumab, VELCADE, and dexamethasone with VD. Both studies are in patients
with relapsed or refractory multiple myeloma and are planned to start in the second half of 2014.
1.2.2.3 Daratumumab Subcutaneous
A new formulation of daratumumab for subcutaneous (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 (IRRs) observed with
daratumumab IV. A recombinant human hyaluronidase PH20 (rHuPH20) was used to facilitate the
SC administration of daratumumab to decrease the volume required for SC administration.
This SC formulation of daratumumab has been evaluated in the Phase 3 Study MMY3012,
(COLUMBA), which compared efficacy, pharmacokinetics, and safety of SC vs IV daratumumab
in 522 subjects. Adults with relapsed/refractory multiple myeloma were randomized 1:1 to SC
(1800 mg; co-formulated with rHuPH20; n 263) or IV (16 mg/kg; n 259) daratumumab.
Randomization was stratified by body weight, prior therapy lines, and myeloma subtype. Primary
objectives were to demonstrate non-inferiority of SC vs. IV administration in overall response rate
(ORR; at least partial response) and maximum trough concentrations (Ctrough) (Cycle 3, Day 1).
Co-primary endpoints ORR and Ctrough  met predefined non-inferiority criteria, demonstrating that
daratumumab SC is non-inferior to IV. ORR was 41% and 37% with SC and IV daratumumab
administration, respectively (relative risk, 1.11; 95% CI, 0.89 1.37). Geometric mean ratio for
Ctrough  was 107.93% (90% CI, 95.74 121.67). Median duration of injection was 5 minutes (range
1 18) for the first, second, and subsequent SC administrations vs. 7 hours (1 14), 4.3 hours
(3-10.5), and 3.4 hour (2 7.7) for corresponding IV infusions. IRRs were reported in 13% of
patients receiving daratumumab SC versus 35% receiving daratumumab IV (odds ratio, 0.28; 95%
CI, 0.18 0.44, p<0.0001) with most occurring during the first administration. Daratumumab SC
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offers consistent safety, efficacy and exposure to standard IV administration, with shorter
administration times.
1.3. 
Lenalidomide
Lenalidomide is an immunomodulatory (IMiD) agent that is thought to mediate antimyeloma
activity by 3 main mechanisms: 1) direct antitumor effect; 2) inhibition of the microenvironment
support for tumor cells; and 3) an immunomodulatory role (Kotla 2009).15 Direct tumor effect is
described both as growth inhibition of myeloma cell lines and induction of apoptosis. The
microenvironment support is affected by downregulation of cell adhesion molecules
(eg, intercellular adhesion molecule), thus inhibiting stromal cell interaction with tumor cells, and
inhibition of growth factors (eg, insulin growth factor 1 and vascular endothelial growth factor)
induced by myeloma cell adhesion. Finally, lenalidomide exhibits immunomodulatory activity
including inhibition of proinflammatory signaling molecules (cytokines) such as tumor necrosis
factor , IL-1, and IL-6, the latter of which is a known growth factor for myeloma cells
(Vallet 2008).37
Importantly, it has also been shown that lenalidomide causes upregulation of natural killer (NK)
cells in myeloma (Kotla 2009)15 and enhances the effector cells of ADCC (Tai 2005, Tai 2008).36,35
Lenalidomide is currently approved in the US and EU for the treatment for relapsed/refractory
myeloma. However, there is accumulating evidence that lenalidomide is an effective treatment
strategy for new diagnosed patients as well. The Eastern Cooperative Oncology Group (ECOG)
published a study in which patients with newly diagnosed myeloma were randomized to either
high-dose (160 mg/week) or low-dose (40 mg/week) dexamethasone in combination with
lenalidomide (Rajkumar 2010).31 Patients randomized to the low-dose dexamethasone treatment
arm had an improved overall survival at one year (96% vs 87%). In terms of response rates, patients
in the low-dose cohort had an overall response rate (≥PR) of 68.3%. Median time to progression
was 26.1 months in the low dose group.
A large, randomized Phase 3 study (FIRST Study) compared Rd given until disease progression
(Arm A) or for eighteen 28-day cycles (Arm B) with MPT (Arm C) in subjects newly diagnosed
with multiple myeloma (Facon 2013, Benboubker 2014).9,2 Continuous treatment with Rd
(Arm A) significantly improved the primary endpoint of PFS compared with MPT (Arm C).
Secondary endpoints (overall response rate [ORR], defined as PR or better, duration of response,
and PFS2) consistently showed improvement in favor of Arm A over Arm C. The safety profile of
Rd was manageable, with reduced hematologic second primary malignancies compared with MPT. 
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REVLIMID® (lenalidomide) in combination with dexamethasone was approved by both U.S.
Food and Drug Administration and the European Commission for the treatment of adult patients
with previously untreated multiple myeloma who are not eligible for transplant, on
18 February 2015 and 20 February 2015, respectively.
1.4. 
Lenalidomide and Daratumumab
Preclinically, using bone marrow mononuclear cells from patients with multiple myeloma,
increased killing of tumor cells was demonstrated when daratumumab was combined with
lenalidomide as compared with that of either agent alone as shown in (Figure 1A)
(Van der Veer 2011a).38 Notably, daratumumab and lenalidomide acted in a synergistic fashion to
generate an extra effect (Figure 1B).
Figure 1: 
Improvement of Daratumumab-induced Antibody-dependent Cell-mediated Cytotoxicity by
Lenalidomide in Bone Marrow Mononuclear Cells from Patients with Multiple Myeloma
Key: 
DARA
daratumumab; LEN
lenalidomide; MM
multiple myeloma.
(A) Bone marrow mononuclear cells of 14 patients with multiple myeloma were incubated for 47 hours with the control antibody,
with lenalidomide (3 M), and/or daratumumab (0.1 g/mL). Surviving multiple myeloma cells were enumerated by
Fluorescence activated Cell Sorting analysis of CD138+ cells. The percentages of lysis of multiple myeloma cells treated
with lenalidomide, daratumumab, and lenalidomide + daratumumab were calculated by the Tukey’s post hoc analysis of
repeated measures analysis of variance.
(B) The observed effect (% lysis) of the combination treatment was compared with the expected additive effect (proportional) of
the combined treatments. Mixed model analysis supported the conclusion that the combination treatment was synergistic.
Finally, it was demonstrated that peripheral blood mononuclear cells isolated from patients during
or just after lenalidomide treatment showed a significantly increased capacity to mediate
daratumumab-dependent ADCC against multiple myeloma cells alone (Van der Veer 2011a).38
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Thus, in this ex vivo clinical setting, daratumumab-mediated multiple myeloma tumor cell killing
was demonstrated to be significantly augmented by stimulating effector cells. In conclusion,
preclinical data, both from the literature and the sponsor’s own ex vivo studies, support the
combination of daratumumab with lenalidomide in the treatment of multiple myeloma.
1.5. 
Overall Rationale for the Study
Multiple myeloma remains incurable with standard chemotherapy, despite the availability of multi
agent therapy. Strategies directed at improving and maintaining response for longer periods of time
and new treatment options directed at alternative mechanisms are also urgently needed for patients
with multiple myeloma.
Recent studies have indicated that multiple drug combinations are superior over single- or
double-agent combinations in treating multiple myeloma (Van der Veer 2011b).39 The addition of
new drugs to available regimens can mediate their clinical benefit because of the induction of a
higher rate of initial CRs, which then improves relapse-free and overall survival. Contingent on
the premise that the combined agents have non-overlapping and synergistic mechanism of actions,
the immediate and effective targeting of the tumors with multiple agents appears to be a successful
strategy in improving the clinical outcome of multiple myeloma therapy. Such a strategy is in
agreement with the emerging concept that the genetic signature of multiple myeloma, and
consequently the patient’s susceptibility to a specific agent, will be highly heterogeneous, which
may lead to drug resistance. Nevertheless, the CR rate of the best chemotherapeutic combinations
is currently <50%, and all current combination therapies eventually induce drug resistance.
Based on data from ongoing studies with and the safety information in the label for lenalidomide,
the expected safety profile of daratumumab in this combination therapy study is considered
manageable. To date, 31 subjects have been treated in Study GEN503, an open-label, Phase 1/2
multicenter, dose-escalating study investigating the safety of daratumumab in combination with
lenalidomide and dexamethasone in subjects with relapsed or refractory multiple myeloma. No
DLTs have been reported, and the safety profile is consistent with what has been previously
reported for lenalidomide monotherapy. Data from several clinical studies support the choice of
16 mg/kg as the daratumumab dose to be administered in this study. Based upon the pre-clinical
synergy observed, and the promising clinical data in the relapsed/refractory setting, this is a
rational combination to investigate in newly diagnosed patients.
2. 
OBJECTIVES AND HYPOTHESIS
2.1. 
Objectives
Primary Objective
The primary objective is to compare the efficacy of daratumumab when combined with
lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms
of progression-free survival (PFS) in subjects with newly diagnosed myeloma who are not
candidates for high dose chemotherapy and autologous stem cell transplant.
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Secondary Objectives
The secondary objectives are:
 
To evaluate clinical outcomes including:
 Time to disease progression (TTP)
 CR rate
 MRD negativity rate
 PFS2 (defined as time from randomization to progression on the next line of therapy or
death, whichever comes first)
 Overall survival
 Time to next treatment
 Stringent CR (sCR) rate
 Overall response rate (partial response [PR] rate or better)
 Proportion of subjects who achieve very good partial response (VGPR) or better
 Time to response
 Duration of response
 
To evaluate the clinical efficacy of daratumumab combination with Rd in high-risk molecular
subgroups
 
To evaluate treatment effects on patient reported outcomes and heath economic/resource
utilization
 
To assess the safety and tolerability of daratumumab when administered in combination with
Rd.
 
To assess the pharmacokinetics of daratumumab in combination with Rd.
 
To assess the immunogenicity of daratumumab in Arm B subjects and the immunogenicity of
rHuPH20 in subjects receiving daratumumab SC.
Exploratory Objective
 
To explore biomarkers predictive of response or resistance to therapy
 
To assess durability of MRD negativity
2.2. 
Hypothesis
The primary hypothesis of this study is that daratumumab in combination with Rd will prolong
PFS as compared with Rd alone in subjects with newly diagnosed multiple myeloma who are
ineligible for high dose chemotherapy and autologous stem cell transplant.
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3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a randomized, open-label, active controlled, parallel-group, multicenter study in subjects
at least 18 years of age with newly diagnosed multiple myeloma who are not candidates for high
dose chemotherapy and ASCT. Approximately 730 subjects will be enrolled in this study with
365 subjects planned per treatment arm.
A diagram of the study design is provided in Figure 2.
Figure 2: 
Schematic Overview of the Study
NOTE: After Study MMY3008 transitions to long-term survival follow-up, an end-of-treatment visit is no longer
required.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase.
The Screening Phase will be up to 21 days before Cycle 1, Day 1. The Treatment Phase will extend
from Day 1 of Cycle 1 until discontinuation of all study treatment. For subjects assigned to DRd,
daratumumab will be administered weekly for the first 8 weeks (Cycles 1-2) of treatment and then
every other week for 16 weeks (Cycles 3-6), then every 4 weeks (from Cycle 7 and beyond) until
disease progression or unacceptable toxicity. This will equate to 9 consecutive weeks of dosing at
the start of the study and a total of 23 doses in the first year. Lenalidomide will be administered at
a dose of 25 mg orally (PO) on Days 1 through 21 of each 28-day cycle, and dexamethasone will
be administered at a dose of 40 mg once a week in both treatment arms. Subjects in both treatment
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arms will continue lenalidomide and dexamethasone until disease progression or unacceptable
toxicity. In the DRd arm, subjects will continue on daratumumab until disease progression or
unacceptable toxicity. Randomization will be stratified by International Staging System (I vs II vs
III), region (North America vs Other), and age (<75 vs ≥75), using an equal allocation ratio of 1:1.
Measures to prevent infusion-related reactions will include medication with dexamethasone,
acetaminophen (paracetamol), and an antihistamine before each daratumumab administration.
All subjects randomized to Treatment Arm B in this study initially received daratumumab IV
formulation; however, following implementation of protocol amendment 8, subjects still receiving
treatment with daratumumab IV will have the option to switch to daratumumab SC on Day 1 of
any cycle, at the discretion of the investigator. Subjects with a known allergy/intolerance to
sorbitol will not be eligible to switch to daratumumab SC. Note: throughout this document, text
has been added to highlight any differences between daratumumab IV and daratumumab SC
dosing, and where there is no clarification, it is implied that the descriptions are the same for
daratumumab IV and daratumumab SC.
The Follow-up Phase will begin once a subject discontinues all study treatments. Subjects who
discontinue study treatment for reasons other than disease progression must continue to have
disease evaluations according to the Time and Events Schedule until confirmed disease
progression (PD) (see Section 8.4, Subsequent Therapies). After PD is documented, follow-up will
be obtained at least every 16 weeks. Subsequent anti-myeloma therapy, PFS2 (per investigator
judgment), second primary malignancies, and survival will be recorded. The Follow-up Phase will
continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first.
Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety,
will be performed after a total of approximately 100 subjects have been treated for at least 8 weeks
or discontinued the study treatment. The second interim analysis will be performed when 234 PFS
events, which is 60% of the total planned events, have been accumulated. The purpose of this
interim analysis is to evaluate cumulative interim safety and efficacy data. The significance level
at this interim analysis to establish the superiority of DRd over Rd with regard to PFS will be
determined based on the observed number of PFS events at the interim analysis, using the
O’Brien-Fleming boundaries as implemented by the Lan-DeMets alpha spending method. If the
experimental arm (DRd) is numerically worse than the control arm in terms of PFS (observed
hazard ratio >1 favoring the control arm), then the study may be terminated for futility.
As the superiority of DRd over Rd alone with respect to PFS was established at the second interim
analysis, the interim PFS analysis will serve as the primary PFS analysis, which otherwise was to
occur when approximately 390 PFS events had been observed. The first interim OS analysis was
performed at the interim PFS analysis. The second interim OS analysis occurred when 273 deaths
had occurred and demonstrated superiority of DRd over Rd alone for OS. The median OS was not
reached.
The date established for the primary PFS analysis (24 September 2018) will serve as the clinical
cut-off date, after which subject monitoring in the study will be conducted as per Section 9.1.5.
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After the second interim OS analysis (19 February 2021), subject monitoring will be conducted
according to Section 9.1.7. 
Following the positive second interim OS analysis that established the superiority of DRd over Rd
alone for OS, the final CSR analysis will be performed approximately 5 years after the last subject
was randomized. The final CSR analysis will provide updates to the primary CSR analysis for both
efficacy and safety. The sponsor will communicate the clinical cut-off for the final CSR analysis
to sites. At the time of this clinical cut-off, the study will transition to long-term survival follow-
up (see Section 9.1.8 and Attachment 11).
The clinical cut-off of the final OS analysis will occur when approximately 390 deaths have
occurred. No additional eCRF data will be collected after the final OS analysis. Data collected up
to this timepoint will be included in the final OS analysis and reported in a separate addendum to
the clinical study report.
The sponsor will ensure that subjects who are benefitting from treatment with daratumumab can
continue to receive daratumumab after the final OS analysis through end of study (see
Section 17.9.1). For these subjects, treatment with daratumumab will be available through
continued access within the current study until it is available through another source such  as
commercial availability, continued access through a long-term extension study, a patient access
program, or until 31 January 2026, whichever occurs first.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to
review efficacy and safety results at the planned interim analyses. After the interim review, they
will make recommendations regarding the continuation of the study. In addition, the IDMC may
also review cumulative safety data every 6 months besides the 2 interim analyses. The IDMC will
no longer review study data after the interim PFS analysis has been completed.
Assessment of tumor response and disease progression will be conducted in accordance with the
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will
be conducted on bone marrow samples. Safety evaluations will include adverse event monitoring,
physical examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters
(hematology and chemistry), vital sign measurements, and ECOG performance status. Blood
samples will be drawn for assessment of pharmacokinetic parameters and immunogenicity.
Following the positive second interim analysis that established the superiority of DRd over Rd
alone with respect to the primary endpoint (PFS), the sponsor will provide access to daratumumab
for subjects randomized to Arm A (Rd) who have sponsor-confirmed disease progression
(see Section 8.4, Subsequent Therapies), if recommended by the investigator. After the cut-off for
the final CSR, sponsor confirmation of PD is no longer required and will be based on investigator
assessment of PD.
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3.2. 
Study Design Rationale
Rationale for Duration of Lenalidomide Administration
Lenalidomide and dexamethasone are commonly given in the front-line setting in the US. Based
upon the FIRST Study (Facon 2013, Benboubker 2014),9,2 the front-line treatment paradigm in the
EU will likely evolve to include Rd in the future. The Facon study showed that treatment until
progression conferred clinical benefit over treatment for a fixed duration of time. A retrospective
analysis of 2 Phase 3 studies, one administering a lenalidomide based regimen and one
administering a VELCADE based regimen, also showed that PFS1, PFS2, and overall survival
(OS) were all significantly longer following continuous treatment to progression
(Palumbo 2014).27 This was observed regardless of the particular chemotherapy backbone. Taken
together, these data support the principle of treatment until progression.
In the current study, treatment with Rd will continue until disease progression or unacceptable
toxicityin the control arm (Arm A). This treatment duration is consistent with best current clinical
practice based on the above published results.
In the experimental arm (Arm B), treatment with DRd will continue until disease progression or
unacceptable toxicity. The protocol was initially designed to discontinue Rd after 24 months to
isolate the efficacy and safety of daratumumab from continued exposure to Rd. Based on the data
from the FIRST study, lenalidomide treatment until disease progression is emerging as the
standard of care and is also consistent with the approved lenalidomide package insert (Hulin 2016;
Revlimid USPI 2017).14,33 Continuous Rd is currently being used as the backbone therapy in many
Phase 3 studies evaluating active compounds in patients with myeloma (eg, bortezomib
[Durie 2017],8 carfilzomib, ixazomib, and elotuzumab [ongoing]). Results from the SWOG S0777
study evaluating a combined patient population of transplant eligible and ineligible subjects
demonstrated improved median PFS with the addition of 6 months of bortezomib treatment to
continuous Rd (43 months vs 30 months) with an acceptable safety profile despite the addition of
a third agent to continuous Rd (Durie 2017).8 Based on these developments, this amendment will
allow for treatment to be consistent with the current standard of care.
Rationale for Daratumumab IV Dose
CD38, the target for daratumumab, is expressed on NK cells and clinical data has shown NK cell
suppression to be a marker of on target drug activity. Clinical pharmacokinetic data have shown
the 16 mg/kg dose to be the lowest dose that results in complete target suppression at all timepoints.
This dose and schedule continuously suppressed NK cells throughout dosing. Daratumumab
maximal target suppression is presented in Figure 3.
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Figure 3: 
Daratumumab Maximal Target Suppression
8 mg/kg: Observed trough concentration
values below predicted 90% suppression
throughout dosing
16 mg/kg: Observed trough
concentration values at 90% suppression
throughout dosing
The ORR appeared higher for the 16 mg/kg dose compared with the 8 mg/kg dose, based on early
preliminary data from Part 2 of Study GEN501 and from Study MMY2002 (both ongoing studies)
as of a cut-off date of 24 January 2014. In Study GEN501, the ORRs (ie, PR or greater) were 11%
and 40% for the 8 mg/kg (n 28) and 16 mg/kg (n 15) dose regimens, respectively. For
Study MMY2002, the unconfirmed ORRs for the 8 mg/kg and 16 mg/kg dose regimens were
similar to those observed in GEN501. In addition, VGPRs were observed for 7 of 30 subjects
treated with the 16 mg/kg dose in the 2 studies. VGPR had not been observed at lower dose levels.
These preliminary data support that full target saturation at the 16 mg/kg dose is needed to achieve
higher and deeper response rates.
Rationale for Daratumumab SC Dose Regimen
The clinical pharmacology assessment of daratumumab SC monotherapy data are available from
daratumumab SC-dosed subjects in a Phase 1/1b study (MMY1004 [Part 2]), a Phase 3 study
(MMY3012), and population pharmacokinetics and exposure-response analyses.
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In MMY1004, the 1800 mg dose achieved maximum Ctrough  (Cycle 3 Day 1 predose) values that
were similar or greater than the maximum Ctrough  observed for the approved 16 mg/kg IV dose
following the same dose schedule. The PK data from Part 2 supported the daratumumab SC
1800 mg dose selection for the Phase 3 study. The PK data from MMY3012 study demonstrated
that daratumumab SC 1800 mg is non-inferior to daratumumab IV 16 mg/kg in terms of maximum
Ctrough (Cycle 3 Day 1 predose), with the lower bound of the 90% CI for the geometric means ratio
for daratumumab SC versus daratumumab IV for maximum Ctrough  (Cycle 3 Day 1 predose)
exceeding 80%, thereby meeting the predefined non-inferiority criterion.
Additionally, daratumumab SC 1800 mg monotherapy consistently produced lower peak-to-trough
fluctuations, similar or slightly higher trough levels over time, and lower peak concentrations
compared with daratumumab IV 16 mg/kg monotherapy. Overall, consistent daratumumab
concentrations were observed across the body weight ranges. As expected, slightly higher
concentrations were observed for subjects with lower body weights.
There was no apparent relationship between exposure and safety endpoints (SAEs, Grade 3 or
higher treatment-emergent adverse events and neutropenia).
Overall, daratumumab SC was well-tolerated with manageable side effects and a significantly
reduced incidence of IRRs relative to daratumumab IV. The safety profile of daratumumab
administered subcutaneously at a flat dose of 1800 mg continued to be generally comparable to
that of the 16 mg/kg IV formulation.
Rationale for DNA and Biomarker Collection
Biomarker samples will be collected to evaluate the depth of clinical response to daratumumab
through evaluation of MRD, using DNA sequencing of immunoglobulin genes, and to determine
response rates in specific molecular subgroups of multiple myeloma, using DNA/RNA sequencing
of multiple myeloma cells to allow for assessment of high risk genomics such as deletion 17p,
t(4;14), t(14;20), t(14;16), deletion13, GEP signatures such as UAMS-70, and mutations in p53,
BRAF, FGFR, IGH, PI3K, or other molecular subtypes associated with disease progression. Other
biomarker goals include evaluation of potential mechanisms of resistance, inter-individual
variability in clinical outcomes or identification of population subgroups that respond differently
to treatment.
4. 
SUBJECT POPULATION
Screening for eligible subjects will be performed within 21 days before randomization.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the
investigator should consult with the appropriate sponsor representative before enrolling a subject
in the study.
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, Sample
Size Determination.
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4.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1. 
Subject must be at least 18 years of age (or the legal age of consent in the jurisdiction
in which the study is taking place).
2. 
Criterion modified as per Amendment INT-2
2.1 Subject must have documented multiple myeloma satisfying the CRAB (calcium
elevation, renal insufficiency, anemia and bone abnormalities) criteria (see
Attachment 1), monoclonal plasma cells in the bone marrow ≥10% or presence of a
biopsy proven plasmacytoma, and measurable disease.
 
