Clinical trial NCT02252172
Conditions: Multiple Myeloma
Keywords: Multiple Myeloma Daratumumab JNJ-54767414 Lenalidomide Dexamethasone
Sponsor: Janssen Research & Development, LLC
Start date: 2015-02-16; Completion date: 2024-10-02
Enrollment: 737 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of daratumumab in combination with lenalidomide and dexamethasone to that of lenalidomide and dexamethasone in terms of progression-free survival (PFS) in participants with newly diagnosed multiple myeloma (a blood cancer of plasma cells) who are not candidates for high dose chemotherapy (treatment of disease, usually cancer, by chemical agents) and autologous stem cell transplant (ASCT).

Detailed description:
This is a Phase 3, randomized (study drug assigned by chance), open-label (participants and researchers are aware about the treatment, participants are receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), parallel-group (each group of participants will be treated at the same time), and multicenter (when more than one hospital or medical school team work on a medical research study) study in participants with newly diagnosed multiple myeloma and who are not candidates for high dose chemotherapy and ASCT. All the eligible participants will be randomly assigned to receive either lenalidomide and dexamethasone (Rd) (Arm A) or daratumumab in combination with lenalidomide and dexamethasone (DRd) (Arm B). Daratumumab (16 milligram per kilogram \[mg/kg\]) will be administered weekly for first 8 weeks (Cycles 1 to 2) of treatment and then every other week for 16 weeks (Cycles 3 to 6), then every 4 weeks (from Cycle 7 and beyond) until progression of disease or unacceptable toxicity. Lenalidomide will be administered at a dose of 25 mg orally on Days 1 through 21 of each 28-day cycle, and dexamethasone will be administered at a dose of 40 mg once a week for both treatment arms. Participants in both treatment arms will continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity. All participants randomized to Treatment Arm B (DRd) in this study initially received daratumumab IV formulation; however, following implementation of protocol amendment 8, participants 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. Daratumumab subcutaneous (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 completion. Participants in Arm A 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. The study consists of 3 phases: Screening Phase (within 21 days prior to the first dose administration on Day 1), Treatment Phase (Day 1 up to discontinuation of all study treatment), and Follow-up Phase (from discontinuation of all study treatment up to death, lost to follow up, consent withdrawal, or study end, whichever occurs first). The maximum duration of study will be 7 years after last participant is randomized. Efficacy will primarily be evaluated by PFS. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants will receive Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first. arm 2: Participants will receive Daratumumab 16 milligram per kilogram (mg/kg) by intravenous infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks, Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously once a week. Following implementation of protocol amendment 8, participants 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. Daratumumab subcutaneous (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 completion. Study treatment continues until disease progression, unacceptable toxicity, or end of study (maximum up to 7 years after last subject is randomized) whichever comes first.
Interventions: intervention 1: Daratumumab IV intervention 2: Lenalidomide intervention 3: Dexamethasone intervention 4: Daratumumab SC
Intervention descriptions: intervention 1: Daratumumab will be administered at a dose of 16 milligram per kilogram (mg/kg) by intravenous (IV) infusion, once a week for 8 weeks, then once every other week for 16 weeks, thereafter once every 4 weeks until documented progression of disease, unacceptable toxicity, or end of study (maximum up to 7 years). intervention 2: Lenalidomide 25 mg capsule orally on Day 1 through Day 21 of each 28-day cycle. intervention 3: Dexamethasone 40 mg orally or intravenously once in a week. intervention 4: 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. Following implementation of protocol amendment 8, participants 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.

Protocol documents:
Prot_001.pdf: 
1
Status: Approved,  Date: 12 June 2019
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 6
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; 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:
12 June 2019
Prepared by:
Janssen Research & Development, LLC  
EDMS number:
EDMS-ERI-85965381; 9.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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JNJ-54767414 Daratumumab
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 32
TIME AND EVENTS SCHEDULE OVERVIEW.......................................................................................... 37
TIME AND EVENTS SCHEDULE, DOSE ADMINISTRATION.................................................................. 41
ABBREVIATIONS ...................................................................................................................................... 43
1.