Measurable disease, as assessed by central laboratory, defined by any of the
following:
 IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or
urine M-protein level ≥200 mg/24 hours; or
 IgA, IgM, IgD, or IgE multiple myeloma: serum M-protein level ≥0.5 g/dL or
urine M-protein level ≥200 mg/24 hours; or
 Light chain multiple myeloma without measurable disease in serum or urine:
Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum
immunoglobulin kappa lambda free light chain ratio.
3. 
Newly diagnosed and not considered candidate for high-dose chemotherapy with SCT
due to:
 
Being age ≥65 years, OR
 
In subjects <65 years: presence of important comorbid condition(s) likely to have
a negative impact on tolerability of high dose chemotherapy with stem cell
transplantation. Sponsor review and approval of subjects under 65 years of age is
required before randomization.
4. 
Subject must have an ECOG performance status score of 0, 1, or 2 (refer to
Attachment 2).
5. 
Subject must have pretreatment clinical laboratory values meeting the following criteria
during the Screening Phase:
a) hemoglobin 7.5 g/dL (mM/L; prior red blood cell [RBC] transfusion or
recombinant human erythropoietin use is permitted);
b) absolute neutrophil count 1.0 x 109/L (granulocyte colony stimulating factor
[GCSF] use is permitted);
c) platelet count 70 x 109/L for subjects in whom <50% of bone marrow
nucleated cells are plasma cells; otherwise platelet count >50 × 109/L
(transfusions are not permitted to achieve this minimum platelet count);
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d) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
e) alanine aminotransferase (ALT) ≤2.5 x ULN;
f) total bilirubin ≤2.0 x ULN, except in subjects with congenital bilirubinemia,
such as Gilbert syndrome (direct bilirubin ≤2.0 x ULN);
g) Criterion modified per Amendment INT-2
g1) Creatinine clearance ≥30 mL/min (for lenalidomide dose adjustment for
subjects with creatinine clearance 30-50 mL/min, refer to Section 6.2).
Creatinine clearance can be calculated using the Cockcroft-Gault formula
provided in Attachment 3; or for subjects with over- or underweight, creatinine
clearance may be measured from a 24-hours urine collection using the formula
provided in Attachment 3;
h) Criterion modified per Amendment INT-2
h1) corrected serum calcium ≤14 mg/dL (≤3.5 mM/L); or free ionized calcium
≤6.5 mg/dL (≤1.6 mM/L) (Attachment 4)
6. 
Criterion modified per Amendment INT-3
6.1 Criterion modified per Amendment INT-2
6.2 Contraceptive use by men or women should be consistent with local regulations
regarding the use of contraceptive methods for subjects participating in clinical studies.
Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse or to use 2 methods of reliable birth control
simultaneously. This includes one highly effective form of contraception (tubal
ligation, intrauterine device [IUD], hormonal [progesterone-only birth control pills or
injections or partner’s vasectomy) and one additional effective contraceptive method
(male latex or synthetic condom, diaphragm, or cervical cap). Contraception must
begin 4 weeks prior to dosing and must continue for 3 months after 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. (Also see
Attachment 5: Lenalidomide Global Pregnancy Prevention Plan).
7. 
A man who is sexually active with a woman of childbearing potential must agree to
use a latex or synthetic condom, even if he had a successful vasectomy. All men must
also 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.
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, please see Section 4.3.
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9. 
Each subject (or their legally acceptable representative) must sign an informed consent
form (ICF) indicating that he or she understands the purpose of and procedures required
for the study and are willing to participate in the study. Subject must be willing and able
to adhere to the prohibitions and restrictions specified in this protocol, as referenced in
the ICF.
4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study.
1. 
Subject has a diagnosis of primary amyloidosis, monoclonal gammopathy of
undetermined significance, or smoldering multiple myeloma. Monoclonal gammopathy
of undetermined significance is defined by presence of serum M-protein <3 g/dL;
absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to
the M-protein; and (if determined) proportion of plasma cells in the bone marrow of
10% or less (Kyle 2003).17 Smoldering multiple myeloma is defined as asymptomatic
multiple myeloma with absence of related organ or tissue impairment end organ damage
(Kyle 2003, Kyle 2007).17,19
2. 
Subject has a diagnosis of Waldenström’s disease, or other conditions in which IgM
M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone
lesions.
3. 
Subject has prior or current systemic therapy or SCT for multiple myeloma, with the
exception of an emergency use of a short course (equivalent of dexamethasone
40 mg/day for 4 days) of corticosteroids before treatment.
4. 
Subject has a history of malignancy (other than multiple myeloma) within 5 years
before the date of randomization (exceptions are squamous and basal cell carcinomas
of the skin and carcinoma in situ of the cervix, or malignancy that in the opinion of the
investigator, with concurrence with the sponsor's medical monitor, is considered cured
with minimal risk of recurrence within 5 years).
5. 
Subject has had radiation therapy within 14 days of randomization.
6. 
Subject has had plasmapheresis within 28 days of randomization.
7. 
Subject is exhibiting clinical signs of meningeal involvement of multiple myeloma.
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8. 
Criterion modified as per Amendment INT-2
8.1a) Subject has known chronic obstructive pulmonary disease (COPD) with a Forced
Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1
testing is required for subjects suspected of having COPD and subjects must be
excluded if FEV1 <50% of predicted normal.
8.1b) Subject has had known moderate or severe persistent asthma within the last
2 years (see Attachment 7), 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).
9. 
Criterion modified as per Amendment INT-2
9.1) Subject is known to be seropositive for human immunodeficiency virus (HIV) or
hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg] or
antibodies to hepatitis B surface and core antigens [Anti-HBs and Anti-HBc,
respectively]) or hepatitis C (Anti-HCV antibody positive or HCV-RNA quantitation
positive).
10. 
Subject has any concurrent medical or psychiatric condition or disease (eg, active
systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease)
that is likely to interfere with the study procedures or results, or that in the opinion of
the investigator, would constitute a hazard for participating in this study.
11. 
Subject has clinically significant cardiac disease, including:
 
myocardial infarction within 1 year before randomization, or an unstable or
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable
angina, congestive heart failure, New York Heart Association Class III-IV
 
uncontrolled cardiac arrhythmia (National Cancer Institute Common Terminology
Criteria for Adverse Events [NCI CTCAE] Version 4 Grade ≥3) or clinically
significant ECG abnormalities
 
screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s
formula (QTcF) >470 msec
12. 
Subject has known allergies, hypersensitivity, or intolerance to corticosteroids,
monoclonal antibodies or human proteins, lenalidomide, or their excipients (refer to
respective package inserts or Investigator's Brochure), or known sensitivity to
mammalian-derived products.
13. 
Subject has plasma cell leukemia (according to World Health Organization [WHO]
criterion: ≥20% of cells in the peripheral blood with an absolute plasma cell count of
more than 2 × 109/L) or POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin changes).
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14. 
Subject is known or suspected of not being able to comply with the study protocol
(eg, because of alcoholism, drug dependency, or psychological disorder). Subject has
any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the subject (eg, compromise the well-being) or that could prevent,
limit, or confound the protocol-specified assessments. Subject is taking any prohibited
medications as per Section 8.3.
15. 
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant
while enrolled in this study, within 4 weeks after the last dose of lenalidomide, or within
3 months after the last dose of daratumumab. Or, subject is a man who plans to father a
child while enrolled in this study, within 4 weeks after the last dose of lenalidomide, or
within 3 months after the last dose of daratumumab.
16. 
Subject has had major surgery within 2 weeks before randomization or has not fully
recovered from surgery, or has surgery planned during the time the subject is expected
to participate in the study. Kyphoplasty or vertebroplasty is not considered major
surgery.
17. 
Subject has received an investigational drug (including investigational vaccines) or
used an invasive investigational medical device within 4 weeks before randomization
or is currently enrolled in an interventional investigational study.
18. 
Subject has contraindications to required prophylaxis for deep vein thrombosis and
pulmonary embolism.
19. 
Incidence of gastrointestinal disease that may significantly alter the absorption of oral
drugs.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a subject's status changes (including laboratory results or receipt of additional medical records)
after screening but before the first dose of study treatment is given such that he or she no longer
meets all eligibility criteria, then the subject should be excluded from participation in the study.
Section 17.4, describes the required documentation to support meeting the enrollment criteria.
Subjects who fail to meet the inclusion and exclusion criteria (ie, screen failures) may be
rescreened once if their condition changes. Rescreening must be discussed with and approved by
the sponsor on a case-by-case basis. Subjects who are determined to be eligible for rescreening
must sign a new ICF and will then be assigned a new screening number.
4.3. 
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions
during the course of the study to be eligible for participation. For restrictions related to concomitant
medications, please refer to Section 8.3.
1. For women of childbearing potential, adequate contraception, as specified in Section 4.1,
without interruption, must begin 28 days before starting lenalidomide and continue during
the Treatment Phase, during any dose interruptions, and for at least 4 weeks after the last
dose of lenalidomide, and for 3 months after the last dose of daratumumab. All women
must not donate ova during the study, and for at least 4 weeks after the last dose of
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lenalidomide, and for 3 months after the last dose of daratumumab. All women must not
breastfeed while taking lenalidomide and for at least 28 days after the last dose of
lenalidomide.
2. Prior to starting lenalidomide, two negative pregnancy tests are required. The first
pregnancy test must be performed within 10 to 14 days prior to the start of lenalidomide
and the second pregnancy test must be performed within 24 hours prior to the start of
lenalidomide.
3. 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 and 28 days following the last dose of lenalidomide for women
with regular menstrual cycles or 14 and 28 days following the last dose of lenalidomide for
women with irregular menstrual cycles. Additional pregnancy tests may be required, as
specified in the local lenalidomide Risk Evaluation and Mitigation Strategy (REMS)
(where lenalidomide is supplied locally) or the Lenalidomide Global Pregnancy Prevention
Plan in Attachment 5 (where lenalidomide is supplied centrally and no local lenalidomide
REMS program exists).
4. A man who is sexually active with a pregnant woman or a woman of childbearing potential
must always use a latex or synthetic condom during the study and for at least 4 weeks after
discontinuing lenalidomide, and for 3 months after discontinuing daratumumab (even if he
has undergone a successful vasectomy). All men must not donate semen or sperm during
the study, during dose interruptions, for at least 4 weeks after the last dose of lenalidomide,
and for 3 months after the last dose of daratumumab.
5. Because of the embryo-fetal risk of lenalidomide, all subjects must adhere to the local
lenalidomide REMS program (when lenalidomide is supplied locally), or the lenalidomide
Global Pregnancy Prevention Plan provided in Attachment 5 (when lenalidomide is
supplied centrally and no local lenalidomide REMS program exists).
6. Subjects must not donate blood during therapy, during dose interruptions, and for at least
4 weeks following discontinuation of lenalidomide.
7. 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.
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5. 
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Eligible subjects will be stratified by International Staging System (I vs II vs III see Attachment 8),
region (North America vs Other), and age (<75 vs ≥75) and then randomized to treatment in a 1:1
ratio to either Treatment Arm A (Rd alone) or Treatment Arm B (daratumumab+Rd [DRd]). The
method of randomization is randomly permuted blocks. An interactive web response system
(IWRS) will be used. Each subject will be assigned a unique subject number.
Blinding
As this is an open study, blinding procedures are not applicable.
6. 
DOSAGE AND ADMINISTRATION
In this protocol, the term “study drug” refers to daratumumab only (daratumumab IV or
daratumumab SC), and “study treatment” refers to daratumumab, lenalidomide, and
dexamethasone. Daratumumab is to be administered as described in the Time and Events Schedule.
Each cycle is 28 days. The first visit of a cycle should be 4 weeks after the start of the previous
cycle. The start of each cycle may occur ±3 days of the scheduled day in order to accommodate
the schedule of the site or subject. Day 1 of subsequent cycles should be adjusted accordingly to
maintain the 28-day cycle duration. In Cycles 1 through 6, weekly or bi-weekly daratumumab
doses may be given within ±1 day of the scheduled day in order to accommodate the schedule of
the site or subject. In all cycles, weekly dexamethasone doses may be given within ±1 day of the
scheduled day in order to accommodate the schedule of the site or subject. Changes to within-
cycle dosing should not impact Day 1 of the next cycle.  Subjects will continue to receive study
treatment according to the Time and Events Schedule until disease progression, unacceptable
toxicity, or other reasons as listed in Section 10.2.
Subjects whose study treatment is delayed for more than 4 weeks (Cycle 1 to Cycle 6) or more
than 6 weeks (Cycle 7 and beyond) should have study treatment discontinued, unless, upon
consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon.
A schematic of study treatment administration is provided in Figure 4.
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Figure 4: 
Schematic Overview Study Treatment Administration
6.1. 
Daratumumab (Arm B Only)
6.1.1. 
Daratumumab Preparation
Daratumumab doses will be prepared on the day of the planned administration. Detailed
instructions for preparation and administration of daratumumab will be supplied in the Site
Investigational Product Procedures Manual (SIPPM) or equivalent document.
6.1.2. 
Daratumumab IV Administration
Daratumumab (16 mg/kg) will be administered by IV infusion to subjects in Arm B initially once
every week for 8 weeks; then once every other week for 16 weeks; thereafter once every 4 weeks
until documented progression, unacceptable toxicity, or study end (as defined in Section 17.9.1).
Each subject’s dose will be calculated based on the subject’s weight rounded to the nearest
kilogram. There is no cap on the absolute dose allowed, as long as the dose does not exceed
16 mg/kg. If a subject’s weight changes by more than 10% from baseline, the dose of daratumumab
will be re-calculated. For recommendations on daratumumab infusion rate, please refer to the
SIPPM. All infusions will be performed as outpatient visits. Subjects will receive preinfusion
medications and postinfusion medications as outlined in Section 6.1.4.
Every effort should be made to keep subjects on the planned dosing schedule. Time windows for
daratumumab administration are outlined in Table 3.
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As noted in the Time and Events Schedule, vital signs should be monitored extensively on Cycle 1
Day 1 before, during, and after the first infusion of daratumumab. For all other infusions, vital
signs should be measured before the start of infusion and at the end of the infusion. If a subject
experiences any significant medical event, then the investigator should assess whether the subject
should stay overnight for observation.
6.1.3. 
Daratumumab SC Administration
Daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg once every
4 weeks until documented progression, unacceptable toxicity, or study end (as defined in
Section 17.9.1). Doses will be administered by manual push over 3-5 minutes in the abdominal SC
tissue, rotating between the four quadrants. 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 daratumumab SC.
The dose of daratumumab will remain constant throughout the study. For subjects who initially
received daratumumab IV and then switch to daratumumab SC following Amendment 8, it is
recommended subjects are observed for a period of time deemed appropriate by the investigator
following the first daratumumab SC dose and, if necessary, after subsequent injections. Reasons
for continued observation on subsequent daratumumab administrations 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 IRR with prior administrations
of study drug, subject with a decreased condition on day of dosing compared to prior dosing day.
6.1.4. 
Prevention of Infusion -Related and Injection-Site Reactions
6.1.4.1. 
Pre-dose Medication
Pre-dose medications for subjects receiving daratumumab will be administered as described in the
Time and Events Dose Administration Schedule. On daratumumab dose (IV or SC) days, subjects
will receive the following medications prior to dose:
 
Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less
prior to daratumumab dose
 
An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of
promethazine) approximately 1 hour prior to administration (see Attachment 9 for list of
antihistamines that may be used); after Cycle 6, if a subject has not developed an
infusion-related and injection-site reaction and is intolerant to antihistamines, modifications
are acceptable as per investigator discretion.
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 
Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior to
daratumumab dose. For subjects older than 75 years or underweight (body mass index [BMI]
<18.5), dexamethasone 20 mg may be administered as appropriate (see Section 6.3). An
equivalent intermediate-acting or long-acting corticosteroid may substitute (see Attachment 6
for conversion table). On days when subjects receive this dose of dexamethasone in the clinic,
dexamethasone will not be self-administered at home. If weekly dexamethasone dosing has
been reduced below 10 mg due to adverse events during study, a minimum of dexamethasone
10 mg IV should continue to be administered prior to daratumumab dose.
If necessary, all PO pre-dose medications may be administered outside of the clinic on the day of
the administration, provided they are taken within 3 hours before the administration.
6.1.4.2. 
Post-dose Medication
For subjects with higher risk of respiratory complications (ie, subjects with mild asthma, or
subjects with COPD who have a FEV1 <80%), the following post-dose medications should be
considered:
 
Antihistamine (diphenhydramine or equivalent)
 
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol
 
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or
salmeterol ± inhaled corticosteroids for subjects with COPD)
For subjects previously treated with daratumumab IV who switch to daratumumab SC, post-dose
medications may be offered after 1 or more doses of daratumumab SC, per investigator discretion.
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after a
daratumumab administration. If subjects are hospitalized, then their FEV1 should be measured
before discharge. If these subjects are not hospitalized, then a follow up telephone call should be
made to monitor their condition within 48 hours after all administrations. If the subject has not
experienced a significant medical event but is hospitalized overnight only for observation, then the
hospitalization should not be reported as a serious adverse event. Investigators may prescribe
bronchodilators, antihistamines, and corticosteroids that are deemed necessary to provide adequate
supportive care in the event a bronchospasm occurs after subjects are released from the
hospital/clinic. If an at-risk subject experiences no major infusion-related reactions, then these
post-dose medications may be waived after 4 full doses at the investigator’s discretion.
6.1.5. 
Management of Infusion-related Reactions
Infusion-related reactions (IRRs) are systemic reactions related to daratumumab administration
(IV or SC). Subjects in Arm B should be carefully observed during daratumumab administrations.
Trained study staff at the clinic should be prepared to intervene in case of any infusion reactions
occurring, and resources necessary for resuscitation (eg, agents such as epinephrine and
aerosolized bronchodilator, also medical equipment such as oxygen tanks, tracheostomy
equipment, and a defibrillator) must be available at the bedside. Attention to staffing should be
considered when multiple subjects will be dosed at the same time.
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If an infusion-related reaction develops during daratumumab administration, then the
administration should be paused. Subjects who experience adverse events during the daratumumab
administration must be treated according to the investigator’s judgment and best clinical practice.
The following guidelines may apply:
 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. Intravenous
saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may require
antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, subjects may
require vasopressors.
 
In the event of a life-threatening infusion-related reaction (which may include pulmonary or
cardiac events), or anaphylactic reaction, daratumumab should be discontinued and no
additional daratumumab should be administered to the subject. Aggressive symptomatic
treatment should be applied.
For subjects treated with daratumumab IV, if an infusion is paused, then a longer-than-anticipated
infusion time may occur. Overnight stays at the hospital because of slow infusion times should not
be reported as a serious adverse event. However, if the underlying cause of the delayed infusion
time is an adverse event or serious adverse event, then that should be reported as such.
6.1.5.1. 
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses a Grade 1 or 2 adverse event to be related to daratumumab, then
daratumumab administration should be paused. When the subject’s condition is stable, the
daratumumab administration may be restarted at the investigator’s discretion. For subjects treated
with daratumumab IV, upon restart, the infusion rate should be half of that used before the
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher
event of bronchospasm that does not respond to systemic therapy and does not resolve within
6 hours from the onset, then the subject must be withdrawn from treatment.
6.1.5.2. 
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related adverse events that are Grade 4, daratumumab should be stopped and
treatment with daratumumab will be discontinued for that subject.
For infusion-related adverse events that are Grade 3, the daratumumab administration must be
stopped, and the subject must be observed carefully until the resolution of the adverse event or
until the intensity of the event decreases to Grade 1, at which point the daratumumab may be
restarted at the investigator’s discretion. For subjects treated with daratumumab IV, upon restart,
the infusion rate should be half of that used before the interruption. Subsequently, the infusion rate
may be increased at the investigator’s discretion.
If the intensity of the adverse event returns to Grade 3 after restart of daratumumab, then the
procedure described in this section may be repeated at the investigator’s discretion. Should the
intensity of the adverse event increase to Grade 3 for a third time, then treatment with
daratumumab will be discontinued for that subject.
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6.1.5.3. 
Injection-Site Reactions
In clinical studies, SC administration of daratumumab 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.
6.2. 
Lenalidomide (Arm A and Arm B)
Lenalidomide will be self-administered at a dose of 25 mg PO each day on Days 1 through 21 of
each 28-day cycle for subjects with creatinine clearance >50 mL/min. If creatinine clearance is
between 30 and 50 mL/min, the dose of lenalidomide will be 10 mg every 24 hours. Once the
creatinine clearance is >50 mL/min during the course of the treatment, lenalidomide can be
increased to 25 mg. In both treatment arms, subjects will continue on lenalidomide until
progression of disease or unacceptable toxicity. Subjects in Arm B who discontinued treatment
with Rd at 24 months may re-start treatment with Rd as per Amendment INT-4.
On daratumumab administration days, it is recommended that lenalidomide should be
administered either prior to or at the same time (preferred) as the premedications. 
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.
6.3. 
Dexamethasone (Arm A and Arm B)
Dexamethasone (or equivalent in accordance with local standards; see Attachment 6 for
conversion table) will be administered at a total dose of 40 mg weekly. For subjects older than
75 years or underweight (BMI <18.5), the dexamethasone dose may be administered at a dose of
20 mg weekly. In both treatment arms, dexamethasone will be administered until the subject
experiences disease progression or unacceptable toxicity, whichever comes first. Subjects in
Arm B who discontinued treatment with Rd at 24 months may re-start treatment with Rd as per
Amendment INT-4.
On days when subjects in Arm B receive a dose of daratumumab, dexamethasone will not be self-
administered but instead will be administered in the clinic. In this setting, dexamethasone will be
utilized as the treatment dose of steroid for that particular day, as well as the required
pre-medication prior to daratumumab administration.
If a weekly dexamethasone dose is missed, it may be taken if <4 days have elapsed since the time
that it should have been taken. If the next dose is scheduled to be taken within 3 days, the missed
dexamethasone dose should be skipped.
6.4. 
Dose Delays and Dose Modification
Subjects who need to discontinue treatment with any one component of study treatment
(lenalidomide, dexamethasone, or daratumumab) may continue to receive treatment with the other
components of study treatment, as assigned.
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6.4.1. 
Daratumumab Dose Modification
Dose modification of daratumumab is not permitted, but dose delay is the primary method for
managing daratumumab-related toxicities.
6.4.1.1. 
Daratumumab-Related Toxicity Management
Refer to Section 6.1.4 for details on management of infusion-related reactions. ONLY if any of
the following criteria are met and the event cannot be ascribed to lenalidomide, the daratumumab
administration must be held to allow for recovery from toxicity. The criteria for a dose delay are:
 
Grade 4 hematologic toxicity
 
Grade 3 thrombocytopenia with bleeding
 
Febrile neutropenia
 
Neutropenia with infection, of any grade
 
Grade 3 or higher nonhematologic toxicities with the following exceptions:
 Grade 3 nausea that responds to antiemetic treatment within 7 days
 Grade 3 vomiting that responds to antiemetic treatment within 7 days
 Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
 Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
 Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last
administration of daratumumab
Other than on Day 1 of a cycle, if a daratumumab dose does not commence within the prespecified
window (Table 3) of the scheduled administration date, then the dose will be considered a missed
dose. Administration may resume at the next planned dosing date. A missed dose will not be made
up.
Table 3: 
Daratumumab-Related Toxicity Management
Cycles 
Frequency  
Dose Held 
Dosing Re start
1 and 2 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date
3 to 6 
Biweekly (q2wks)` 
>1 week  
next planned biweekly dosing date
7+ 
Every 4 weeks (Q4W) 
>2 weeks 
next planned every 4 weeks dosing date
Doses of daratumumab may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up to 6 weeks
(Cycle 7 and beyond). Day 1 of a cycle should not be skipped; however, Day 1 of a cycle may be
delayed, and Day 1 of subsequent cycles should be adjusted accordingly to maintain the 28-day
cycle duration. However, if a within-cycle dose is delayed, then the dates of the subsequent
within-cycle doses should not be adjusted. Any adverse event deemed to be related to
daratumumab that requires a dose hold of more than 4 weeks (Cycle 1 to Cycle 6) or more than
6 weeks (Cycle 7 and beyond) will result in permanent discontinuation of daratumumab. If a dose
delay occurs, then pharmacokinetic and pharmacodynamic assessments should be performed on
the actual administration day of daratumumab, not on the original scheduled administration day.
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6.4.1.2. 
Daratumumab Interruption or Missed Doses
A daratumumab dose that is held for more than the permitted time (Table 3) from the per-protocol
administration date for any reason other than toxicities suspected to be related to daratumumab
should be brought to the attention of the Sponsor at the earliest possible time. Subjects whose dose
was delayed for more than 4 weeks (Cycle 1 to Cycle 6) or more than 6 weeks (Cycle 7 and
beyond) should have study treatment discontinued, unless, upon consultation with the sponsor and
the review of safety and efficacy, continuation is agreed upon. Infusion-related reactions may
occur upon re-initiation of daratumumab after a prolonged delay in  treatment and subjects
receiving daratumumab SC should have prolonged observation following the first dose post re-
initiation.
6.4.2. 
Lenalidomide Dose Reductions
Dose adjustments of lenalidomide will follow the approved labeling as follows:
 
Starting dose: 25 mg
 
Dose level 1: 15 mg
 
Dose level 2: 10 mg
 
Dose level 3: 5 mg
Dose adjustments should be based on the highest grade of toxicity that is ascribed to lenalidomide.
After initiation of lenalidomide, subsequent lenalidomide dose adjustment is based on individual
subject treatment tolerance. If the investigator determines that an adverse event may be related to
lenalidomide, dose adjustment can be done even if not specified in this protocol. In the event of a
dose adjustment, lenalidomide doses maybe re-escalated at the investigator’s discretion.
6.4.2.1. 
Thrombocytopenia
If the subject’s platelet count decreases, dose adjustments should be made according to the
recommendations in Table 4.
Table 4: 
Lenalidomide Dose Adjustment for Thrombocytopenia
Platelet Count 
Recommended Course of Action
 
When count first falls to <30 109/L
 
When count returns to 30 109/L
 
Interrupt lenalidomide treatment, follow complete
blood count weekly
 
Resume lenalidomide at the next lower dose
 
For each subsequent drop in count to <30 109/L
 
When count returns to 30 109/L
 
Interrupt lenalidomide treatment
 
Resume lenalidomide at the next lower dose
6.4.2.2. 
Neutropenia
If the subject experiences neutropenia, the investigator should consider the use of growth factors
in the subject’s management. If the subject’s neutrophil count decreases further, dose adjustments
should be made according to the recommendations in Table 5.
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Table 5: 
Lenalidomide Dose Adjustment for Neutropenia
Neutrophil Count 
Recommended Course of Action
 
When count first falls to <1.0 109/L
 
When count returns to 1.0 109/L and neutropenia is
the only observed toxicity
 
Interrupt lenalidomide treatment, consider G CSF
treatment, follow complete blood count weekly
 
Resume lenalidomide at 25 mg daily or initial starting
dose
 
When count returns to 1.0 109/L and dose dependent
hematological toxicities other than neutropenia are
observed
 
Resume lenalidomide at the next lower dose
 
For each subsequent drop in count to <1.0 109/L
 
When count returns to 1.0 109/L
 
Interrupt lenalidomide treatment
 
Resume lenalidomide at the next lower dose level
6.4.2.3. 
Renal Impairment
Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the dose of
lenalidomide are recommended to provide appropriate drug exposure in subjects with moderate or
severe renal impairment. Lenalidomide dose adjustment should be instituted for subjects with a
creatinine clearance of 50 mL/minute or less. The recommended doses for subjects with multiple
myeloma and renal impairment are shown in Table 6.
Table 6: 
Lenalidomide Dose Adjustment for Renal Impairment
Category  
Renal Functiona 
Dose
Moderate renal impairment 
CrCl 30 50 mL/min  
10 mg every 24 hours
Severe renal impairment 
CrCl <30 mL/min (not requiring 
dialysis)
15 mg every 48 hours
End stage renal disease 
CrCl <30 mL/min (requiring dialysis) 
5 mg once daily. On dialysis days, administer
the dose after dialysis
Key: CrCl
creatinine clearance.
a 
Estimated by creatinine clearance as calculated by the Cockcroft Gault equation and adjusted for body weight in subjects
with a body mass index >30 kg/m2.
6.4.2.4. 
Other Adverse Events
For other Grade 3 or 4 non-hematologic and non-renal toxicities judged by the investigator to be
related to lenalidomide alone, treatment with lenalidomide should be interrupted and restarted at
the next lower dose level once the toxicity has resolved to Grade 2 or less. Treatment with
daratumumab and dexamethasone may continue.
Note that the dose modifications above are suggested, but physician discretion and clinical
judgment should prevail.
6.4.3. 
Dexamethasone Dose Modifications
Dexamethasone may be reduced, if necessary, according to Table 7. For other Grade 3 or 4
non-hematologic and non-renal toxicities judged by the investigator to be related to
dexamethasone alone, treatment with dexamethasone should be interrupted and restarted at the
next lower dose level once the toxicity has resolved to Grade 2 or less. Treatment with
daratumumab and lenalidomide may continue. In the event of a dose adjustment, dexamethasone
doses maybe re-escalated at the investigator’s discretion. For complete details on dexamethasone,
refer to the most current local product prescribing information.
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Note that Table 7 represents suggested dose modifications of dexamethasone, but physician
discretion and clinical judgment should prevail.
If weekly dexamethasone dosing has been reduced below 10 mg due to adverse events during
study, a minimum of dexamethasone 10 mg IV should continue to be administered prior to
daratumumab doses.
Table 7: 
Recommended Dose Reduction for Dexamethasone
CTCAE Category  
Toxicity  
Dose Change
Gastrointestinal 
Grade 1 2 Dyspepsia, gastric or 
duodenal ulcer, gastritis 
requiring medical management 
Treat with H2 blockers, sucralfate, or omeprazole. If symptoms
persist despite above measure, decrease dexamethasone dose by
50%.
> Grade 3 requiring 
hospitalization or surgery  
Hold dexamethasone until symptoms adequately controlled.
Restart at 50% of current dose along with concurrent therapy with
H2 blockers, sucralfate or omeprazole. If symptoms persist despite
above measure, discontinue dexamethasone and do not resume.
Acute pancreatitis 
Discontinue dexamethasone and do not resume
Cardiovascular 
>  Grade 3 Edema limiting 
function and unresponsive to 
therapy or anasarca 
Diuretics as needed and decrease dexamethasone dose by 25%; if
edema persists despite above measures, decrease dose to 50% of
initial dose; discontinue dexamethasone and do not resume if
symptoms persist despite 50% reduction
Neurology/ 
Psychiatric 
>  Grade 2 interfering with 
function but not interfering with 
activities of daily living 
Hold dexamethasone until symptoms adequately controlled.
Restart at 50% of current dose. If symptoms persist despite above
measure, discontinue dexamethasone and do not resume
Musculoskeletal 
>  Grade 2 Muscle weakness 
Symptomatic and interfering 
with function but not interfering 
with activities of daily living 
Decrease dexamethasone dose by 25%; if weakness persists
despite above measures, decrease dose to 50% of initial dose;
discontinue dexamethasone and do not resume if symptoms persist
despite 50%
Metabolic 
>  Grade 3 Hyperglycemia 
Treatment with insulin or oral hypoglycemic agents as needed. If
uncontrolled despite above measure, decrease dose by 25%
decrements until levels are satisfactory
7. 
TREATMENT COMPLIANCE
Study drug (daratumumab) will be administered by qualified site staff, and the details of each
administration will be recorded in the electronic case report form (eCRF). Subjects will be
provided with a treatment diary which will be used to assess compliance with lenalidomide and
dexamethasone treatment. Additional details are provided in the SIPPM or equivalent document.
8. 
CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 8.3. The
sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which
prohibited therapies are administered.
Routine systemic use of the following concomitant medications will be collected in the eCRF and
recorded in the source documents beginning with signing of the ICF to 30 days after the last dose
of the last study treatment until the long-term survival follow-up starts (defined in Section 9.1.8),
or until the start of subsequent anti-myeloma treatment, if earlier: growth factors, transfusions,
anti-infectives (antibacterials, antivirals, and antimycotics), steroids, anti-arrhythmics and other
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cardiac supportive therapy, anti-epileptics, centrally acting psychiatric medication, anti-histamines
and other medications targeting post-dose systemic reactions, bisphosphonates, and any anti-
myeloma therapy (including radiation). Concomitant medications to manage adverse events and
SAEs will be recorded as per Section 12.3.1.
8.1. 
Recommended Therapies
8.1.1. 
Prevention of Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide has been associated with increased incidence of deep vein thrombosis and
pulmonary embolism. Therefore, prophylaxis of venous thromboembolism (VTE) for all subjects
is recommended according to IMWG guidelines as well as at the investigator’s discretion
(Palumbo 2008).28 Both individual and myeloma-related risks of VTE should be taken into account
in determining the type of thromboprophylaxis. In summary:
 
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, low molecular weight heparin (LMWH) (equivalent of
enoxaparin 40 mg once daily) or full-dose warfarin, international normalized ratio (INR) 2-3,
is recommended
 
If any myeloma therapy-related risk factor is present, then LMWH (equivalent of 40 mg
enoxaparin once daily) or full-dose warfarin (target INR 2-3) is recommended
8.1.2. 
Bisphosphonate Therapy
Bisphosphonate therapy is recommended to be continued per treatment guidelines
(NCCN 2013).23 Commercially available IV bisphosphonates (pamidronate and zoledronic acid)
are preferred when available, and should be used according to the manufacturer’s
recommendations, as described in the prescribing information, for subjects with osteolytic or
osteopenic myelomatous bone disease. Oral bisphosphonates may be used as alternatives if IV
bisphosphonates are not available at the study site.
Subjects who are currently using bisphosphonate therapy when they enter the study should
continue the same treatment. If clinically indicated, subjects may initiate bisphosphonate therapy
as soon as possible during Screening and no later than the end of Cycle 1. After Cycle 1,
investigators should not prescribe bisphosphonates to subjects who have not received it before,
unless it has been discussed with the sponsor and there is no sign of disease progression.
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8.1.3. 
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor lysis
syndrome, including hydration and monitoring for abnormal laboratory test results such as
hyperkalemia, hyperuricemia, and hypocalcemia, are highly recommended. It is also
recommended that high-risk subjects, ie, those with a high tumor burden, be treated
prophylactically in accordance with local standards (eg, rehydration; diuretics; allopurinol 300 mg
daily and medication to increase urate excretion).
8.1.4. 
Prophylaxis for Pneumocystis carinii
Pneumocystis carinii pneumonia (PCP) prophylaxis should be considered, as per institutional
guidelines.
8.1.5. 
Prophylaxis for Herpes Zoster Reactivation
Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase, as per
institutional guidelines.
8.1.6. 
Prevention of Steroid Induced Gastritis
Dexamethasone and other steroids may induce gastritis. Medications to prevent gastritis are
permitted per institutional guidelines, for example proton pump inhibitors (omeprazole or
equivalent) or sucralfate, or H2 blockers (ranitidine or equivalent).
8.1.7. 
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, hepatitis B
virus (HBV) DNA testing by polymerase chain reaction (PCR) is required 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 standard of care.
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 blood cells. If
erythropoietin is given, then this should be given according to the local lenalidomide label, as
there is an increased risk of thrombosis with lenalidomide.
 
It is important to prevent constipation (eg, adequate hydration, high-fiber diet, and stool
softeners if needed)
 
Adequate hydration is recommended for prevention of myeloma-related kidney disease
 
Prophylactic antiemetics, with the exception of corticosteroids
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 
Vaccination is allowed per local guidelines (see Section 8.3 for Prohibited Therapies).
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered (see Section 8.3).
8.3. 
Prohibited Therapies
Concomitant administration of any other antineoplastic therapy for the intention of treating
multiple myeloma is prohibited prior to confirmation of disease progression, including
medications that target CD38, as well as clarithromycin (Ghosh 2013).12 For management of
second primary malignancies please see Section 10.2. Continuation of the study treatment during
or after emergency orthopedic surgery or radiotherapy because of the subject’s benefit may occur
only in the absence of disease progression and after review by the sponsor. Such emergency
radiotherapy may consist of localized radiotherapy for pain control or for stabilization of an
extensive bone lesion at high risk of pathologic fracture or damage to surrounding tissues in a
subject in whom delay of systemic therapy is not appropriate. Such radiotherapy is to occur within
the first 2 cycles of treatment and the absence of evidence of disease progression is to be reviewed
by the sponsor.
Concomitant administration of investigational agents is prohibited. Administration of
commercially available agents with activity against or under investigation for multiple myeloma,
including systemic corticosteroids (>10 mg prednisone per day or equivalent) should be avoided
(other than those given for infusion-related reactions as described in Section 6.1.4.2 or for the
treatment of adverse events [if no other treatment options are available]). Nonsteroidal
anti-inflammatory agents should be used with caution in order to prevent myeloma-related kidney
disease.
Administration of live attenuated and replication-competent viral vector vaccines are prohibited.
Typically, IV contrast is NOT used in computed tomography (CT) scanning of the subjects with
secretory multiple myeloma because of the risk to the kidney. If administration of IV contrast is
necessary, then adequate precautions including hydration are indicated. The sponsor must be
notified in advance (or as soon as possible thereafter) of any instances in which prohibited
therapies are administered.
8.4. 
Subsequent Therapies
After discontinuation of study therapy subjects should continue disease evaluations per the Time
and Events Schedule until confirmed PD or until the cut-off date for the final CSR analysis,
whichever is earlier. Subsequent anti-myeloma therapy cannot be started before disease
progression is established per the IMWG criteria (Section 9.2.1.1, Response Categories) and
confirmed by the sponsor. This sponsor confirmation is no longer required after the cut-off for the
final CSR analysis.
After PD  (and sponsor confirmation when required), choice of subsequent therapy is at the
discretion of the investigator. Subjects randomized to Arm A (Rd) may have the option to receive
daratumumab provided by the sponsor (in any subsequent line of therapy) if recommended by the
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investigator. Eligibility for and administration of daratumumab including safety management (eg,
infusion-related reactions and HBV monitoring) must be in accordance with local prescribing
information and local regulations. For these subjects, daratumumab should not be added to an
ongoing subsequent therapy regimen until the subject has progressed on that regimen. Subjects in
Arm A (Rd) who receive daratumumab after PD through the sponsor will remain in the long-term
survival follow-up phase of the study. Serious adverse events must be reported for these subjects
until 30 days after daratumumab is discontinued. Second primary malignancies will continue to be
reported until end of study.
All subsequent therapy for multiple myeloma (including start and end date, best response, and date
of progression to the subsequent therapy) should be documented in the appropriate section of the
eCRF, including during long-term survival follow-up.
9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy,
pharmacokinetic, immunogenicity, biomarker, patient reported outcomes, and safety
measurements applicable to this study. Every effort should be made to keep subjects on the planned
study schedule, including subjects who switch from daratumumab IV to daratumumab SC
following Amendment 8.
All visit-specific PRO assessments should preferably be conducted/completed before any tests,
procedures, or other consultations for that visit to prevent influencing subject perceptions. Refer
to Section 9.7 for details.
Blood collections for pharmacokinetic assessments should be kept as close to the specified time as
possible. Other measurements may be done earlier than specified timepoints if needed. Actual
dates and times of assessments will be recorded in the source documentation.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the subject's participation in the study.
The blood volume for the study is estimated at approximately 65 mL during screening and 360 mL
during the first year (approximately 20-35 mL per cycle for routine testing, plus additional PK and
biomarker samples). In the Follow-up Phase, subjects prior to PD will continue to have
approximately 20 mL blood drawn per month for serum disease evaluations. This includes
laboratory assessments associated with safety, efficacy, and pharmacokinetic evaluations, as well
as scientific research samples. Repeat or unscheduled samples may be taken for safety reasons or
for technical issues with the samples. After the final CSR analysis, no blood will be collected, only
local routine testing will be performed as per local institutional practice to ensure patients’ safety
for continued treatment.
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With the implementation of Amendment 8, site visits may be replaced with virtual visits or other
local arrangements in exceptional circumstances, with site visits resuming as soon as possible
thereafter.
9.1.2. 
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. The
Screening Phase begins when the first screening assessment is conducted (that was not performed
as part of the subject’s standard of care). During the Screening Phase, eligibility criteria will be
reviewed, and a complete clinical evaluation will be performed as specified in Time and Events
Schedule. Screening procedures will be performed within 21 days before randomization; however,
results of tests such as skeletal survey, radiologic tests (eg, magnetic resonance imaging [MRI] to
document baseline size of known or suspected extramedullary plasmacytomas; ECG; chest x rays
[or full chest CT scan]; or bone marrow aspirate or biopsy) performed up to 6 weeks (42 days)
before randomization  as routine standard of care for the subject’s disease can be used. See
Attachment 1 for the modified IMWG Diagnostic Criteria.
Subjects <65 years must have known presence of important comorbid condition(s) likely to have
a negative effect on the tolerability of high dose chemotherapy with SCT. Documentation of the
condition, for example diagnosis of concomitant infectious disease(s), should be provided.
Sponsor review and approval of subjects under 65 years of age is required before randomization.
A negative pregnancy test for women of childbearing potential must be documented twice, once
within 10-14 days before the first dose and a second time within 24 hours before the first dose of
any component of the treatment regimen.
All attempts should be made to determine eligibility of the subject based on the central laboratory
results of Screening blood and urine M-protein measurements. In exceptional circumstances, the
local laboratory results of blood and urine M-protein measurements may be used to determine
eligibility, but only if the results are clearly (eg, 25% or more) above the thresholds for
measurability.
9.1.3. 
Treatment Phase
Details of the procedures performed during the Treatment Phase are outlined in the Time and
Events Schedule. Subjects should start study treatment within 72 hours after randomization. A
window of ±3 days is allowed for Day 1 of each cycle visits to the clinic. Each cycle is 28 days.
The first visit of a cycle should be 4 weeks after the start of the previous cycle. The start of each
cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or
subject. Day 1 of subsequent cycles should be adjusted accordingly to maintain the 28-day cycle
duration. In Cycles 1 through 6, weekly or bi-weekly daratumumab infusions may be given within
±1 day of the scheduled day in order to accommodate the schedule of the site or subject. In all
cycles, weekly dexamethasone doses may be given within ±1 day of the scheduled day in order to
accommodate the schedule of the site or subject. Changes to within-cycle dosing should not impact
Day 1 of the next cycle. Subjects will be closely monitored for adverse events, laboratory
abnormalities, and clinical response. Clinical evaluations and laboratory studies may be repeated
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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.
If disease progression has not occurred at the time of the End-of-Treatment visit, disease
evaluations must continue until disease progression is confirmed. Subsequent anti-myeloma
treatment will not be started until after disease progression is confirmed by the Sponsor. After the
cut-off for the final CSR analysis, confirmation of PD by the sponsor is no longer required.
For those subjects continuing treatment after the final CSR analysis, routine safety monitoring
should comply with the local institution practice (Attachments 11 and 12).
End-of-Treatment Visits
Unless a subject withdraws consent for study participation or is lost to follow up, an
End-of-Treatment Visit is to occur within 4 weeks after the last dose of all study treatments. Every
effort should be made to conduct the End-of-Treatment Visit before the subject starts subsequent
treatment. If a subject is unable to return to the site for the End-of-Treatment Visit, then the subject
should be contacted to collect information on adverse events that occur up to 30 days after the last
dose of study treatment. Additional information on reporting of adverse events is presented in
Section 12.
After the final CSR analysis, end of treatment visits are no longer required.
9.1.4. 
Follow-up Phase
The Follow-up Phase will begin once a subject discontinues all study treatments. Subjects who
discontinue study treatment before disease progression must continue to have disease evaluations.
Ideally, the timing of disease evaluations should follow the Time and Events Schedule until
confirmed PD (see Section 8.4, Subsequent Therapies), death, the start of a new anti-myeloma
therapy, withdrawal of consent, lost to follow-up, or the end of the study. After disease progression
is documented, subsequent anti-myeloma therapy, PFS2 (per investigator judgment), second
primary malignancies and survival status will be obtained at least every 16 weeks ±2 weeks until
the start of the long-term survival follow-up. Every 16-week follow-up contacts, as well as Week
8 and Week 16 post-PD ECOG and ePRO assessments, should be scheduled from the date of
confirmed progression (ie, the date of the confirmatory laboratory assessment, not the date of
confirmation by the sponsor). In subjects for whom disease progression will not be documented
(eg, received subsequent anti-myeloma treatment or refused disease evaluations, but agreed to
follow-up contacts), the every 16-week follow-up should be scheduled from the date of the
End-of-Treatment Visit.
For Follow-up Phase procedures during long-term survival follow-up, please see Attachment 11.
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.
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9.1.5. 
Assessments Following the Positive Second Interim Analysis of PFS
Following the positive second interim analysis of PFS, subjects remaining in the study will
continue to be monitored as follows until the next interim analysis of OS (ie, when 260 deaths
have occurred):
Subjects who Have had Disease Progression
For subjects whose disease has already progressed, every-16-week follow-up contacts should be
performed to capture:
 