INTRODUCTION................................................................................................................................ 45
1.1.
Background .................................................................................................................................... 45
1.1.1.
Multiple Myeloma........................................................................................................................ 45
1.1.2.
Treatment Options for Multiple Myeloma.................................................................................... 45
1.1.3.
Transplant-ineligible Population ................................................................................................. 46
1.2.
Daratumumab ................................................................................................................................ 46
1.2.1.
Nonclinical Studies ..................................................................................................................... 46
1.2.2.
Clinical Studies ........................................................................................................................... 47
1.2.2.1.
Single-Agent Daratumumab Studies (GEN501 and MMY2002) ............................................. 47
1.2.2.2.
Combination Daratumumab Studies ....................................................................................... 48
1.3.
Lenalidomide.................................................................................................................................. 49
1.4.
Lenalidomide and Daratumumab................................................................................................... 50
1.5.
Overall Rationale for the Study...................................................................................................... 51
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 52
2.1.
Objectives ...................................................................................................................................... 52
2.2.
Hypothesis ..................................................................................................................................... 53
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 53
3.1.
Overview of Study Design.............................................................................................................. 53
3.2.
Study Design Rationale.................................................................................................................. 56
4.
SUBJECT POPULATION.................................................................................................................. 58
4.1.
Inclusion Criteria ............................................................................................................................ 58
4.2.
Exclusion Criteria ........................................................................................................................... 60
4.3.
Prohibitions and Restrictions ......................................................................................................... 63
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 64
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 64
6.1.
Daratumumab (Arm B Only) .......................................................................................................... 65
6.1.1.
Daratumumab Preparation ......................................................................................................... 65
6.1.2.
Daratumumab Administration ..................................................................................................... 65
6.1.3.
Prevention of Infusion Reactions................................................................................................ 66
6.1.3.1.
Preinfusion Medication ............................................................................................................ 66
6.1.3.2.
Postinfusion Medication........................................................................................................... 66
6.1.4.
Management of Infusion-related Reactions................................................................................ 67
6.1.4.1.
Infusion-Related Events of Grade 1 or Grade 2...................................................................... 67
6.1.4.2.
Infusion-Related Reactions of Grade 3 or Higher ................................................................... 68
6.2.
Lenalidomide (Arm A and Arm B) .................................................................................................. 68
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6.3.
Dexamethasone (Arm A and Arm B) ............................................................................................. 68
6.4.
Dose Delays and Dose Modification.............................................................................................. 69
6.4.1.
Daratumumab Dose Modification ............................................................................................... 69
6.4.1.1.
Daratumumab-Related Toxicity Management......................................................................... 69
6.4.1.2.
Daratumumab Interruption or Missed Doses........................................................................... 70
6.4.2.
Lenalidomide Dose Reductions.................................................................................................. 70
6.4.2.1.
Thrombocytopenia................................................................................................................... 70
6.4.2.2.
Neutropenia ............................................................................................................................. 71
6.4.2.3.
Renal Impairment .................................................................................................................... 71
6.4.2.4.
Other Adverse Events ............................................................................................................. 71
6.4.3.
Dexamethasone Dose Modifications.......................................................................................... 72
7.
TREATMENT COMPLIANCE............................................................................................................ 72
8.
CONCOMITANT THERAPY.............................................................................................................. 72
8.1.
Recommended Therapies.............................................................................................................. 73
8.1.1.
Prevention of Deep Vein Thrombosis and Pulmonary Embolism............................................... 73
8.1.2.
Bisphosphonate Therapy............................................................................................................ 73
8.1.3.
Therapy for Tumor Lysis Syndrome ........................................................................................... 74
8.1.4.
Prophylaxis for Pneumocystis carinii.......................................................................................... 74
8.1.5.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 74
8.1.6.