Survival
 
Subsequent anti-myeloma therapy
 
New second primary malignancies
These data may be collected directly from subject or indirectly (eg, from medical correspondence
or visits).
Subjects who Have not had Disease Progression
For subjects in the randomized portion of the study who have not experienced disease progression,
disease assessments will continue to occur per the Time and Events Schedule until disease
progression is confirmed by the sponsor.
ECOG and ePRO will be collected every 6 months (± 14 days)until PD. Also 8 and 16 weeks after
PD (see Section 9.1.4).
9.1.6. 
Assessments Following Implementation of Amendment 8
Following the implementation of Amendment 8, disease evaluations are to be performed locally
per the site’s standard of care. Quantitative immunoglobulin testing is no longer required. All
subjects must still meet IMWG criteria for progression (see Table 8), prior to initiation of
subsequent anti-myeloma therapy.
Daratumumab pharmacokinetic, anti-daratumumab antibody, and rHuPH20 immunogenicity
sampling at EOT and 8 weeks after the last daratumumab SC dose are required for subjects who
switch from daratumumab IV to daratumumab SC treatment. Following Amendment 8, subjects
in Arm B who remain on daratumumab IV will no longer have pharmacokinetic and
immunogenicity samples collected.
9.1.7. 
Assessments Following the Interim OS Analysis
Following the interim OS analysis (ie, when 260 deaths have occurred), subjects remaining in the
study will continue to be monitored as follows until the cut-off for the final CSR analysis:
 
For subjects whose disease has already progressed at the time of the interim OS analysis, only
survival, subsequent anti-myeloma therapy, PFS2 and all new second primary malignancy
information will be collected, which may be obtained directly from subject or indirectly
(eg, from medical correspondence or visits).
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 
Once the interim OS analysis has occurred and when the median PFS is reached in the DRd
arm, the sponsor will notify the investigators that from that point onward, sponsor
confirmation of disease progression will no longer be required, with the exception of subjects
who progress on the Rd arm and then request subsequent therapy with daratumumab
(Section 8.4). All subjects must still meet IMWG criteria for progression (see Table 8), prior
to initiation of subsequent anti-myeloma therapy.
9.1.8. 
Final CSR Analysis and Long-term Survival Follow-up
Sites will be notified by the sponsor of the clinical cut-off date for the final CSR analysis.
Following the final CSR analysis, which will provide updates to the primary CSR analysis for both
efficacy and safety, all subjects will enter long-term survival follow-up. Attachment 11 describes
study procedures to be followed for subjects in the long-term survival follow-up phase. Long-term
survival follow-up will continue until the final OS analysis (defined in Section 9.1.9).
9.1.9. 
Final OS analysis Until End of Study
Sites will be notified by the sponsor of the clinical cut-off date for the final OS analysis, which
will occur when approximately 390 deaths have occurred. After the final OS analysis, all eCRF
data collection will end. Attachment 12 describes study procedures to be followed for subjects who
continue study treatment after the final OS analysis until the end of study (defined in
Section 17.9.1).
9.2. 
Efficacy
9.2.1. 
Evaluations
Disease response and progression will be based on assessments from IMWG Guidelines as defined
in Section 9.2.1.1. Previous studies have demonstrated potential interference of therapeutic
monoclonal antibodies with detection of endogenous myeloma M-protein on serum
immunofixation (IFE) (McCudden 2010).22 Daratumumab detection on serum immunofixation has
been demonstrated in subjects treated with 16 mg/kg, and may interfere with the traditional IMWG
criteria of negative serum IFE for complete response or stringent complete response. To mitigate
this interference, the sponsor has developed a reflex assay that utilizes anti-idiotype antibody to
bind daratumumab and confirm its interference on IFE (see laboratory manual). For all subjects
with VGPR, and a negative endogenous M-protein by serum M-protein quantitation by
electrophoresis (SPEP), reflex IFE testing will be performed to confirm the presence of
daratumumab on IFE.
9.2.1.1. 
Response Categories
Disease evaluations must be performed every 28 days for the first 2 years and then every 8 weeks
until disease progression (or other reasons as per Section 10). A window of ±7 days is allowed. If
treatment has been delayed for any reason, the disease evaluations must be performed according
to schedule, regardless of any changes to the dosing regimen.
Disease evaluations will be performed by a central laboratory (unless otherwise specified). This
study will use the IMWG consensus recommendations for multiple myeloma treatment response
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criteria (Durie 2006, Rajkumar 2011)7,32 presented in Table 8. For quantitative immunoglobulin,
M-protein, and immunofixation measurements in serum and 24-hour urine, the investigator will
use results provided by the central laboratory. Subjects with positive serum IFE and confirmed
daratumumab IFE interference, that meet all other clinical criteria for complete response or
stringent complete response, will be considered CR/sCR.
Disease progression must be consistently documented across clinical study sites using the criteria
in Table 8. For patients with measurable disease by SPEP or UPEP at baseline, increases in serum
free light chains (FLC) or the FLC ratio alone do not meet criteria for progressive disease.
Table 8: 
International Uniform Response Criteria Consensus Recommendations
Response 
Response Criteria
Stringent complete 
Response (sCR) 
 
CR as defined below, plus
 
Normal FLC ratio, and
 
Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2 to 4 color flow
cytometry
Complete 
response (CR)* 
 
Negative immunofixation on the serum and urine, and
 
Disappearance of any soft tissue plasmacytomas, and
 
<5% PCs in bone marrow
Very good partial 
Response 
(VGPR)* 
 
Serum and urine M component detectable by immunofixation but not on electrophoresis,
or
 
≥90% reduction in serum M protein plus urine M protein <100 mg/24 hours
Partial response 
(PR) 
 
≥50% reduction ofserum M protein and reduction in 24 hour urinary M protein by ≥90% or to
<200 mg/24 hours
 
If the serum and urine M protein are not measurable, a decrease of ≥50% in the difference between
involved and uninvolved FLC levels is required in place of the M protein criteria
 
In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue
plasmacytomas is also required.
Stable disease 
(SD)
 
Not meeting criteria for CR, VGPR, PR, or progressive disease
Progressive 
disease (PD)†
 
Increase of 25% from lowest response value in any one of the following:
 
Serum M component (absolute increase must be ≥0.5 g/dL),
 
Urine M component (absolute increase must be ≥200 mg/24 hours),
 
Only in subjects without measurable serum and urine M protein levels: the difference between
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)
 
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
FLC  free light chain; PC  plasma cell
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the
institution of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new
bone lesions if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of
whether disease at baseline was measurable on serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be
confirmed. For PD, serum M component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting
M component is ≥5 g/dL.
* Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC
levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in
such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.
† Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be used only in subjects without
measurable disease by M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow results,
and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response value” does not
need to be a confirmed value.
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
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Clinical Relapse
Clinical relapse is defined using the definition of clinical relapse in the IMWG criteria (Durie 2006, Rajkumar 2011).7,32 In the
IMWG criteria, clinical relapse is defined as requiring one or more of the following direct indicators of increasing disease or
end organ dysfunction that are considered related to the underlying plasma cell proliferative disorder:
1. Development of new soft tissue plasmacytomas or bone lesions on skeletal survey, magnetic resonance imaging, or other
imaging
2. Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and at least
1 cm) increase as measured serially by the sum of the products of the cross diameters of the measurable lesion
3. Hypercalcemia (>11.5 mg/dL; >2.875mM/L)
4. Decrease in hemoglobin of more than 2 g/dL (1.25 mM) or to less than 10 g/dL
5. Rise in serum creatinine by more than or equal to 2 mg/dL (≥177 mM/L)
6. Hyperviscosity
In some subjects, bone pain may be the initial symptom of relapse in the absence of any of the above features. However, bone
pain without imaging confirmation is not adequate to meet these criteria in studies.
For continuation of treatment, the IMWG response will be determined on an ongoing basis by the
investigator. For data analysis and reporting, however, the sponsor will use a validated computer
algorithm that has been shown to provide consistent review of the data necessary to determine
disease progression and response according to the IMWG criteria. For CR/sCR, the IMWG criteria
require subjects to have a negative SPEP and serum IFE. As an immunoglobulin, daratumumab
can be picked up by SPEP and serum IFE and may cause false positive SPEP and IFE results. A
reflex assay has been developed by the sponsor to confirm daratumumab interference on these
assays.
Serum free light chain assay test results will be analyzed by the central laboratory for the
assessment of stringent complete response (sCR), according to the most recently published IMWG
criteria (Durie 2006).7 For subjects who discontinue study treatment before disease progression,
disease evaluations should continue to be performed as described in the Time and Events Schedule,
until confirmed disease progression (see Section 8.4, Subsequent Therapies), death, the start of a
new treatment for multiple myeloma, withdrawal of consent for study participation, lost to follow-
up, or until the final CSR analysis, whichever occurs first. Disease evaluations scheduled for
treatment days should be collected before study treatment is administered.
During the long-term survival follow-up until final OS analysis (defined in Section 9.1.9), subjects
still receiving study treatment will have efficacy evaluations performed as detailed in
Attachment 11.
After the final OS analysis until the end of study (defined in Section 17.9.1) subjects still receiving
study treatment will have efficacy evaluations performed as detailed in Attachment 12.
9.2.1.2. 
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the
central laboratory to perform the following tests. If the 24-h urine collection (UPEP) began before
informed consent was obtained as part of routine patient care, the sample can be used in this study
as long as it was sent to the central lab for analysis after the informed consent was obtained.
 
Serum quantitative immunoglobulins (QIgs)
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 All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD at Screening. Every
16 weeks during treatment and at the EOT visit, subjects with IgD or IgE disease will be
evaluated for IgG, IgA, IgM, IgE, and IgD and subjects with IgG, IgA, or IgM disease
will be evaluated for IgG, IgA, and IgM.
 
Serum M-protein quantitation by electrophoresis (SPEP)
 
Serum immunofixation at Screening and thereafter when a CR is suspected or maintained. If
daratumumab interference is suspected based on SPEP and IFE results, additional reflex IFE
testing may be performed.
 
Serum free light chain assay (monthly for subjects with free light chain (FLC) disease, all
others per Time and Events Schedule)
 
24-hour urine M-protein quantitation by electrophoresis (UPEP)
 
Urine immunofixation at Screening and thereafter when a CR is suspected or maintained.
Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule
until the development of confirmed disease progression. After subjects have completed 24 months
of study treatment, the timing of collection for SPEP and UPEP (and the timing of collection of
FLC for subjects with light chain multiple myeloma) will change from every 4 weeks to every
8 weeks. Disease progression based on 1 of the laboratory tests alone must be confirmed by at least
1 repeat investigation performed at least 1 day later. Disease evaluations will continue beyond
relapse from CR until disease progression is confirmed. Serum and urine immunofixation test and
serum free light chain assay will be performed at Screening and thereafter when a CR is suspected
(when serum or 24-hour urine M-protein electrophoresis [by SPEP or UPEP] are 0 or
nonquantifiable) or maintained. However, for subjects with light chain multiple myeloma, serum
free light chain assay will be performed routinely. Serum immunofixation (IFE) assay samples
will be split into 2 aliquots, with 1 reserved for potential follow-on testing if daratumumab
interference with IFE is suspected. As daratumumab is a monoclonal IgG antibody, additional
serum samples may be utilized to monitor for potential daratumumab interference with the IFE.
9.2.1.3. 
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected and analyzed
centrally (as specified in the Time and Events Schedules) until the development of confirmed
disease progression. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or
2.8 mM/L) can indicate disease progression or relapse if it is not attributable to any other cause
(see disease response criteria). Calcium binds to albumin and only the unbound (free) calcium is
biologically active; therefore, the serum calcium level must be adjusted for abnormal albumin
levels (“corrected serum calcium”). The formula for adjustment is presented in Attachment 4.
Measurement of free ionized calcium is an acceptable alternative to corrected serum calcium for
determining hypercalcemia. Free ionized calcium levels greater than the ULN (local laboratory
reference ranges) are considered to be hypercalcemic for this study.
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9.2.1.4. 
β2-microglobulin and Albumin
Blood samples for β2 microglobulin and albumin are to be collected at Screening, and will be
analyzed by the central laboratory.
9.2.1.5. 
Bone Marrow Examination
Bone marrow aspirate or biopsy will be performed at Screening for clinical characterization
(morphology, IHC or immunofluorescence or 2- to 4- color flow cytometry, and cytogenetics), to
establish baseline multiple myeloma clonality to monitor for MRD and to perform molecular
subtyping to monitor daratumumab activity in high-risk molecular subgroups. Good quality slides
are required for morphological examination to determine plasma cell percentage in the bone
marrow. Assessment by flow cytometry alone is not sufficient. Bone marrow examination for
disease assessment will be performed locally; however, a portion of the bone marrow aspirate must
be sent to the central laboratory for analysis of MRD and molecular subtyping. A fresh bone
marrow aspirate at screening is required if at all possible, by exception non-decalcified diagnostic
tissue (bone marrow aspirate slides or FFPE tissue) may be supplied for MRD assessment instead.
Additional bone marrow aspirates will be performed to confirm sCR and CR (only one analysis is
required, with either IHC or immunofluorescence or 2- to 4- color flow cytometry included in the
analysis) and to monitor for MRD at time points detailed in Table 9. If feasible, a bone marrow
aspirate may be collected from subjects at disease progression to evaluate mechanisms of
daratumumab resistance.
Bone marrow assessments to be performed locally and centrally are summarized in Table 9.
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Table 9: 
Bone Marrow Testing
Local Testing 
Central Testing
Screening 
Disease characterization (morphology, and 
either immunohistochemistry, 
immunofluorescence, or flow cytometry). 
Cytogenetic analysis by conventional 
karyotype or FISH. 
MRD and molecular subtyping: a portion of bone
marrow aspirates collected at screening will be sent to a
central laboratory.
If a fresh bone marrow aspirate will not be performed at
screening because the procedure has already been done
within 42 days prior to randomization, then the
unstained or stained, non decalcified diagnostic tissue
(3 5 bone marrow aspirate smears, or 3 5 touch prep
slides from biopsy, or 3 5 bone marrow clot slides)
should be collected for MRD assessment at baseline.
During Treatment 
At time of suspected CR/sCR: 
Evaluate Plasma cell percentage in the 
bone marrow to confirm CR  
Evaluate clonality of plasma cells (by flow
cytometry, IHC or IF**) in the bone
marrow to confirm sCR
(If sCR criteria are not met, repeat local
testing for sCR with subsequent bone
marrow testing.)
A portion of bone marrow aspirates collected at time of
suspected CR/sCR, and 12, 18, 24, 30, 36, 48, and 60
(+/ 1) months post C1D1, will be analyzed for MRD*.
Disease Progression  Not applicable. 
If feasible, a bone marrow aspirate is requested to be
collected from subjects at disease progression and sent
to central laboratory to evaluate mechanisms of
daratumumab resistance.
CR complete response; FISH fluorescence in situ hybridization; MRD minimal residual disease; sCR stringent complete
response
* If one of these time points occurs within 1 month of suspected CR/sCR, a repeat bone marrow will not be requested.
These bone marrow tests will only be required if patient’s response is near CR or better by blood and urine evaluations.
** Immunohistochemistry or immunofluorescence (both require kappa/lambda ratio from analysis of >100 plasma cells) or 2
to 4 color flow cytometry are acceptable methods to evaluate plasma cell clonality.
9.2.1.6. 
Minimal Residual Disease Assessment
Minimal Residual Disease (MRD) assessment by next-generation sequencing (NGS) is a relatively
new and effective tool in the assessment of patients with multiple myeloma (Ladetto 2014).20
Several studies have demonstrated that MRD status is correlated with PFS and OS
(Martinez-Lopez 2014).21 In this study, bone marrow 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.
9.2.1.7. 
Assessment of Lytic Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, femora,
and any other bones for which the investigator suspects involvement by disease) is to be performed
and evaluated locally by X-ray or low-dose CT during the Screening Phase. Please note that the
same methodology used at Screening should be used throughout the study for comparison
purposes. During the Treatment Phase and before disease progression is confirmed, imaging
should be performed whenever clinically indicated based on symptoms, to document response or
progression. Magnetic resonance imaging (MRI) may be included as an additional assessment at
the discretion ofthe investigator; however, focal lesions identified by MRI alone cannot be counted
as lytic disease. If a radionuclide 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
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performed at the same time. However, a radionuclide bone scan does not replace a complete
skeletal survey.
Sometimes subjects present with disease progression manifested by symptoms of pain due to bone
changes. Therefore, disease progression may be documented, in these cases, by skeletal survey or
other radiographs, depending on the symptoms that the subject experiences. If the diagnosis of
disease progression is obvious by radiographic investigations, then no repeat confirmatory imaging
is necessary. In instances where changes may be more subtle, repeat imaging may be performed
in 1 to 3 weeks per investigator discretion.
9.2.1.8. 
Documentation of Extramedullary Plasmacytomas
Sites of known extramedullary plasmacytomas must be documented during the Screening Phase.
Clinical examination or MRI may be used to document extramedullary sites of disease. Computed
tomography scan evaluations are an acceptable alternative if there is no contraindication to the use
of intravenous contrast. Positron emission tomography scan or ultrasound tests are not acceptable
to document the size of extramedullary plasmacytomas.
Extramedullary plasmacytomas should be assessed for all subjects with a history of
plasmacytomas or if clinically indicated at Screening, by clinical examination or radiologic
imaging. 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 development of
confirmed CR or confirmed disease progression. If assessment can only be performed
radiologically, then evaluation of extramedullary plasmacytomas may be done every 12 weeks.
For every subject, the methodology used for evaluation of each disease site should be consistent
across all visits. Irradiated or excised lesions will be considered not measurable, and will be
monitored only for disease progression.
To qualify for PR, the sum of products of the perpendicular diameters of the existing
extramedullary plasmacytomas must have decreased by at least 50%, and new plasmacytomas
must not have developed (see the disease response criteria in Table 8). To qualify for disease
progression, either the sum of products of the perpendicular diameters of the existing
extramedullary plasmacytomas must have increased by at least 50% or a new plasmacytoma must
have developed. In the cases where not all existing extramedullary plasmacytomas are reported,
but the sum of products of the perpendicular diameters of the reported plasmacytomas have
increased by at least 50%, this will also qualify as disease progression.
9.2.2. 
Endpoints
Primary Endpoints
The primary endpoint is PFS, which is defined as the duration from the date of randomization to
either progressive disease, or death, whichever occurs first. Disease progression will be determined
according to the IMWG criteria (Durie 2006, Rajkumar 2011).7,32 For subjects who have not
progressed and are alive, data will be censored at the last disease evaluation before the start of any
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subsequent anti-myeloma therapy. Relapse from CR by positive immunofixation or trace amount
of M-protein is not considered to be progressive disease and is not included in the PFS calculation. 
As the superiority of DRd over Rd alone with respect to PFS was established at the second interim
analysis, the interim PFS analysis will serve as the primary PFS analysis, which otherwise was to
occur when approximately 390 PFS events had been observed.
Secondary Endpoints
The secondary efficacy endpoints include:
 
Time to disease progression (TTP) is defined as the time from the date of randomization to
the date of first documented evidence of PD, as defined in the IMWG criteria. For subjects
who have not progressed, data will be censored at the date of the disease evaluation before the
start of any subsequent anti-myeloma therapy.
 