Prevention of Steroid Induced Gastritis...................................................................................... 74
8.1.7.
Management of Hepatitis B Virus Reactivation .......................................................................... 74
8.2.
Permitted Therapies....................................................................................................................... 74
8.3.
Prohibited Therapies...................................................................................................................... 75
8.4.
Subsequent Therapies................................................................................................................... 75
9.
STUDY EVALUATIONS .................................................................................................................... 76
9.1.
Study Procedures........................................................................................................................... 76
9.1.1.
Overview..................................................................................................................................... 76
9.1.2.
Screening Phase ........................................................................................................................ 76
9.1.3.
Treatment Phase ........................................................................................................................ 77
9.1.4.
Follow-up Phase......................................................................................................................... 78
9.1.5.
Assessments Following the Positive Second Interim Analysis of PFS ...................................... 78
9.1.6.
Assessments Following the Interim OS Analysis ....................................................................... 79
9.2.
Efficacy........................................................................................................................................... 79
9.2.1.
Evaluations ................................................................................................................................. 79
9.2.1.1.
Response Categories .............................................................................................................. 80
9.2.1.2.
Myeloma Protein Measurements in Serum and Urine ............................................................ 81
9.2.1.3.
Serum Calcium Corrected for Albumin.................................................................................... 82
9.2.1.4.
β2-microglobulin and Albumin.................................................................................................. 83
9.2.1.5.
Bone Marrow Examination ...................................................................................................... 83
9.2.1.6.
Minimal Residual Disease Assessment .................................................................................. 84
9.2.1.7.
Assessment of Lytic Disease................................................................................................... 84
9.2.1.8.
Documentation of Extramedullary Plasmacytomas................................................................. 84
9.2.2.
Endpoints.................................................................................................................................... 85
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 87
9.3.1.
Evaluations ................................................................................................................................. 87
9.3.2.
Analytical Procedures................................................................................................................. 87
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 87
9.3.4.
Immunogenicity Assessments (Antibodies to daratumumab) .................................................... 88
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 88
9.5.
Biomarkers ..................................................................................................................................... 88
9.6.
Medical Resource Utilization.......................................................................................................... 89
9.7.
Patient Reported Outcomes........................................................................................................... 89
9.8.
Safety Evaluations ......................................................................................................................... 90
9.9.
Sample Collection and Handling.................................................................................................... 93
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10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 94
10.1.
Completion ..................................................................................................................................... 94
10.2.
Discontinuation of Study Treatment............................................................................................... 94
10.3.
Withdrawal From the Study............................................................................................................ 95
11.
STATISTICAL METHODS................................................................................................................. 95
11.1.
Subject Information ........................................................................................................................ 95
11.2.
Sample Size Determination ........................................................................................................... 96
11.3.
Efficacy Analyses ........................................................................................................................... 96
11.4.
Pharmacokinetic Analyses............................................................................................................. 97
11.5.
Immunogenicity Analyses .............................................................................................................. 97
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 97
11.7.
Biomarker Analyses ....................................................................................................................... 97
11.8.
Patient Reported Outcomes........................................................................................................... 98
11.9.
Safety Analyses ............................................................................................................................. 98
11.10.
Interim Analysis.............................................................................................................................. 99
11.11.
Data Monitoring Committee ......................................................................................................... 100
12.
ADVERSE EVENT REPORTING .................................................................................................... 100
12.1.
Definitions .................................................................................................................................... 100
12.1.1.
Adverse Event Definitions and Classifications ......................................................................... 100
12.1.2.
Attribution Definitions................................................................................................................ 101
12.1.3.
Severity Criteria ........................................................................................................................ 102
12.2.
Special Reporting Situations........................................................................................................ 103
12.3.
Procedures................................................................................................................................... 103
12.3.1.
All Adverse Events.................................................................................................................... 103
12.3.2.
Serious Adverse Events ........................................................................................................... 104
12.3.3.
Suspected Unexpected Serious Adverse Reactions................................................................ 105
12.3.4.
Pregnancy................................................................................................................................. 105
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 106
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 106
13.1.
Procedures................................................................................................................................... 106
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 106
14.
STUDY DRUG INFORMATION....................................................................................................... 107
14.1.
Physical Description of Study Drug.............................................................................................. 107
14.2.
Packaging .................................................................................................................................... 107
14.3.
Labeling........................................................................................................................................ 107
14.4.
Preparation, Handling, and Storage............................................................................................. 107
14.5.
Drug Accountability ...................................................................................................................... 107
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 108
16.
ETHICAL ASPECTS ....................................................................................................................... 108
16.1.
Study-Specific Design Considerations......................................................................................... 108
16.2.
Regulatory Ethics Compliance..................................................................................................... 109
16.2.1.
Investigator Responsibilities ..................................................................................................... 109
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 109
16.2.3.
Informed Consent ..................................................................................................................... 110
16.2.4.
Privacy of Personal Data .......................................................................................................... 111
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 112
16.2.6.
Country Selection ..................................................................................................................... 112
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 112
17.1.
Protocol Amendments.................................................................................................................. 112
17.2.
Regulatory Documentation .......................................................................................................... 113
17.2.1.
Regulatory Approval/Notification .............................................................................................. 113
17.2.2.
Required Prestudy Documentation........................................................................................... 113
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17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 114
17.4.
Source Documentation................................................................................................................. 114
17.5.
Case Report Form Completion .................................................................................................... 115
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 116
17.7.
Record Retention ......................................................................................................................... 116
17.8.
Monitoring .................................................................................................................................... 117
17.9.
Study Completion/Termination..................................................................................................... 117
17.9.1.
Study Completion ..................................................................................................................... 117
17.9.2.
Study Termination..................................................................................................................... 117
17.10.
On-Site Audits .............................................................................................................................. 118
17.11.
Use of Information and Publication.............................................................................................. 118
REFERENCES.......................................................................................................................................... 120
INVESTIGATOR AGREEMENT .......................................................ERROR! BOOKMARK NOT DEFINED.
LIST OF ATTACHMENTS
Attachment 1: 
Modified IMWG Diagnostic Criteria for Multiple Myeloma........................................ 123
Attachment 2: 
ECOG Performance Status Scale ............................................................................ 124
Attachment 3:
Calculated and Measured Creatinine Clearance ..................................................... 125
Attachment 4: 
Serum Calcium Corrected for Albumin..................................................................... 126
Attachment 5:
Lenalidomide Global Pregnancy Prevention Plan.................................................... 127
Attachment 6: 
Conversion Table for Glucocorticosteroid Dose....................................................... 136
Attachment 7: 
Asthma Guidelines ................................................................................................... 137
Attachment 8: 
International Staging system .................................................................................... 140
Attachment 9: 
The Family of antihistamine medications ................................................................. 141
Attachment 10:
Anticipated Adverse Events...................................................................................... 142
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Daratumumab Single-Agent Studies GEN501 and MMY2002................................................. 47
Table 2:
Daratumumab Combination Studies GEN503 and MMY1001 ................................................. 48
Table 3:
Daratumumab-Related Toxicity Management .......................................................................... 69
Table 4:
Lenalidomide Dose Adjustment for Thrombocytopenia............................................................ 71
Table 5:
Lenalidomide Dose Adjustment for Neutropenia ...................................................................... 71
Table 6:
Lenalidomide Dose Adjustment for Renal Impairment ............................................................. 71
Table 7:
Recommended Dose Reduction for Dexamethasone .............................................................. 72
Table 8:
International Uniform Response Criteria Consensus Recommendations ................................ 80
Table 9:
Bone Marrow Testing................................................................................................................ 83
FIGURES
Figure 1:
Improvement of Daratumumab-induced Antibody-dependent Cell-mediated 
Cytotoxicity by Lenalidomide in Bone Marrow Mononuclear Cells from Patients with 
Multiple Myeloma...................................................................................................................... 51
Figure 2:
Schematic Overview of the Study............................................................................................. 54
Figure 3:
Daratumumab Maximal Target Suppression ............................................................................ 57
Figure 4:
Schematic Overview Study Treatment Administration ............................................................. 65
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JNJ-54767414 Daratumumab
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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
Amendments below are listed beginning with the most recent amendment.