CR rate, defined as the percentage of subjects achieving CR, as defined:
 Negative immunofixation of serum and urine, and
 Disappearance of any soft tissue plasmacytomas, and
 <5% plasma cells (PCs) in bone marrow
 For those subjects with negative SPEP and suspected daratumumab interference on
immunofixation, a reflex assay using anti-idiotype antibody will be utilized to confirm
daratumumab interference and rule out false positive immunofixation. Subjects who have
confirmed daratumumab interference, but meet all other clinical criteria for CR or sCR,
will be considered CR/sCR.
 
MRD negativity rate, defined as the proportion of subjects assessed as MRD negative, at any
timepoint after the date of randomization.
 
Progression-free Survival on Next line of Therapy (PFS2), defined as the time from
randomization to progression on the next line of treatment or death, whichever comes first.
Disease progression will be based on investigator judgment. For those subjects who are still
alive and not yet progressed on the next line of treatment, they will be censored on the last
date of follow-up.
 
OS, measured from the date of randomization to the date of the subject’s death. If the subject
is alive or the vital status is unknown, then the subject’s data will be censored at the date the
subject was last known to be alive.
 
sCR rate, defined as the percentage of subjects achieving CR in addition to having a normal
FLC ratio and an absence of clonal cells in bone marrow by immunohistochemistry,
immunofluorescence, 2-4 color flow cytometry.
 
Time to next treatment, defined as the time from randomization to the start of the next-line
treatment.
 
Overall response rate (ORR), defined as the proportion of subjects who achieve PR or better,
according to the IMWG criteria, during or after the study treatment.
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 
Proportion of subjects who achieve VGPR or better, defined as the proportion of subjects
achieving VGPR and CR (including sCR) according to the IMWG criteria during or after the
study treatment at the time of data cut-off.
 
Time to response, defined as the time between the randomization and the first efficacy
evaluation that the subject has met all criteria for CR or PR. For subjects without response
(CR/PR), data will be censored either at the date of progressive disease or, in the absence of
progressive disease, at the last disease evaluation before the start of subsequent anti-myeloma
therapy.
 
Duration of response, calculated from the date of initial documentation of a response (PR or
better) to the date of first documented evidence of progressive disease, as defined in the
IMWG criteria. For subjects who have not progressed, data will be censored at the last disease
evaluation before the start of any subsequent anti-myeloma therapy.
 
To evaluate clinical efficacy of DRd in high risk molecular subgroups compared to Rd alone.
 
To evaluate the impact of DRd compared to Rd on patient-reported perception of global
health.
Exploratory Endpoints
 
Biomarkers predictive of response or resistance to daratumumab.
 
Durability of MRD negativity.
9.3. 
Pharmacokinetics and Immunogenicity
9.3.1. 
Evaluations
For subjects in Arm B, pharmacokinetic samples to determine the serum concentration of
daratumumab and immunogenicity samples to determine the generation of antibodies to
daratumumab will be obtained according to the Time and Events Schedule. In the Follow-up Phase,
for all subjects in Arm B (DRd), samples are to be collected for PK and immunogenicity
assessments 8 weeks after the last dose of daratumumab, regardless of whether there has been
confirmed disease progression. Daratumumab pharmacokinetic and anti-daratumumab antibody
sampling at EOT and 8 weeks after the last daratumumab SC dose are required for subjects who
switch from daratumumab IV to daratumumab SC treatment. Following Amendment 8, subjects
in Arm B who remain on daratumumab IV will no longer have pharmacokinetic and
immunogenicity samples collected.
Venous blood samples (5 mL per sample) will be collected to determine serum concentration of
daratumumab and the serum will be divided into 3 aliquots (1 aliquot for pharmacokinetic analysis,
1 aliquot for antibodies to daratumumab analysis [when appropriate], and 1 aliquot as a backup).
Samples collected for determining serum concentrations of daratumumab in this study may be
retained to address questions about drug characteristics that may arise at a later time point.
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Samples will also be collected from all subjects receiving daratumumab SC to evaluate the
immunogenicity of rHuPH20 according to the Time and Events Schedule. At specified time point,
venous blood samples (5 mL per sample) will be collected and the plasma will be divided into 5
aliquots to accommodate immunogenicity screening, confirmatory, and titer assays and
neutralizing antibody analysis (when appropriate) as well as volume for backup. The exact dates
and times of blood sampling must be recorded. Refer to the Laboratory Manual or equivalent
document for sample collection requirements. Collected samples must be stored under the
specified and controlled conditions for the temperatures indicated in the laboratory manual.
9.3.2. 
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of
antibodies to daratumumab using validated immunoassay methods by or under the supervision of
the sponsor’s bioanalytical facility.
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
The pharmacokinetic parameters are defined as:
CL 
Total systemic clearance of drug after IV administration
Cmax  
Maximum observed concentration
Cmin  
Minimum observed concentration
V 
Volume of distribution
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained from
all subjects. Pharmacokinetic endpoints include:
 Minimum observed concentration (Cmin)
 Maximum observed concentration (Cmax)
If sufficient data are available, then other pharmacokinetic parameters may be calculated,
including but not limited to total systemic clearance of drug after IV administration (CL) and
volume of distribution (V).
9.3.4. 
Immunogenicity Assessments (Antibodies to daratumumab and
rHuPH20)
Venous blood samples drawn from subjects in the DRd arm will be assessed for the generation of
antibodies to daratumumab (immunogenicity), according to the Time and Events Schedule. Plasma
samples will be collected from subjects treated with daratumumab SC according to the Time and
Events Schedule for the assessment of the generation of antibodies to rHuPH20. In the Follow-up
Phase, for subjects in Arm B (DRd), samples are to be collected for immunogenicity assessments
8 weeks after the last dose of daratumumab, regardless of whether there has been confirmed disease
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progression. Following Amendment 8, subjects in Arm B who remain on daratumumab IV will no
longer have immunogenicity samples collected.
All samples collected for immunogenicity analysis of daratumumab will also be evaluated for
daratumumab serum concentration to ensure appropriate interpretation of immunogenicity data.
At each time point, immunogenicity and serum daratumumab concentration analyses will be
performed on aliquots from the same blood draw and no additional sampling is required.
Procedures for sample collection, preparation, identification, storage, and shipment will be
provided in the Laboratory Manual or equivalent document.
Serum samples will be screened for antibodies binding to daratumumab and serum titer will also
be determined from confirmed positive samples using validated assay methods by or under the
supervision of the sponsor. Other immunogenicity analyses (eg, assessment of neutralizing
capabilities) may be performed to further characterize the immune responses that are generated.
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab (IV
or SC treatment) any time an infusion reaction is observed or reported during the study.
Daratumumab serum concentration will also be determined from the same infusion reaction
sample for the purpose of interpreting immunogenicity data. In the subjects receiving
daratumumab SC, a plasma sample should also be obtained for determination of antibodies to
rHuPH20. These samples will be stored and evaluated if deemed necessary. If the infusion reaction
results in treatment discontinuation, then subjects should undergo all scheduled safety and efficacy
evaluations. Samples collected for the analysis of daratumumab immunogenicity/serum
concentration or rHuPH20 immunogenicity may additionally be used to evaluate safety or efficacy
aspects that address concerns arising during or after the study period or for the evaluation of
relevant biomarkers by the sponsor or sponsor’s designee.
9.4. 
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other pharmacokinetic/pharmacodynamic modeling may be
performed, including exploring the relationship between serum concentrations of daratumumab
and endpoints of clinical efficacy. If these analyses are performed, then the details and results will
be presented in a separate report.
9.5. 
Biomarkers
Biomarker assessments will focus on 2 main objectives including evaluating the ability of
daratumumab + Rd to reduce MRD in subjects who achieve a complete response (compared to Rd
alone) and to determine the clinical benefit (ORR, PFS, and OS) of daratumumab + Rd in high-risk
molecular subtypes (del17p, t(4;14), t(14;16), specific gene signatures, specific mutations). Bone
marrow aspirates will be collected at screening and following treatment as outlined in the Time
and Events Schedule.  Baseline bone marrow aspirate samples will be subjected to DNA and RNA
sequencing in order to classify subjects into high-risk molecular subgroups and to establish the
myeloma clone for MRD monitoring. A fresh bone marrow aspirate at Screening is required if at
all possible, by exception non-decalcified diagnostic tissue (please see Table 9 Bone Marrow
Testing for further information) may be supplied for MRD assessment instead. For subjects who
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achieve a CR or sCR, bone marrow aspirates will be utilized for assessment of MRD by
next-generation sequencing (NGS) of immunoglobulin heavy and light chains (Vij 2013).40 If this
methodology is unavailable, or determined to be scientifically inferior, then alternative methods
for MRD assessment may be utilized. In cases where daratumumab is suspected of interfering with
serum IFE and preventing clinical CR response calls, subjects with VGPR will also be evaluated
for MRD by NGS.
In addition to planned bone marrow aspirate assessments, a whole blood sample will be collected
from subjects as outlined in the Time and Events Schedule for processing to plasma and PBMCs.
These samples may be used to evaluate specific subsets of immune cells such as cytotoxic T cells,
regulatory T cells, MDSCs, and activated NK cells. Cells may also be used for additional
phenotypic and functional profiling. Proteomic analysis may also be used to evaluate changes in
cytokines, complement proteins, soluble CD38, soluble CD59, IFNγ, granzyme, perforin, and
other proteins associated with ADCC/CDC/ADCP to evaluate potential biomarkers of response
and resistance.
Potential mechanisms of tumor resistance, such as changes in antigen (CD38) expression or
increased expression in complement inhibitory proteins (CD46, CD55, and CD59) in multiple
myeloma cells, may be monitored in subjects if a bone marrow aspirate sample is deemed feasible
for collection at progressive disease. In addition, changes in expression patterns of genes
associated with ADCC, CDC, or other mechanisms of action of daratumumab may be evaluated.
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may
be deferred or not performed if during or at the end of the study it becomes clear that the analysis
will have no scientific value, or if there are not enough samples or not enough responders to allow
for adequate biomarker evaluation. In the event the study is terminated early or shows poor clinical
efficacy, completion of biomarker assessments is based on justification and intended utility of the
data. Samples for biomarker evaluations will be collected as specified in the Time and Events
Schedule and may be used for additional biomarker testing that may arise at a later time point
(see Section 16.2.5).
9.6. 
Medical Resource Utilization
Medical resource utilization (MRU) data, including primary non-protocol driven hospitalizations,
outpatient visits, and emergency room visits, should be collected in the eCRF
(Hospitalization/Outpatient Visits CRF) by the Investigator and study-site personnel for all
subjects throughout the study. Please see CRF completion guidelines.
9.7. 
Patient Reported Outcomes
It is anticipated that the addition of daratumumab will provide benefits in terms of symptom
reduction, improved functioning, and improved utilities. To measure functional status, well-being,
and symptoms, the EORTC QLQ-C30 and the EQ-5D-5L instruments will be used. Both
questionnaires will be completed at the timepoints outlined in the Time and Events Schedule. All
visit-specific PRO assessments should be conducted before any tests, procedures, or other
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consultations for that visit to prevent influencing subject perceptions. All PRO measures will be
completed using an electronic device (ePRO). For more details refer to the ePRO user manual.
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning,
role functioning, emotional functioning, cognitive functioning, and social functioning), 1 Global
Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items
(dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The recall
period is 1 week (the past week). The EORTC QLQ-C30 has been widely used among cancer
patients. Scores are transformed to a 0 to 100 scale. Administration time is approximately
11 minutes. Reliability, validity, and clinically meaningful change have been demonstrated in
multiple myeloma patients (Wisloff 1996, Wisloff 1997).41,42 The focus of the PRO assessment
will be the global health scale which is designated as a secondary endpoint.  The remaining
domains are included as exploratory endpoints.
The EQ-5D-5L is a standardized instrument for use as a measure of health status. For purposes of
this study, the EQ-5D-5L will be used to generate utility scores for use in cost effective analyses.
The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care,
usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating “health
today” with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health
state) (Herdman 2011).13 The scores for the 5 separate questions are categorical and cannot be
analyzed as cardinal numbers. However, the scores for the 5 dimensions are used to compute a
single utility score ranging from zero (0.0) to 1 (1.0) representing the general health status of the
individual.
9.8. 
Safety Evaluations
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign measurements,
physical examination findings, and assessment of ECOG performance status score. Any clinically
relevant changes occurring during the study must be recorded on the Adverse Event section of the
eCRF. Any clinically significant abnormalities persisting at the final CSR analysis (defined in
Section 9.1.8)/early withdrawal will be followed by the investigator until resolution or until a
clinically stable endpoint is reached.
Based on the previous human experience with daratumumab, in vitro studies, and animal
toxicological 
findings, 
infusion-related 
reactions/allergic 
reactions, 
hemolysis, 
and
thrombocytopenia will be closely monitored. As a biologic agent, immunogenicity also will be
monitored. Any of the safety monitoring assessments may be performed more frequently, and
adverse events should be evaluated by the investigator according to the standard practice, if
clinically indicated.
Adverse Events
Adverse events (with the exception of progression of multiple myeloma) will be reported by the
subject (or, when appropriate, by a caregiver, surrogate, or the subject's legally acceptable
representative) for the duration of the study. Adverse events will be followed by the investigator
as specified in Section 12, Adverse Event Reporting.
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For subjects who continue to receive study treatment after the final CSR analysis, only serious
adverse events will be collected until end of study (defined in Section 17.9.1), as described in
Attachment 11 and Attachment 12.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology will be collected. The investigator must
review the laboratory report, document this review, and record any clinically relevant changes
occurring during the study in the adverse event section of the eCRF. The laboratory reports must
be filed with the source documents.
The tests below will be performed by the local laboratory unless otherwise noted.
 
Hematology Panel
-hemoglobin  
-white blood cell (WBC) count with absolute
neutrophils and lymphocytes
-platelet count
 
Serum Chemistry Panel
-blood urea nitrogen (BUN) or urea 
-alkaline phosphatase
-creatinine 
-lactic acid dehydrogenase (LDH)
-glucose 
-uric acid
-aspartate aminotransferase (AST) 
-total; direct bilirubin (not required except in case
of congenital bilirubinemia, such as Gilbert
disease)
-alanine aminotransferase (ALT) 
-creatinine clearance (calculated or 
measured) 
-total protein
-sodium*
-potassium*
*Sodium and potassium assessment was added in Protocol Amendment 2, however collection of sodium and
potassium results will be done retrospectively from the date of subject consent for the duration of the study, if
collected as part of routine care.
Serum or Urine Pregnancy Testing
For women of childbearing potential only: lenalidomide is a thalidomide analogue and is
contraindicated for use during pregnancy. Birth defects have been observed in preclinical studies
of lenalidomide similar to thalidomide in humans. Therefore, strict monitoring for pregnancy must
be conducted during Screening and throughout the Treatment Phase, as specified in the Time and
Events Schedule. Where lenalidomide is supplied locally, subjects must adhere to the local
lenalidomide REMS program. Where lenalidomide is supplied centrally and no local lenalidomide
REMS program exists, then subjects must adhere to the lenalidomide Global Pregnancy Prevention
Plan in Attachment 5.
If pregnancy or a positive pregnancy test does occur, then study treatment should be discontinued
immediately, and the subject should be referred to an obstetrician experienced in reproductive
toxicity for further evaluation and counseling.
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Calcium and Albumin Adjusted Calcium:
These parameters will be part of the efficacy evaluations as specified in Section 9.2.1.3, and will
be analyzed by the central laboratory. Measurement of calcium and albumin should follow the
schedule for disease assessments. Measurement of free ionized calcium is an acceptable alternative
to corrected serum calcium for determining hypercalcemia.
Daratumumab Interference with Indirect Antiglobulin Test (IAT) results:
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine
pre-transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/RhD typing.
CD38 is expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 on
erythrocytes, which results in a positive IAT (Indirect Coombs Test). This positive result masks
the detection of antibodies to minor antigens and may prevent or delay blood banks from issuing
donor blood for transfusion. This effect occurs during daratumumab treatment and for up to
6 months after treatment ends. Subjects will receive a patient identification wallet card for the
study that includes the blood profile (ABO, Rh, and IAT) determined before the first infusion of
daratumumab along with information on the IAT interference for healthcare providers/blood
banks. Subjects are to carry this card throughout the treatment period and for at least 6 months
after treatment ends. Blood banks can eliminate the daratumumab IAT interference by treating
reagent RBCs with dithiothreitol (DTT) (Chapuy 20154, Chapuy 2016).5
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving
daratumumab include:
 
Providing ABO/RhD compatible, phenotypically or genotypically matched units
 
Providing ABO/RhD compatible, K-negative units after ruling out or identifying
alloantibodies using dithiothreitol (DTT)-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is needed
emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant
hemolysis has been observed in daratumumab studies. For additional details, refer to the
Daratumumab IB.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during screening. Refer to
Section 6.1.4.2 for details on subjects with higher risk of respiratory complications.
Electrocardiogram (ECG)
ECGs will be performed as specified in the Time and Events Schedule. During the collection of
ECGs, subjects should be in a quiet setting without distractions (eg, television, cell phones).
Subjects should rest in a supine position for at least 5 minutes before ECG collection and should
refrain from talking or moving arms or legs. If blood sampling or vital sign measurement is
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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.
Vital Signs
Vital signs (pulse/heart rate, temperature, and blood pressure) will be performed as specified in
the Time and Events Schedule. It is recommended that blood pressure (sitting) and pulse
measurements be preceded by at least 5 minutes of rest in a quiet setting without distractions
(eg, television, cell phones). Only vital signs associated with an adverse event will be entered in
the eCRF; all measurements will be recorded in the source documents.
Physical Examination and ECOG Performance Status
A complete physical examination (including neurological examination) should be performed
during the Screening Phase. Thereafter, only a symptom and disease directed physical examination
is required. Height will be measured at screening only; weight will be measured regularly as
specified in the Time and Events Schedule. Abnormalities will be recorded in the appropriate
sections of the eCRF. ECOG Performance Status (Attachment 2) will be used to evaluate the
impact of the disease status on the activities of daily living. When scheduled, ECOG assessments
along with PRO questionnaires should be obtained prior to any other study procedures planned for
the same day.
HBV Serology and DNA Testing
Closely monitor subjects with a known history of hepatitis B infection or positive hepatitis B
serologies (HBsAg, Anti-HBc and/or Anti-HBs with exception of serologic findings suggestive of
HBV vaccination [Anti-HBs positivity as the only serologic marker] and a known history of prior
HBV vaccination)  who are enrolled in Arm B for clinical signs of active HBV infection and obtain
serial testing for HBV DNA every 3 months during treatment and for 6 months following the last
dose of daratumumab. If the hepatitis B serologic status of a subject in the DRd arm is unknown,
HBsAg, Anti-HBs, and Anti-HBc testing is recommended if the subject is still receiving
daratumumab (or is within 6 months after the last dose).
After the final CSR analysis until end of study (defined in Section 17.9.1), subjects still receiving
will have HBV DNA testing performed as detailed in Attachment 11 and Attachment 12.
9.9. 
Sample Collection and Handling
If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed
from the cannula and discarded before each blood sample is taken. After blood sample collection,
the cannula will be flushed with  0.9% sodium chloride, United States Pharmacopeia
(or equivalent)/sodium heparin of 10 U/mL and charged with a volume equal to the dead space
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
For samples collected from the central laboratory, sample dates and times must be recorded on the
laboratory requisition form. Further instructions for the collection, handling, storage, and shipment
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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.
Subjects still receiving study treatment after the final CSR analysis will have safety and efficacy
assessments performed as per local institution practice (see Attachments 11 and 12).
10. 
SUBJECT COMPLETION/WITHDRAWAL
10.1. Completion
A subject will be considered to have completed the study if he or she has finished all
protocol-specified procedures, has not been lost to follow up, or has not withdrawn consent for
study participation before the final OS analysis.
10.2. Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the treatment regimen, this
will not result in automatic withdrawal of the subject from the study. After treatment
discontinuation, the subject will move into the Follow-up Phase. The End-of-Treatment Visit and
Follow-up visit assessments should continue as specified in the Time and Events Schedule. If study
treatment is discontinued for a reason other than disease progression, then disease evaluations will
continue to be performed as specified in the Time and Events Schedule.
Subjects who need to discontinue treatment with any one component of study treatment
(lenalidomide, dexamethasone, or daratumumab) may continue to receive treatment with the other
components of study treatment, as assigned.
A subject's study treatment will be discontinued if:
 