Amendment 6 (12 June 2019)
The overall reason for the amendment: The overall reason for the amendment is in response to identification of 
a new important risk (hepatitis B virus [HBV] reactivation).
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 9.1.6’
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.
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Applicable Section(s)
Description of Change(s)
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 daratumamb by the sponsor for subjects 
randomized to Arm A (Rd) who are receiving any subsequent line of therapy.
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;
Details of IDMC reviews and planned interim analyses have been revised.
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Applicable Section(s)
Description of Change(s)
3.1. Overview of 
Study Design;
11.10. Interim 
Analysis
Synopsis, Overview of 
Study Design;
Synopsis, Statistical 
Methods;
3.1. Overview of 
Study Design;
9.2.2. Endpoints;
11.10. Interim 
Analysis
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.
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.
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
9
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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
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)’
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
10
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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
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.
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
11
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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).
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 
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
12
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
(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
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. 
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 6
13
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
Dexamethasone 
(Arm A and Arm B)
6.2. Lenalidomide 
(Arm A and Arm B); 
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
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
14
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
6.4.2.2. Neutropenia 
(Table 5)
<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.
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 6
15
Approved, Date: 12 June 2019
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.
Excusion 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.
4.2 Exclusion Criteria
Exclusion criterion 3: the following text is revised: (equivalent of dexamethasone 
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
16
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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, If Day 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.
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
17
Approved, Date: 12 June 2019
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 6
18
Approved, Date: 12 June 2019
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 
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 
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
19
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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
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
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
20
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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.
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.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
21
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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 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:
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
22
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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
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.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
23
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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.
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 
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
24
Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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 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 
Entire attachment updated to be consistent with other Daratumumab protocols
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
Criteria for Multiple 
Myeloma
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 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
Added the formula to measure CrCL to the attachment:
Eligible subjects will be stratified by International Staging System (I vs II vs III see
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
6.1.3.1 Preinfusion 
Medication
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.
NCT02252172


JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
27
Approved, Date: 12 June 2019
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
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
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.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
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. 
Rationale: To align with other protocols in the daratumumab program.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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.
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.
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
Applicable Section(s)
Description of Change(s)
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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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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Approved, Date: 12 June 2019
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. 

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
Exploratory Objectives

To explore biomarkers predictive of response or resistance to therapy

To assess durability of MRD negativity
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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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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 preinfusion medication with dexamethasone,
acetaminophen (paracetamol), and an antihistamine before each daratumumab infusion. 
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 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 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. 
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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 (ie, when 260 deaths have occurred) subject monitoring will be conducted according 
to Section 9.1.6. Investigators will be informed when each interim analysis is to occur.
The end of the study will occur when 330 subjects have died, or 7 years after the last subject is 
randomized, whichever comes first. The sponsor will ensure that subjects benefiting from treatment with 
daratumumab will be able to continue treatment after the end of the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to review 
efficacy and safety results at the 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.
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 (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.
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.
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JNJ-54767414 Daratumumab
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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.

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 PR or 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 cutoff.

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.
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PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
For all subjects in Arm B, pharmacokinetic samples to determine serum concentration of 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 8 weeks after the last dose of daratumumab, regardless of 
whether there has been confirmed disease progression. 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). 
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.
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 will continue until 330 deaths have been observed or 7 years after the last 
subject is randomized. Therefore, this study will achieve approximately 80% power to detect a 27% 
reduction in the risk of death (hazard ratio = 0.73) with a log-rank test (two-sided alpha = 0.05).