The investigator believes that for safety reasons (eg, adverse event) it is in the best interest of
the subject to discontinue study treatment
 
The subject becomes pregnant or a positive pregnancy test does occur
 
The subject (or the subject’s legally acceptable representative) withdraws consent for
administration of study treatment
 
The subject initiates treatment with a prohibited medication
 
The subject received concurrent (non-protocol) treatment for multiple myeloma
 
The subject experiences unacceptable toxicity, including infusion-related reactions described
in Section 6.1.5
 
The subject’s dose of daratumumab is held for more than 4 weeks in Cycles 1- 6 or for more
than 6 weeks in Cycle 7 and beyond (unless Sponsor approves continuation)
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 
The subject experiences disease progression (please see below). Relapse from CR is not
considered as disease progression
A subject who experiences a second primary malignancy that can be treated by surgery may
continue to receive the assigned study treatment and the subject 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 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.
Before subjects discontinue study treatment due to disease progression, sites will document disease
progression (for example by completing a disease progression form or by contacting the IWRS) as
soon as possible and within 48 hours. The medical monitor will confirm that treatment should be
discontinued. After confirmation from the sponsor, study treatment may be discontinued and the
subject entered into Follow-up.
The primary reason for discontinuation of study treatment is to be recorded in the eCRF.
10.3. Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent for study participation
 
Death
 
The study investigator or Sponsor, for any reason, stops the study or stops the subject’s
participation in the study
Before a subject is considered lost to follow-up, every reasonable effort must be made by the study
site personnel to contact the subject and determine the reason for discontinuation/withdrawal. The
measures taken to follow up must be documented.
When a subject withdraws from the study, the reason for withdrawal is to be documented in the
eCRF and in the source document. Study treatment assigned to the withdrawn subject may not be
assigned to another subject. Subjects who withdraw will not be replaced. If a subject withdraws
from the study, assessments outlined in the End-of-Treatment Visit should be obtained.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section 16.2.5).
In such a case, samples will be destroyed after they are no longer needed for the clinical study.
Details of the sample retention for research are presented in the main ICF.
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11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
11.1. Subject Information
The primary analysis population will be the intent-to-treat (ITT) population, which will include all
randomized subjects. Safety will be evaluated for the population of all treated subjects. The
pharmacokinetic analyses will be performed on the pharmacokinetic evaluable population.
Continuous variables will be summarized using descriptive statistics such as mean, standard
deviation, and range. Categorical variables will be summarized using frequency tables. For
time-to-event variables, the Kaplan-Meier method will be used for descriptive summaries.
11.2. Sample Size Determination
The sample size calculation is performed on the basis of the following assumption. Based on the
published data, the median PFS for Rd arm is assumed to be approximately 24 months. Assuming
that DRd can reduce the risk of the disease progression or death by 25%, ie, assuming the hazard
ratio (DRd vs Rd) of 0.75, a total of 390 PFS events is needed to achieve a power of 80% to detect
this hazard ratio with a log-rank test (two-sided alpha is 0.05). With a 21-month accrual period
and an additional 24-month follow-up, the total sample size needed for the study is approximately
730 (365/arm) subjects. The sample size calculation has taken into consideration an annual dropout
rate of 5%.
Long-term survival follow-up was originally planned to continue until 330 deaths had been
observed or 7 years after the last subject was randomized. Therefore, this study would achieve
approximately 80% power to detect a 27% reduction in the risk of death (hazard ratio  0.73) with
a log-rank test (two-sided alpha  0.05). However, after reaching statistical significance at the
second interim OS, the long-term survival follow-up will be extended to approximately 390 deaths
when the median survival for the DRd group has likely been reached.
11.3. Efficacy Analyses
Response to study treatment and progressive disease will be evaluated by a validated computer
algorithm.
Primary Endpoint
For the primary endpoint of PFS, the primary analysis will consist of a stratified log rank test for
the comparison of the PFS distribution between the 2 treatment arms. The Kaplan-Meier method
will be used to estimate the distribution of overall PFS for each treatment. The treatment effect
(hazard ratio) and its two-sided 95% confidence intervals are to be estimated using a stratified Cox
regression model with treatment as the sole explanatory variable.
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Secondary Endpoints
Other time-to-event efficacy endpoints, including TTP, PFS2, OS, and time to subsequent anti
myeloma treatment, will be analyzed using the same method as for PFS. For overall survival, the
final analysis will occur after approximately 390 deaths have been observed. Earlier analyses, in
which overall survival is analyzed, will be considered as interim analyses. Even though the
significance of PFS has already been established at the second interim analysis, testing of OS will
continue as planned until a definitive conclusion on OS is reached. The details about testing of OS
over time are specified in Section 11.10. The analysis of OS may be confounded by subjects from
Arm A receiving daratumumab after disease progression. Exploratory analysis may be performed
to adjust for the effect daratumumab exposure may have on OS for the subjects who were
randomized to Arm A (Rd).
Comparison between the 2 treatment arms of overall response rates, VGPR or better rate, CR or
better rate, and other binary endpoints will be conducted using the stratified Cochran Mantel
Haenszel test. The Mantel-Haenszel odds ratio will be provided along with its two-sided 95%
confidence interval, and will be provided as the measure of treatment effect. Duration of response
will be provided descriptively without formal statistical comparison.
Strong control of familywise Type I error rate will be controlled at a two-sided significance level
of 0.05 for the following major secondary endpoints: TTP, CR rate, MRD negativity rate, PFS2
and OS. A sequential hierarchical testing procedure will be used. Details about this hierarchical
procedure will be specified in the statistical analysis plan for this study prior to any efficacy
analysis.
11.4. Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population,
defined as subjects who have received one dose of daratumumab and at least one post-dose sample.
All serum concentrations below the lowest quantifiable concentration or missing data will be
labeled as such in the concentration data presentation. Concentrations below the lowest
quantifiable concentration will be treated as zero in the summary statistics. All subjects and
samples excluded from the analysis will be clearly documented in the study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling time point and pharmacokinetic parameters of daratumumab such as Cmin and Cmax. If
sufficient data are available, then other pharmacokinetic parameters may be calculated, including
but not limited to CL and V.
If sufficient data are available, then population pharmacokinetic analysis of serum concentration
time data of daratumumab, will be performed using nonlinear mixed-effects modeling. The
potential population PK analysis may also include PK data from other studies. If the population
pharmacokinetic analysis is conducted, then details will be given in a population pharmacokinetic
analysis plan and the results of the analysis will be presented in a separate report.
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11.5. Immunogenicity Analyses
The incidence of antibodies to daratumumab will be summarized for all subjects who receive a
dose of daratumumab and have appropriate samples for detection of antibodies to daratumumab.
The incidence of antibodies to rHuPH20 will be summarized for all subjects who receive a dose
of daratumumab SC and have appropriate samples for detection of antibodies.
11.6. Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then population pharmacokinetic analysis serum concentrations of
serum concentration-time data of daratumumab will be performed using nonlinear mixed-effects
modeling. If the population pharmacokinetic analysis is conducted, then details will be given in a
population pharmacokinetic analysis plan and results of the analysis will be presented in a separate
report.
11.7. Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to
daratumumab. Analyses will be performed and stratified by clinical covariates or molecular
subgroups using the appropriate statistical methods (eg, parametric or non-parametric, univariate
or multivariate, analysis of variance, or survival analysis, depending on the endpoint). Correlation
of baseline expression levels or changes in expression levels with response or time-to-event
endpoints will identify responsive (or resistant) subgroups in addition to genes and pathways
attenuated following treatment with daratumumab. In order to remove any confounding influence
of prognostic factors, any predictive biomarker identified in this study could be verified in a
prospective clinical study with a control treatment arm.
Any biomarker measures will be listed, tabulated, and where appropriate, plotted. Subjects will be
grouped by prescribed dose. Complete responders will be utilized to investigate the prognostic
effect of MRD on PFS. MRD analysis will include evaluation of data from other studies to
determine if decreased MRD is seen with daratumumab + Rd based chemotherapy regimen
compared with the Rd based chemotherapy alone.
Results of biomarker and pharmacodynamic analyses may be presented in a separate report.
Planned analyses are based on the availability of clinically valid assays and may be deferred if
emerging study data show no likelihood of providing useful scientific information.
In addition, due to the small sample sizes of high-risk subgroups within the multiple myeloma
subject population, a meta-analyses may be performed across daratumumab Phase 3 studies to
evaluate clinical efficacy of daratumumab with standard of care agents in pre-specified subgroups
of multiple myeloma subjects. The meta-analysis protocol will pre-specify the objective of the
meta-analysis, the criteria for inclusion and exclusion of studies, the hypotheses and endpoints,
and statistical methods including a method for investigation of heterogeneity. This meta-analytic
approach, supported by high-quality data from the individual studies, should be able to provide
definitive evidence on the effectiveness of daratumumab in the subpopulation of multiple myeloma
subjects with high-risk molecular abnormalities. In a similar fashion, a meta-analysis examining
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MRD negativity in daratumumab treated subjects in frontline, newly diagnosed multiple myeloma
(MMY3006, MMY3007, MMY3008) may also be performed.
11.8. Patient Reported Outcomes
EORTC-QLQ-C30 scores will be evaluated for all domains except “financial problems” among
subjects with at least one post-baseline assessment and 50% completion of the relevant items for
a domain. Descriptive analyses followed by mixed model repeated measures will be used to
analyze each domain score. No adjustment for multiple comparisons will be made.
EQ-5D-5L scores will be summarized at each time point.
11.9. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA). The severity assessment for
an adverse event or serious adverse event should be completed using the NCI CTCAE Version 4.
All reported adverse events with onset during the treatment phase (ie, treatment-emergent adverse
events, and adverse events that have worsened since baseline) will be included in the analysis. For
each adverse event, the percentage of subjects who experience at least 1 occurrence of the given
event will be summarized by treatment arm.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Changes from
baseline results will be presented in pre- versus post treatment cross-tabulations (with classes for
below, within, and above normal ranges). Frequency tabulations of the abnormalities will be made.
A listing of subjects with any laboratory results outside the reference ranges will be provided. A
listing of subjects with any markedly abnormal laboratory results will also be provided.
Parameters with predefined NCI CTCAE toxicity grades will be summarized. Change from
baseline to the worst toxicity grade experienced by the subject during the study will be provided
as shift tables. Worst toxicity grade during treatment will be presented, according to NCI CTCAE
(version 4). Clinically relevant changes (i.e. causing a treatment intervention and/or need for
concomitant therapy) will be also recorded on the adverse event eCRF. All other lab abnormalities
need not be recorded as adverse events.
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Electrocardiogram (ECG)
Electrocardiogram data will be summarized and listed.
Vital Signs
Descriptive statistics of baseline temperature, pulse/heart rate, and blood pressure (systolic and
diastolic) values will be summarized.
11.10. Interim Analysis
Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety,
will be performed after a total of approximately 100 subjects have been treated for at least 8 weeks
or discontinued the study treatment. The second interim analysis will be performed when 234 PFS
events, which is 60% of the total planned events, have been accumulated. The purpose of this
interim analysis is to evaluate cumulative interim safety and efficacy data. The significance level
at this interim analysis to establish the superiority of DRd over Rd with regard to PFS will be
determined based on the observed number of PFS events at the interim analysis, using the O’Brien-
Fleming boundaries as implemented by the Lan-DeMets alpha spending method. If the
experimental arm (DRd) is numerically worse than the control arm in terms of PFS
(observed hazard ratio >1 favoring the control arm), then the study may be terminated for futility,
with a conditional power of less than 20% under the alternative hypothesis given the observed
interim data.
As the superiority of DRd over Rd alone with respect to PFS was established at the second interim
analysis, the interim PFS analysis will serve as the primary PFS analysis, which otherwise was to
occur when approximately 390 PFS events had been observed. The first interim OS analysis was
performed at the interim PFS analysis. The second interim OS analysis will now occur when
approximately 260 deaths have occurred which will be about the same time the primary
PFS analysis would have taken place. All applicable available data prior to that time will be
included in each of the respective analyses.
11.11. Data Monitoring Committee
An IDMC, consisting of 2 clinicians and 1 statistician who are independent experts not otherwise
participating in the study, will be established to review efficacy and safety results at the planned
interim analyses. After the interim review, they will make recommendations regarding the
continuation of the study. In addition, the IDMC may also review cumulative safety data every
6 months besides the 2 interim analyses. The IDMC will no longer review study data after the
interim PFS analysis has been completed. The details will be provided in a separate IDMC charter.
12. 
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
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information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
12.1. Definitions
12.1.1. 
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a
medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not related
to that medicinal (investigational or non-investigational) product. (Definition per International
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting
is also appropriate in other situations, such as important medical events including any second
primary malignancy  that may not be immediately life threatening or result in death or
hospitalization but may jeopardize the subject or may require intervention to prevent one of
the other outcomes listed in the definition above. These should usually be considered serious.
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Suspected Unexpected Serious Adverse Reactions (SUSARs)
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study treatment and the event (eg, death from anaphylaxis), the event
must be reported as a serious and unexpected suspected adverse reaction even if it is a component
of the study endpoint (eg, all-cause mortality). Refer to Section 12.3.3 for SUSAR Reporting
Requirements.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For daratumumab, the expectedness of an adverse event will
be determined by whether or not it is listed within the Reference Safety Information included in
the Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible,
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2. 
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s),
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation,
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s),
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
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12.1.3. 
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using
the NCI-CTCAE Version 4.03. Any adverse event or serious adverse event not listed in this
document will be graded according to investigator clinical judgment by using the standard grading
outlined in the NCI-CTCAE Version 4.03.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
12.2. Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety
evaluation include, but are not limited to:
 
Overdose of a sponsor study drug. No MTD has been reached for daratumumab. However, if
the dose exceeds the maximum tested dose of 24 mg/kg, then it will be considered as overdose
in this study.
 
Suspected abuse/misuse of a sponsor study drug
 
Inadvertent or accidental exposure to a sponsor study drug
 
Medication error involving a sponsor product (with or without subject exposure to the sponsor
study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of a serious adverse event should be recorded on the adverse event page of the
eCRF.
12.3. Procedures
12.3.1. 
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated ICF is obtained until 30 days after the last dose of study treatment
until the start of the long-term survival follow-up, unless the subject withdraws consent for study
participation, or starts subsequent anti-myeloma therapy. For subjects still receiving study
treatment after the final CSR analysis and until the end of study, serious adverse events will
continue to be reported as detailed in Attachments 11 and 12. For subjects who have received
subsequent treatment with therapeutic intent for multiple myeloma during the adverse event
reporting period, only adverse events that are considered to be possibly, probably, or definitely
related to daratumumab need to be reported. Serious adverse events, including those spontaneously
reported to the investigator within 30 days after the last dose of study treatment, must be reported
using the Adverse Event Form. The sponsor will evaluate any safety information that is
spontaneously reported by an investigator beyond the time frame specified in the protocol.
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
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disease progression, should be reported per the usual reporting requirements (see Section 12.1).
Death should not be recorded as an adverse event or serious adverse event, but as the outcome of
an adverse event. The adverse event that resulted in the death should be reported as a serious
adverse event. All events that meet the definition of a serious adverse event will be reported as
serious adverse events, regardless of whether they are protocol-specific assessments. Anticipated
events will be recorded and reported as described in Attachment 10. Anticipated events will be no
longer be reported after the final CSR analysis.
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment,
must be recorded using medical terminology in the source document and the eCRF. Whenever
possible, diagnoses should be given when signs and symptoms are due to a common etiology
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
respiratory infection"). Investigators must record in the eCRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For
anticipated events reported as individual serious adverse events the sponsor will make a
determination of relatedness in addition to and independent of the investigator’s assessment. The
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence
and the sponsor has determined there is a reasonable possibility that the drug caused a serious
anticipated event, they will submit a safety report in narrative format to the investigators (and the
head of the investigational institute where required). The investigator (or sponsor where required)
must report these events to the appropriate Independent Ethics Committee/Institutional Review
Board (IEC/IRB) that approved the protocol unless otherwise required and documented by the
IEC/IRB.
Subjects (or their designees, if appropriate) will be provided with a "wallet (study) card" and
instructed to carry this card with them for the duration of the study and for at least 6 months (Arm
B) after treatment ends indicating the following:
 
Study number
 
Statement, in the local language(s), that the subject is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
 
Site number
 
Subject number
 
Blood type (and IAT testing as described in Section 9.8 for subjects in Arm B)
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12.3.2. 
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form, which must be completed and signed by a physician from the study site, and
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse
event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the subject's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study drug or to factors unrelated to study
conduct
 
It becomes unlikely that any additional information can be obtained (subject or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during the course of a subject's participation in a study must be reported as a serious adverse event,
except hospitalizations for the following:
 
If the subject has not experienced a significant medical event but is hospitalized overnight
only for observation following administration of daratumumab, then the hospitalization
should not be reported as a serious adverse event.
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
For subjects still receiving study treatment during the long-term survival follow-up until end of
study, serious adverse events will continue to be reported as detailed in  Attachment 11 and
Attachment 12.
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12.3.3. 
Suspected Unexpected Serious Adverse Reactions
The sponsor assumes responsibility for appropriate reporting of all Suspected Unexpected Serious
Adverse Reactions (SUSAR) [serious adverse events that are unlisted (unexpected) and associated
with the use of the study drug] to the regulatory authorities in accordance with GCP. The sponsor
will also report to the investigator (and the head of the investigational institute where required) all
serious adverse events that are unlisted (unexpected) and associated with the use of the study drug.
The investigator (or sponsor where required) must report these events to the appropriate
Independent Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol
unless otherwise required and documented by the IEC/IRB.
12.3.4. 
Pregnancy
All initial reports of pregnancy 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, stillbirth, and congenital anomaly) are
considered serious adverse events 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 further study treatment. The subject should be referred to a physician experienced in
teratology for evaluation and advice. Investigators should follow the local label for guidance on
subject education and ensure that all subjects adhere to the local lenalidomide REMS  program
(when lenalidomide is supplied locally), or the lenalidomide Global Pregnancy Prevention Plan
provided in Attachment 5 (when lenalidomide is supplied centrally and no local lenalidomide
REMS program exists). Follow-up information regarding the outcome of the pregnancy and any
postnatal sequelae in the infant will be required.
Pregnancies or positive pregnancy tests in partners of male subjects included in the study will be
reported by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form.
During the long-term survival follow-upand until the end of study, pregnancy reporting will continue
as described in Attachment 11 and Attachment 12.
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 on the Contact Information
page(s), which will be provided as a separate document.
13. 
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, investigators,
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting
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of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
13.1. Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained
for further investigation if requested by the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed on the Contact Information page(s), which will be
provided as a separate document.
14. 
STUDY DRUG INFORMATION
14.1. Physical Description of Study Drug
Daratumumab IV
The daratumumab supplied for IV infusion in this study is a colorless to yellow liquid and sterile
concentrate of20 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.
Daratumumab SC
The daratumumab supplied for SC injection in this study is a colorless to yellow liquid and sterile
concentrate of 120 mg/ml daratumumab + 2000 U/ml rHuPH20 as a liquid in 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 IV
Daratumumab IV is supplied in glass vials containing daratumumab at a concentration of
20 mg/mL.
Daratumumab SC
Daratumumab SC is supplied in glass vials containing daratumumab at a concentration of
120 mg/mL and rHuPH20 at a concentration of2000U/ml (~20µg/mL).
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14.3. Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each
vial will contain a study-specific label with a unique identification number.
14.4. Preparation, Handling, and Storage
Daratumumab IV
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.
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl)
prior to IV administration. Refer to the IPPI for IV dosing and SIPPM for details regarding dose
preparation, storage, and handling of diluted solutions.
Daratumumab SC
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 SIPPM 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
studysite monitor during on-site monitoring visits. The return to the sponsor of unused study drug,
or used returned study drug for destruction, will be documented on the drug return form. When the
study site is an authorized destruction unit and study drug supplies are destroyed on-site, this must
also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member of
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to
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subjects participating in the study. Study drug may not be relabeled or reassigned for use by other
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site
other than the study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
Investigator Brochure for daratumumab
 
Site Investigational Product Procedures Manual
 
Laboratory manual
 
PRO questionnaires and user guidelines
 
eCRF completion guidelines
 
Sample ICF
 
Subject diaries
 
Subject wallet card indicating blood type (and IAT testing for Arm B; see Section 9.8)
 
Other manuals and guidance documents as needed
16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with infusion-related reactions; see
Section 6.1.4 for prevention details. Based on the mode of action of daratumumab, a potential risk
could be infection; therefore the protocol requires the review of hematological laboratory results
prior to daratumumab administration. CD38 is distributed in erythrocytes and platelets. A significant
reduction of platelets was reported in an animal study. In a human clinical study (Study GEN501),
thrombocytopenia was also reported. However, safety laboratory monitoring did not show a
clinically meaningful reduction of platelets. Anemia was also reported in Study GEN501. Free
hemoglobin was mildly elevated, but other parameters did not support hemolysis. No bleeding events
were observed. Routine safety laboratory measurement of RBCs and platelets will be closely
monitored in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The blood volume for the study is estimated at approximately 65 mL during screening and 360 mL
during the first year (approximately 20-35 mL per cycle for routine testing, plus additional PK and
biomarker samples). In the Follow-up Phase, subjects prior to PD will continue to have
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approximately20 mL blood drawn per month for serum disease evaluations. These blood volumes
are not burdensome and fall within the normal range of a single blood donation.
16.2. Regulatory Ethics Compliance
16.2.1. 
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
16.2.2. 
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for subjects
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation
programs, and the sponsor has received a copy of this approval. This approval letter must be dated
and must clearly identify the IEC/IRB and the documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct)
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 
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 adverse events that are serious, unlisted/unexpected, and associated with the study
drug
 
New information that may adversely affect the safety of the subjects or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
 
Report of deaths of subjects under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
Furthermore, where required, progress reports/written summaries of the study status will be
submitted to the IRB/IEC annually, or more frequently if requested.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
16.2.3. 
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local
requirements after the nature of the study has been fully explained. The ICF(s) must be signed
before performance of any study-related activity. The ICF(s) that is/are used must be approved by
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and
understand. The informed consent should be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential subjects or their legally acceptable representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
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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 for the treatment of his or her
disease. Subjects will be told that alternative treatments are available if they refuse to take part and
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator
will maintain a subject identification register for the purposes of long-term follow up if needed
and that their records may be accessed by health authorities and authorized sponsor personnel
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s)
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing
such access, including permission to obtain information about his or her survival status, and agrees
to allow his or her study physician to recontact the subject for the purpose of obtaining consent for
additional safety evaluations, if needed, and subsequent disease-related treatments, or to obtain
information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and
the opportunity to ask questions. After this explanation and before entry into the study, consent
should be appropriately recorded by means of either the subject's or his or her legally acceptable
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable representative
is not available, enrollment procedures should be described in the protocol with documented
approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-being of the
subject and to ensure compliance with applicable regulatory requirements. The subject or legally
acceptable representative must be informed about the study as soon as possible and give consent
to continue.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorizeddisclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative)
includes explicit consent for the processing of personal data and for the investigator/institution to
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allow direct access to his or her original medical records (source data/documents) for study-related
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the
transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete. Reasonable steps will
be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker/PK/immunogenicity research is not conducted under standards appropriate
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the
significance of any findings resulting from exploratory research. Therefore, exploratory research
data will not be returned to subjects or investigators, unless required by law or local regulations.
Privacy and confidentiality of data generated in the future on stored samples will be protected by
the same standards applicable to all other clinical data.
16.2.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand daratumumab, to understand
multiple myeloma, to understand differential drug responders, and to develop tests/assays related
to daratumumab and multiple myeloma.  The research may begin at any time during the study or
the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be
stored for research (refer to Section 10.3, Withdrawal From the Study (Withdrawal From the Use
of Samples in Future Research).
16.2.6. 
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product, unless explicitly addressed as a specific ethical
consideration in Section 16.1, Study-Specific Design Considerations.
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17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
(see Contact Information page(s) provided separately). Except in emergency situations, this
contact should be made before implementing any departure from the protocol. In all cases, contact
with the sponsor must be made as soon as possible to discuss the situation and agree on an
appropriate course of action. The data recorded in the eCRF and source documents will reflect any
departure from the protocol, and the source documents will describe this departure and the
circumstances requiring it.
17.2. Regulatory Documentation
17.2.1. 
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
17.2.2. 
Required 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
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obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated clinical trial agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
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 randomized 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 documentation must be available for the following to confirm data collected
in the eCRF: subject identification, eligibility, and study identification; study discussion and date
of signed informed consent; dates of visits; results of safety and efficacy parameters as required
by the protocol; record of all adverse events and follow-up of adverse events; concomitant
medication; drug receipt/dispensing/return records; study treatment administration information;
and date of study completion and reason for early discontinuation of study treatment or withdrawal
from the study, if applicable.
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In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be
consistent with that commonly recorded at the study site as a basis for standard medical care.
Specific details required as source data for the study will be reviewed with the investigator before
the study and will be described in the monitoring guidelines (or other equivalent document).
Subject- and investigator-completed scales and assessments designated by the sponsor
(EORTC QLQ-C30 and EQ-5D-5L) will be recorded directly into an electronic device or other
tool and will be considered source data.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 
Referral letter from treating physician or
 
Complete history of medical notes at the site
 
Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by subject interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
17.5. Case Report Form Completion
Case report forms are provided for each subject in electronic format.
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by
study-site personnel from the source documents onto an eCRF, and transmitted in a secure manner
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The
electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the subject's source documentation. Data must be entered into
eCRFs in English. Study site personnel must complete the eCRF as soon as possible after a subject
visit, and the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible. The
investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or
study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 3
different ways:
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 
Study site personnel can make corrections in the eDC  tool at their own initiative or as a
response to an auto query (generated by the eDC tool).
 
Study site manager can generate a query for resolution by the study-site personnel.
 
Clinical data manager can generate a query for resolution by the study-site personnel.
The sponsor will communicate the clinical cut-off date for the final CSR analysis to sites. At the
time of this clinical cut-off, the study will transition to long-term survival follow-up (see
Section 9.1.8). Attachment 11 describes data collection and procedures for subjects who continue
to receive study treatment during the long-term survival follow up.
The sponsor will notify sites of the clinical cut-off date for the final OS analysis, which will occur
when approximately 390 deaths have occurred. No additional eCRF data collection will occur after
the final OS analysis. Attachment 12 describes procedures for subjects who continue to receive
study treatment after the final OS analysis until the end of study (defined in Section 17.9.1).
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 database, and
direct transmission of PRO data to the ePRO vendor database and then to the sponsor’s database.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor will review eCRFs for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study database they will
be verified for accuracy and consistency with the data sources.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs
and all source documents that support the data collected from each subject, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
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If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8. Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the eCRFs with the hospital or clinic records
(source documents). The nature and location of all source documents will be identified to ensure
that all sources of original data required to complete the eCRF are known to the sponsor and
study-site personnel and are accessible for verification by the sponsor study-site contact. If
electronic records are maintained at the study site, the method of verification must be discussed
with the study-site personnel.
Direct access to source documentation (medical records) must be allowed for the purpose of
verifying that the data recorded in the eCRF are consistent with the original source data. Findings
from this review of eCRFs and source documents will be discussed with the study-site personnel.
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be
available, the source documentation will be accessible, and a suitable environment will be provided
for review of study-related documents. The monitor will meet with the investigator on a regular
basis during the study to provide feedback on the study conduct.
17.9. Study Completion/Termination
17.9.1. 
Final OS Analysis/End of Study
The sponsor will notify sites of the final OS analysis cut-off, which will occur when approximately
390 deaths have occurred. After the cut-off for the final OS analysis, no additional eCRF data will
be collected, and the clinical database will be closed. Data collected in the eCRF will be included
in the final OS analysis and reported in a separate addendum to clinical study report.
The final data from the study site will be sent to the sponsor (or designee) after completion of the
final subject at that study site, in the time frame specified in the Clinical Trial Agreement.
The sponsor will ensure that subjects who are benefitting from treatment with daratumumab can
continue to receive study treatment after the final OS analysis until the end of study is complete.
The end of study is defined as when one of the following occurs, whichever is first:
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• 
when all subjects who are still receiving study treatment after the final OS analysis
have access through another source such as a commercial availability, continued
access through a dedicated long-term extension study, or a patient access program,
• 
when all subjects have discontinued daratumumab treatment,
• 
by 31 January 2026.
Attachment 12 describes data collection and reporting procedures for subjects who continue to
receive study treatment after the final OS analysis.
17.9.2. 
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 
Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 
Inadequate recruitment of subjects by the investigator
 
Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection and comparison with the eCRFs. Subject
privacy must, however, be respected. The investigator and study-site personnel are responsible for
being present and available for consultation during routinely scheduled study-site audit visits
conducted by the sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
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17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study, and will not use it for other purposes without the sponsor's prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of daratumumab, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain eCRF data from all study sites that participated in the study, and direct transmission
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in
a separate report and will not require a revision of the Clinical Study Report. Study subject
identifiers will not be used in publication of results. Any work created in connection with
performance of the study and contained in the data that can benefit from copyright protection
(except any publication by the investigator as provided for below) shall be the property of the
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and
information without approval from the investigator. The investigator has the right to publish study
site-specific data after the primary data are published. If an investigator wishes to publish
information from the study, a copy of the manuscript must be provided to the sponsor for review
at least 60 days before submission for publication or presentation. Expedited reviews will be
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 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
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will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as
required by law.
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2. 
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J et al. Lenalidomide and Dexamethasone in
Transplant-Ineligible Patients with Myeloma. N Engl J Med. 2014;371:906-17.
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Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd ed. Philadelphia; WB Saunders, 1999.
4. 
Chapuy C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility
testing. Transfusion. 2015;55:1545-1554.
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Chapuy C, Aguad MD, Nicholson RT, et al. International validation of dithiothreitol (DTT)-based method to
resolve the daratumumab interference with blood compatibility testing. Transfusion. 2016;00:1-9.
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de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal
antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol.
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Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma.
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Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide
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Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial Phase 3 Results Of The First (Frontline Investigation Of
Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly
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10. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J
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11. Gay F and Palumbo A. Management of older patients with multiple myeloma. Blood Reviews. 2011;25:65-73.
12. Ghosh N, Tucker N, Zahurak M, et al. Addition of clarithromycin to lenalidomide and dexamethasone (BiRd)
is effective in MM after progression on lenalidomide and dexamethasone. Session 653. Myeloma: Therapy,
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14. Hulin C, Belch A, Shustik C, et al. Updated outcomes and impact of age with lenalidomide and low-dose
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15. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies.
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16. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response
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17. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma.
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18. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple
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19. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic)
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20. Ladetto M, Bruggemann M, Monitello L, et al. Next-generation sequencing and real-time quantitative PCR for
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22. McCudden CR, Voorhees PM, Hainsworth SA, et al. Interference of monoclonal antibody therapies with serm
protein electrophoresis tests. Clin Chem. 2010;56(12):1897-1899.
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Guidelines): Multiple Myeloma, version 2.2013. Fort Washington, PA: National Comprehensive Cancer
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24. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology
Group. Am J Clin Oncol. 1982;5(6):649-655.
25. Overdijk MB, Verploegen S, Bogels M, et al. Phagocytosis is a potent mechanism of action for the therapeutic
human monoclonal antibody daratumumab in lymphoma and multiple myeloma. Submitted to Blood.
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26. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364(11):1046-1060.
27. Palumbo A, Gay F, Musto P, et al. Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly
diagnosed myeloma patients: PFS1, PFS2, OS endpoints. J Clin Oncol. 325s, 2014 (suppl; abstr 8515).
28. Palumbo A, Rajkumar S, Dimopoulos M, et al. Prevention of thalidomide- and lenalidomide-associated
thrombosis in myeloma. Leukemia. 2008;22:414-423.
29. Palumbo A, Sezer O, Kyle R, et al. International Myeloma Working Group guidelines for the management of
multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell
transplantation. Leukemia. 2009;23:1716-1730.
30. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for
the diagnosis ofmultiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48
31. Rajkumar SV, Greipp PR, Jacobus S, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide
plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label
randomised controlled trial. Lancet Oncol. 2010;11(1):29–37.
32. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;4691-4695.
33. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2017.
34. Smith A, WisloffF, Samson D. Guidelines on the diagnosis and management of multiple myeloma. Br J
Haematol. 2005;132:410-451.
35. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell
adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood.
2008;112(4):1329-1337.
36. Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, et al. Immunomodulatory drug lenalidomide (CC
5013, IMiD3) augments anti CD40 SGN 40-induced cytotoxicity in human multiple myeloma: clinical
implications. Cancer Res. 2005;65(24):11712-11720.
37. Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC. Thalidomide and lenalidomide: mechanism-based
potential drug combinations. Leuk Lymphoma. 2008;49(7):1238-1245.
38. Van der Veer M, de Weers M, van Kessel B. Towards effective immunotherapy of myeloma: enhanced
elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody
daratumumab. Haematol. 2011a:96(2):284-290.
39. Van der Veer M, de Weers M, van Kessel B. The therapeutic human CD38 antibody daratumumab improves
the anti-myeloma effect of newly emerging multi-drug therapies. Blood Cancer Journal. 2011b; 1 e41.
Doi:10.1038/bcj.2011.
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40. Vij R, Mazumder A, Klinger M, et al. Deep sequencing reveals myeloma cells in peripheral blood in majority
of multiple myeloma patients, Clinical Lymphoma, Myeloma and Leukemia (2013), doi:
10.1016/j.clml.2013.09.013.
41. Wisloff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Nordic
Myeloma Study Group. Br J Haematol. 1996;92:604-613.
42. Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemotherapy predicts for
survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol. 1997;97:29-37.
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Attachment 1: Modified IMWG Diagnostic Criteria for Multiple Myeloma
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytomaa AND
any one or more of the following myeloma defining events:
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder,
specifically:
 
Hypercalcemia: serum calcium >0.25 mM/L (>1 mg/dL) higher than ULN or >2.75 mM/L
(>11 mg/dL)
 
Renal insufficiency: creatinine clearanceb <40mL/min or serum creatinine >177 µM/L
(>2 mg/dL)
 
Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dLc
 
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTd
Note: Subjects only meeting SLiM CRAB are not eligible.
Footnotes:
a) Clonality should be established by showing / light-chain restriction on flow cytometry,
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should
preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and
the core biopsy, the highest value should be used.
b) Measured or estimated by validated equations.
c) Hemoglobin measurement performed as part of standard of care within 42 days before randomization
is acceptable for screening for CRAB criteria; but must be performed within 21 days before
randomization for other eligibility requirements.
d) If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to
distinguish from solitary plasmacytoma with minimal marrow involvement.
Reference: Rajkumar 2014 30
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Attachment 2: ECOG Performance Status Scale
Grade 
ECOG Performance Status
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of
a light or sedentary nature, eg, light house work, office work
2 
Ambulatory and capable of all 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 198224
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Attachment 3: Calculated and Measured Creatinine Clearance
Cockcroft-Gault formula:
To calculate the subject’s creatinine clearance (CrCl), use the following Cockcroft-Gault formula:
CrCl =  (140 - age [in years]) x weight (kg) 
(x 0.85 for females)
(72 x serum creatinine [mg/dL])
If the serum creatinine is obtained using the International System of Units (SI) (ie, micromol/L), use the
following formula to convert SI units to conventional (mg/dL) units (Manual of Laboratory & Diagnostic
Tests, 2004):
• 
serum creatinine (micromol/L) divided by 88.4 = serum creatinine (mg/dL)
Formula to measure creatinine clearance:
CrCl = UCr x Uvol
PCr x Tmin
Corrected CrCl = CrCl  x 1.73
BSA
Notes: UCr, Urine creatinine concentration; Uvol, Urine volume from 24hrs collection; PCr, plasma creatinine
concentration; Tmin, collection time in minutes (24h x 60min); BSA, body surface area.
If the body mass index of a subject is >30kg/m2, lenalidomide dosing should be based on the CrCl calculated
with adjusted body weight.
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Attachment 4: 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 19993
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Attachment 5: Lenalidomide Global Pregnancy Prevention Plan
Where lenalidomide is supplied locally, subjects must adhere to the local lenalidomide REMS program.
Where lenalidomide is supplied centrally and no local lenalidomide REMS program exists, then subjects
must adhere to the lenalidomide Global Pregnancy Prevention Plan provided in this attachment.
Within this attachment only, use of the phrase “study drug” refers to lenalidomide.
1.1 Pregnancy Prevention Risk Management Plans
1.1.1 Lenalidomide Pregnancy Prevention Risk Management Plan
1.1.1.1 Lenalidomide Pregnancy Risk Minimisation Plan for Celgene Clinical Trials
This attachment applies to all patients receiving lenalidomide therapy. The following Pregnancy Risk
Minimisation Plan documents are included:
1) Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control
Methods (Section 1.1.1.2);
2) Lenalidomide Education and Counseling Guidance Document (Section 1.1.1.3);
3) Lenalidomide Information Sheet (Section 1.1.1.4).
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth
Control Methods document (Section 1.1.1.2) provides the following information:
 Potential risks to the fetus associated with lenalidomide exposure
 Definition of Female of Childbearing Potential
 Pregnancy testing requirements for patients receiving Lenalidomide who are females of
childbearing potential
 Acceptable birth control methods for both female of childbearing potential and male patients
receiving Lenalidomide in the study
 Requirements for counseling of all study patients receiving Lenalidomide about pregnancy
precautions and the potential risks of fetal exposure to lenalidomide
2. The Lenalidomide Education and Counseling Guidance Document (Section 1.1.1.3) must be
completed and signed by either a trained counselor or the Investigator at the participating clinical
center prior to each dispensing of lenalidomide study treatment. A copy of this document must be
maintained in the patient records.
3. The Lenalidomide Information Sheet (Section 1.1.1.4) will be given to each patient receiving
lenalidomide study therapy. The patient must read this document prior to starting lenalidomide
study treatment and each time they receive a new supply of study drug.
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1.1.1.2 Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth
Control Methods)
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. An embryofetal development study in animals
indicates that lenalidomide produced malformations in the offspring of female monkeys who received the
drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore,
a risk minimization plan to prevent pregnancy must be observed.
Criteria for females of childbearing potential (FCBP)
This protocol defines a female of childbearing potential as a sexually mature woman who: 1) has not
undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive
months (i.e., has had menses at any time in the preceding 24 consecutive months).
Counseling
For a female of childbearing potential, lenalidomide is contraindicated unless all of the following are met
(i.e., all females of childbearing potential must be counseled concerning the following risks and
requirements prior to the start of lenalidomide study therapy):
 She understands the potential teratogenic risk to the unborn child
 She understands the need for effective contraception, without interruption, 4 weeks before
starting study treatment, throughout the entire duration of study treatment, dose interruption
and 28 days after the end of study treatment
 She should be capable of complying with effective contraceptive measures
 She is informed and understands the potential consequences of pregnancy and the need to
notify her study doctor immediately if there is a risk ofpregnancy
 She understands the need to commence the study treatment as soon as study drug is dispensed
following a negative pregnancy test
 She understands the need and accepts to undergo pregnancy testing based on the frequency
outlined in this protocol (Section 1.1.1.2)
 She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide
The investigator must ensure that for females of childbearing potential:
 Complies with the conditions for pregnancy risk minimization, including confirmation that
she has an adequate level of understanding
 Acknowledge the aforementioned requirements
For a female NOT of childbearing potential, lenalidomide is contraindicated unless all of the following
are met (i.e., all females NOT of childbearing potential must be counseled concerning the following risks
and requirements prior to the start of lenalidomide study therapy):
 She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide
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Traces of lenalidomide have been found in semen.  Male patients taking lenalidomide must meet the
following conditions (i.e., all males must be counseled concerning the following risks and requirements
prior to the start of lenalidomide study therapy):
 Understand the potential teratogenic risk if engaged in sexual activity with a pregnant female
or a female of childbearing potential
 Understand the need for the use of a condom even if he has had a vasectomy, if engaged in
sexual activity with a pregnant female or a female of childbearing potential. 
Contraception
Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of
contraception simultaneously or to practice complete abstinence from heterosexual contact during the
following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while
participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment
discontinuation.
The two methods of reliable contraception must include one highly effective method and one additional
effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if
needed. The following are examples of highly effective and additional effective methods of contraception: 
 Highly effective methods:
 Intrauterine device (IUD)
 Hormonal (birth control pills, injections, implants)
 Tubal ligation
 Partner’s vasectomy
 Additional effective methods:
 Male condom
 Diaphragm
 Cervical Cap
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is
currently using combined oral contraception the patient should switch to one of the effective method
listed above. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing
combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment
with dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in patients with neutropenia.
Pregnancy testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for
females of childbearing potential, including females of childbearing potential who commit to complete
abstinence, as outlined below.
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Before starting study drug
Female Patients:
FCBP must have two negative pregnancy tests (sensitivity of at least 25 mIU/mL) prior to starting study
drug. The first pregnancy test must be performed within 10 to 14 days prior to the start of study drug and
the second pregnancy test must be performed within 24 hours prior to the start of study drug. The patient
may not receive study drug until the study doctor has verified that the results of these pregnancy tests are
negative.
Male Patients:
Must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female
or a female of childbearing potential while participating in the study, during dose interruptions and for at
least 28 days following study drug discontinuation, even if he has undergone a successful vasectomy. 
During study participation and for 28 days following study drug discontinuation
Female Patients:
 FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the
first 28 days of study participation and then every 28 days while on study, at study
discontinuation, and at day 28 following study drug discontinuation. If menstrual cycles are
irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14
days while on study, at study discontinuation, and at days 14 and 28 following study drug
discontinuation. 
 At each visit, the Investigator must confirm with the FCBP that she is continuing to use two
reliable methods of birth control. 
 Counseling about pregnancy precautions and the potential risks of fetal exposure must be
conducted at a minimum of every 28 days.
 If pregnancy or a positive pregnancy test does occur in a study patient, study drug must be
immediately discontinued.
 Pregnancy testing and counseling must be performed if a patient misses her period or if her
pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be
discontinued during this evaluation.
 Females must agree to abstain from breastfeeding during study participation and for at least
28 days after study drug discontinuation.
Male Patients:
 Counseling about the requirement for complete abstinence or condom use during sexual
contact with a pregnant female or a female of childbearing potential and the potential risks of
fetal exposure to lenalidomide must be conducted at a minimum of every 28 days. 
 If pregnancy or a positive pregnancy test does occur in the partner of a male study patient
during study participation, the investigator must be notified immediately.
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Additional precautions
 Patients should be instructed never to give this medicinal product to another person and to
return any unused capsules to the study doctor at the end of treatment.
 Female patients should not donate blood during therapy, during dose interruptions and for at
least 28 days following discontinuation of study drug.
 Male patients should not donate blood, semen or sperm during therapy, during dose
interruptions and for at least 28 days following discontinuation of study drug.
 Only enough study drug for one cycle of therapy may be dispensed with each cycle of
therapy.
1.1.1.3 Lenalidomide Education and Counseling Guidance Document
To be completed prior to each dispensing of study drug.
Protocol Number: 
Patient Name (Print): 
 DOB: 
/
/
 (mm/dd/yyyy)
(Check the appropriate box to indicate risk category)
Female: □
If female, check one:
□ FCBP (Female of childbearing potential): sexually mature female who: 1) has not
undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or 2) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least
24 consecutive months (i.e., has had menses at any time during the preceding 24
consecutive months)
□ NOT FCBP
Male: 
□
Do Not Dispense study drug if:
 The patient is pregnant.
 No pregnancy tests were conducted for a FCBP.
 The patient states she did not use TWO reliable methods of birth control (unless
practicing complete abstinence of heterosexual contact) [at least 28 days prior to
therapy, during therapy and during dose interruption].
FCBP:
1. I verified that the required pregnancy tests performed are negative.
2. I counseled FCBP regarding the following:
 Potential risk of fetal exposure to lenalidomide: If lenalidomide is taken during pregnancy, it
may cause birth defects or death to any unborn baby. Females are advised to avoid pregnancy
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while taking lenalidomide. The teratogenic potential of lenalidomide in humans cannot be
ruled out. FCBP must agree not to become pregnant while taking lenalidomide.
 Using TWO reliable methods of birth control at the same time or complete abstinence from
heterosexual contact [at least 28 days prior to therapy, during therapy, during dose
interruption and 28 days after discontinuation of study drug].
 That even if she has amenorrhea she must comply with advice on contraception 
 Use of one highly effective method and one additional method of birth control AT THE
SAME TIME. The following are examples of highly effective and additional effective
methods of contraception: 
 Highly effective methods:
o Intrauterine device (IUD)
o Hormonal (birth control pills, injections, implants)
o Tubal ligation
o Partner’s vasectomy
 Additional effective methods:
o Male condom
o Diaphragm
o Cervical Cap
 Pregnancy tests before and during treatment, even if the patient agrees not to have
reproductive heterosexual contact. Two pregnancy tests will be performed prior to receiving
study drug, one within 10 to 14 days and the second within 24 hours of the start of study
drug.
 Frequency of pregnancy tests to be done:
 Every week during the first 28 days of this study and a pregnancy test every 28 days
during the patient’s participation in this study if menstrual cycles are regular or every 14
days if cycles are irregular.
 If the patient missed a period or has unusual menstrual bleeding. 
 When the patient is discontinued from the study and at day 28 after study drug
discontinuation if menstrual cycles are regular. If menstrual cycles are irregular,
pregnancy tests will be done at discontinuation from the study and at days 14 and 28 after
study drug discontinuation.
 Stop taking study drug immediately in the event of becoming pregnant and to call their study
doctor as soon as possible.
 NEVER share study drug with anyone else.
 Do not donate blood while taking study drug, during dose interruptions and for 28 days after
stopping study drug.
 Do not breastfeed a baby while participating in this study and for at least 28 days after study
drug discontinuation.
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 Do not break, chew, or open study drug capsules.
 Return unused study drug to the study doctor.
3. Provide Lenalidomide Information Sheet to the patient.
FEMALE NOT OF CHILDBEARING POTENTIAL (NATURAL MENOPAUSE FOR AT LEAST
24 CONSECUTIVE MONTHS, A HYSTERECTOMY, OR BILATERAL OOPHORECTOMY):
1. I counseled the female NOT of child bearing potential regarding the following:
 Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP)
 NEVER share study drug with anyone else.
 Do not donate blood while taking study drug, during dose interruptions and for 28 days after
stopping study drug.
 Do not break, chew, or open study drug capsules
 Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the patient.
MALE:
1. I counseled the Male patient regarding the following:
 Potential risks of fetal exposure to lenalidomide (Refer to item #2 in FCBP).
 To engage in complete abstinence or use a condom when engaging in sexual contact
(including those who have had a vasectomy) with a pregnant female or a female of
childbearing potential, while taking study drug, during dose interruptions and for 28 days
after stopping study drug.
 Males should notify their study doctor when their female partner becomes pregnant and
female partners of males taking study drug should be advised to call their healthcare provider
immediately if they get pregnant.
 NEVER share study drug with anyone else.
 Do not donate blood, semen or sperm while taking study drug, during dose interruptions and
for 28 days after stopping study drug.
 Do not break, chew, or open study drug capsules.
 Return unused study drug capsules to the study doctor.
2. Provide Lenalidomide Information Sheet to the patient.
Investigator/Counselor Name (Print): 
(circle applicable)
Investigator/Counselor Signature: 
 Date: 
/
/
(circle applicable)
**Maintain a copy of the Education and Counseling Guidance Document in the patient records.**
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1.1.1.4 Lenalidomide Information Sheet
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES
Please read this Lenalidomide Information Sheet before you start taking study drug and each time you get
a new supply. This Lenalidomide Information Sheet does not take the place of an informed consent to
participate in clinical research or talking to your study doctor or healthcare provider about your medical
condition or your treatment. 
What is the most important information I should know aboutlenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn baby.
Lenalidomide is similar to the medicine thalidomide. It is known that thalidomide causes life-
threatening birth defects. Lenalidomide has not been tested in pregnant women but may also
cause birth defects. Findings from a monkey study indicate that lenalidomide caused birth defects
in the offspring of female monkeys who received the drug during pregnancy.
If you are a female who is able to become pregnant:
 Do not take study drug if you are pregnant or plan to become pregnant
 You must practice complete abstinence or use two reliable, separate forms of effective
birth control at the same time:
 for 28 days before starting study drug
 while taking study drug
 during dose interruptions of study drug
 for 28 days after stopping study drug
 You must have pregnancy testing done at the following times:
 within 10 to 14 days and again 24 hours prior to the first dose of study drug
 weekly for the first 28 days
 every 28 days after the first month or every 14 days if you have irregular menstrual
periods
 if you miss your period or have unusual menstrual bleeding
 28 days after the last dose of study drug (14 and 28 days after the last dose if menstrual
periods are irregular)
 Stop taking study drug if you become pregnant during treatment
 If you suspect you are pregnant at any time during the study, you must stop study drug
immediately and immediately inform your study doctor. Your study doctor will report all
cases of pregnancy to Celgene Corporation
 Do not breastfeed while taking study drug
 The study doctor will be able to advise you where to get additional advice on contraception.
If you are a female not of childbearing potential:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor will
confirm that you are not able to become pregnant.
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If you are a male:
Lenalidomide is detected in trace quantities in human semen. The risk to the foetus in females of
child bearing potential whose male partner is receiving lenalidomide is unknown at this time. 
 Male patients (including those who have had a vasectomy) must practice complete abstinence
or must use a condom during sexual contact with a pregnant female or a female that can
become pregnant:
 While you are taking study drug
 During dose interruptions of study drug
 For 28 days after you stop taking study drug 
 Male patients should not donate sperm or semen while taking study drug and for 28 days
after stopping study drug.
 If you suspect that your partner is pregnant any time during the study, you must
immediately inform your study doctor. The study doctor will report all cases of
pregnancy to Celgene Corporation. Your partner should call their healthcare provider
immediately if they get pregnant.
2. Restrictions in sharing study drug and donating blood:
 Do not share study drug with other people. It must be kept out of the reach of children
and should never be given to any other person.
 Do not donate blood while you take study drug, during dose interruptions and for 28 days
after stopping study drug.
 Do not break, chew, or open study drug capsules.
 You will get no more than a 28-day supply of study drug at one time.
 Return unused study drug capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your study
doctor for more information.
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Attachment 6: Conversion Table for Glucocorticosteroid Dose
Generic Name 
Oral or Intravenous
Dose (mg)
Dexamethasone 
0.75
Methylprednisolone 
4
Prednisolone 
5
Prednisone 
5
Betamethasone 
0.6
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Attachment 7: 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%
60-80 yr 70%
Symptoms
≤2 days/week 
> 2 days/week but not daily 
Daily
Throughout the day
Nighttime
awakenings
0 
≤2x/month
1 2x/
month  
3 4x/month
3 4x/
month
> 1x/week but not nightly  
> 1x/
month  
Often 7x/week
SABA use for
symptom control
(not prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/
week but not
daily, and
not more
than 1x on
any day
Daily  
Several time per day
Interference with
normal activity
None 
Minor limitation  
Some limitation  
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations 
> 80% 
> 85% 
Normal FEV1
between
exacerbations
> 80%
Normal
N/A  
> 80%
> 80%
> 80% Normal 
N/A  
60-80%
75-80%
60-80%
Reduced5%
N/A  
< 60%
< 75%
< 60%
Reduced5%
Risk
Exacerbations
requiring oral
systemic
corticosteroids
0-1/year
≥2
exacerbations
in 6months
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 6months
requiring oral
steroids or >4
wheezing
episodes/1 year
lasting >1 day
andrisk factors
for persistent
asthma
≥ 2/year
Relative
annual risk
may be related
to FEV1.
≥ 2/year
Relative
annual risk
may be
relatedto
FEV1.
≥ 2
exacerbations in
6months
requiring oral
steroids or >4
wheezing
episodes/1 year
lasting >1 day
and risk factors
for persistent
asthma
≥ 2/year
Relative
annual risk
may be related
to FEV1.
≥ 2/year
Relative annual
risk
may be related
to FEV1.
Consider severity andinterval since last exacerbation. Frequency andseverity may fluctuate over time for patients in any severity category.
RecommendedStep for
Initiating Treatment
Step 1 
Step 2
Step 3 and
consider
short course
of oral
steroids
Step 3: 
medium dose 
ICS and 
consider 
short course of
oral steroids
Step 3 and 
consider short 
course of oral 
steroids 
Step 3 and
consider short
course of oral
steroids
Step 3: medium  
dose ICS OR
Step 4 and
consider short
course of oral
steroids
Step 4 or 5 and
consider short
course
of oral steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is 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  
Step up 1
step
Step up at
least 1 step
• Step up
1 step
• Consider short course
of oral steroids
• Step up 1 2 steps
• Consider
short course
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Recommended Action for
Treatment
• Regular follow-up every
1-6 months
• 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 2-6weeks 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.
•
Reevaluate
in 2 6
week
s
• For side
effects,
consider
alternativ
e
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 2-6weeks 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.
of oral
steroids
•
Step up 1-2
steps
•
Reevaluate
in 2 weeks
•
For side
effects,
consider
alternativ
e
treatment
options
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Attachment 8: International Staging system
International Staging System
Stage Criteria 
Median Survival (months)
I 
Serum ß2 microglobulin <3.5 mg/L, serum 
albumin ≥3.5 g/dL
62
II 
Not I or IIIa 
44
III 
Serum ß2 microglobulin ≥5.5 mg/L 
29
a There are 2 possibilities for Stage II:
  1) Serum ß2 microglobulin <3.5 mg/mL but serum albumin <3.5 g/dL, or
  2) Serum ß2 microglobulin 3.5 –5.4 mg/L irrespective of the serum albumin
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Attachment 9: The Family of antihistamine medications
The following antihistamines may be used for daratumumab pre-dose medication (including, but not
limited to):
 Diphenhydramine
 Cetirizine
 Fexofenadine
 Loratadine
 Clemastine
 Dexchlorpheniramine
 Promethazine*
* The IV use of promethazine should be avoided.
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Attachment 10: 
Anticipated Adverse Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:
 Bleeding
 Bone diseases
 Hypercalcaemia
 Hyperuricemia
 Hyperviscosity syndrome
 Infection
 Renal failure or insufficiency
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated
event that meets serious adverse event criteria will be reported to the sponsor as described in
Section 12.3.2, Serious Adverse Events.  Each anticipated event will be assessed by the investigator at the
individual case level and if considered to be drug-related will undergo expedited reporting (if appropriate)
as per applicable clinical trial legislation to Health Authorities and IRB/IECs.  If an anticipated event is
considered disease-related or not related to study drug the event will be exempt from expedited reporting.
To meet US regulatory clinical trial legislation, the sponsor will perform aggregate review of anticipated
events as outlined below, and if determined to be drug-related will implement expedited reporting of these
events to Health Authorities and IRBs/IECs. If an interim analysis of trial results leads to an unblinded,
aggregate review of safety data by the study team, the sponsor may terminate the review of pre-specified
anticipated events outlined above.
Safety Assessment Committee (SAC)
A Safety Assessment Committee (SAC) will be established to perform reviews of pre-specified anticipated
events at an aggregate level. The SAC is a safety committee within the sponsor’s organization that is
independent of the sponsor’s study team. The SAC will meet to aid in the recommendation to the sponsor’s
study team as to whether there is a reasonable possibility that an anticipated event is related to the study
intervention based on a review of the aggregate data by arm.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events
Safety Monitoring Plan (ASMP).
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Attachment 11: 
Long-term Survival Follow-up –After Final CSR Analysis Until Final OS
Analysis
After the final CSR analysis, wich will provide updates to the primary CSR analysis for both efficacy and
safety, all subjects, regardless of whether they are still on study treatment and those who are in follow-up,
will enter the long-term survival follow-up. The subjects who are receiving treatment at the time of the
cut-off for the final CSR analysis will continue to receive study treatment per protocol. The following
limited schedule is applicable for the long-term survival follow-up.
Dosage and Administration
Study treatment will be administered according to the regimen established prior to Protocol Amendment 9
(see Section 6).
Once the sponsor has notified investigators that the final CSR analysis has been achieved, subjects may
continue study treatment until PD per investigator evaluation, unacceptable toxicity, withdrawal of consent,
the investigator decides to stop treatment, the start of subsequent anticancer therapy, or study completion
(Section  17.9.1), whichever comes first.
Efficacy Evaluations
For subjects continuing study treatment during the long-term survival follow-up, investigators should
monitor and assess subjects for response to treatment or disease progression according to local institutional
practice and make decisions if treatment should be continued based on benefit /risk evaluation. The
assessments and outcome should be entered in the subject file/source notes.
Safety Evaluations
For subjects continuing study treatment during the long-term survival follow-up, local hematology
laboratory assessments, chemistry laboratory assessments, and assessment of vital signs should still be
performed in accordance with good clinical practice and as per local label of drugs administered to guide
safe use of study treatment. These local results do not need to be entered in the CRF.
Safety Reporting
For subjects continuing study treatment during the long-term survival follow-up, serious adverse events
that occur while the subject is receiving study drug or are within 30 days after the last dose of study drug,
will be collected and reported to the sponsor’s global medical safety database via serious adverse event
reporting process as indicated by Sponsor or designee (see Section 12.3.2). Serious adverse events that
occur between 30 days after the last dose of the study drug and the end of study should be reported using
the same process if considered by the investigator to be related to study drug. All serious adverse events
should also be documented in the subject file/source notes.
Pregnancy reporting should continue as described in Section 12.3.4. The pregnancy should be documented
in the subject file/source notes.
During long-term survival follow-up, reporting of anticipated events (Attachment 10) is no longer
performed.
Patient Reported Outcomes
For subjects continuing study treatment during the long-term survival follow-up, no PRO data collection
will occur.
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Sample Collection and Handling
For subjects continuing study treatment during the long-term survival follow-up, there will be no PK,
immunogenicity, or biomarker (MRD) assessments during this treatment period. Any sample collection or
test for safety or disease evaluation should comply with local institution practice and be documented in the
subject files/source notes.
Case Report Form Completion
The clinical database will remain partially open during the long-term survival follow-up. For all subjects
on study, whether continuing study treatment or those in survival follow-up, CRF pages to be completed
are:
 subsequent therapies
 survival follow-up
 death information
 end of treatment disposition
 end of study disposition
For survival follow up, the information can be obtained via telephone contact, medical records indicating
the subject visited the hospital (laboratory, consult for other specialty), public records for deaths, etc.
Follow-up Procedures
For subjects who discontinue treatment during the long-term survival follow-up and the subjects who were
in follow-up at the time of final CSR analysis, end of treatment procedures (Section 9.1.4) are not
applicable, except for HBV DNA monitoring in accordance with the local label. These monitoring data
should be documented in files/source notes but not entered in the CRF.
Source Documentation
At a minimum, the source data collected should include: subject and study identification, study discussion,
documentation of the informed consent process including the date of consent, dates of visits, serious adverse
events, pregnancy information, safety monitoring of subject as per local institution practice, drug
dispensing/return records, study drug administration information, subsequent therapies, survival follow-up
and  death information, reason for end of treatment and for end of study.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
163
Approved, Date: 20 July 2021
Attachment 12: 
Final OS Analysis Until End of Study
Protocol Amendment 9 will allow those subjects who are benefitting from daratumumab treatment at the
time of the clinical cut-off date for the final OS analysis to continue to receive daratumumab. The sponsor
will ensure that subjects will be able to continue to receive daratumumab after the final OS analysis until
the end of study (defined in Section 17.9.1). The following limited schedule is applicable.
Documentation of assessments performed is required only in the subject file/source notes.
Dosage and Administration
Daratumumab will be administered according to the regimen established prior to Amendment 9 (see
Section 6).
Treatment Period
Once the sponsor has notified investigators that the clinical cut-off date for the final OS analysis has been
achieved (end of eCRF data collection), subjects may continue treatment with daratumumab until PD per
investigator evaluation, unacceptable toxicity, withdrawal of consent, the investigator decides to stop
treatment, the start of subsequent anticancer therapy, or the end of the study (defined in Section 17.9.1).
For subjects who continue treatment after the final OS analysis, post-treatment follow-up is not applicable,
except for HBV DNA monitoring in accordance with the local label.
Efficacy Evaluations
Investigators should monitor and assess subjects for response to treatment or disease progression according
to local institutional practice. The assessments and outcome should be entered in the subject file/source
notes.
Safety Reporting
For subjects continuing daratumumab after the clinical cut-off date for the final OS analysis, serious adverse
events that occur while the subject is receiving study drug and within 30 days after the last dose of study
drug will be collected and reported to the sponsor’s global medical safety database only via the same serious
adverse event reporting process used over the course of the study. Serious adverse events that occur between
the 30-day post-dose period and completion of the study should be reported using the same process if
considered by the investigator to be related to study drug. Serious adverse events should also be documented
in the subject file/source notes.
Pregnancy reporting should continue as described in Section 12.3.4. The pregnancy should be documented
in the subject file/source notes.
Sample Collection and Handling
For subjects continuing daratumumab after the clinical cut-off date for the final OS analysis, there will be
no PK, immunogenicity, or biomarker assessments during this treatment period, and any sample collection
or test for safety or disease evaluation should comply with local institution practice.
Case Report Form Completion
No data will be collected in the eCRF after the cut-off for the final OS analysis.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
164
Approved, Date: 20 July 2021
Source Documentation
At a minimum, the source data collected should include: subject and study identification, study discussion,
documentation of the informed consent process including the date of consent, dates of visits, serious adverse
events, pregnancy information,  safety monitoring of subject as per local institution practice, drug
dispensing/return records, and study drug administration information.
NCT02252172

JNJ-54767414  (daratumumab)
Clinical Protocol 54767414MMY3008 Amendment 9
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
165
Approved, Date: 20 July 2021
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study drug, the conduct of the study, and the obligations ofconfidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course ofthe study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT02252172

Signature
User 
Date 
Reason
 
22-Jul-2021 
08:06:20
(GMT)
Document Approval
PPD
NCT02252172