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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JNJ-54767414 Daratumumab
Clinical Protocol 54767414MMY3008 Amendment 6
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TIME AND EVENTS SCHEDULE OVERVIEW
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
Study treatment should be initiated within 72 hours after randomization. Day 1 of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject. After 
EOT, subjects in both treatment arms prior to PD will continue to return for disease evaluations. After PD is documented, subjects will be followed for survival, PFS2, second primary 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 and mPFS 
for DRd group has been confirmed, subject monitoring will be conducted according to Section 9.1.6.
Procedures
Informed consent
ICF must be signed before any study-related procedures
Eligibility criteria
X
Demography/
Medical History
X
Height
X
Chest X-ray (or full 
chest CT scan)
Acceptable for screening if performed as part of SOC within 
42 days before randomization
X
PFT
For subjects with COPD, FEV1 should be measured
X
ECOG
Prior to any other study procedures planned for the same 
day
X
D1 of Cycle 3, 6, 9, 12 for year 1; every 6th month ±14 days thereafter until PD. Post-PD 
collect at Wks 8 and 16. 
12-lead ECG
Acceptable for screening if performed as part of SOC within 
42 days before randomization
X
C3D1, C6D1
X
Physical exam
including neurological exam
X
symptom and disease directed exam 
as clinically indicated
Vital signs, weight
X
Please see following table for details.
Blood type and IAT
ABO, Rh, and IAT.  A wallet card with the subject’s blood 
type and IAT will be provided to subjects randomized to 
Arm B.
X
C1D1 predose, Arm B only
Laboratory Assessments
Pregnancy test
For women of childbearing potential only. During screening, within 10-14 days prior to first dose and again within 24 hrs prior to first 
dose. Minimum testing requirements during study: weekly during Cycle 1 and then monthly in women with regular menstrual cycles or 
every 2 weeks in women with irregular menstrual cycles. Please refer to Section 9.8 for details.
X
Hematology
X
Please see following table for details.
X
Serum chemistry
X
Please see following table for details.
X
HBV DNA Testing
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 
Every 3 months during treatment ± 1 month until 6 months after last dose of daratumumab.
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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
vaccination [Anti-HBs positivity as the only serologic 
marker] and a known history of prior HBV vaccination).
Daratumumab PK 
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). Samples to 
be sent to central laboratory.
C1D1, C6D1, C12D1
X
8 wks after last dara 
dose Arm B ONLY
Daratumumab 
immunogenicity
Arm B only. No additional sample needed; will be taken 
from PK sample. If an infusion reaction occurs, obtain 
unscheduled blood sample as soon as possible. 
predose C1D1 only
X
8 wks after last dara 
dose Arm B ONLY
Whole blood
Plasma or PBMC biomarker assessments
predose C1D1 only
X
Disease Evaluations: Every effort should be made to conduct disease evaluations as per schedule (window ± 7 days). Refer to Section 9.2 for details on efficacy evaluations
After EOT, subjects in both treatment arms prior to PD will continue to return for disease evaluations. After PD is documented, subjects will be followed for survival, PFS2, second 
primary 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 9.1.6.
Serum disease 
evaluations (SPEP)
Sample to be sent to central laboratory. IFE and FLC when 
CR is suspected or maintained. FLC every cycle for 
subjects with light chain only myeloma.
X (Repeat on 
C1D1 if not 
within 14 days 
prior to C1D1)
X (for first 2 years and then every 8 wks until PD)
Urine disease 
evaluations (UPEP)
Sample to be sent to central laboratory. IFE when CR is 
suspected or maintained. 
X (Repeat on 
C1D1 if not 
within 14 days 
prior to C1D1)
X (for first 2 years and then every 8 wks until PD)
Calcium, albumin, 
β2-microglobulin
Sample to be sent to central laboratory.
β2-microglobulin at screening only.
X (Repeat 
calcium and 
albumin on 
C1D1 if not 
within 14 days 
prior to C1D1); 
don’t repeat β2-
microglobulin
calcium/albumin every cycle for first 2 years and then every 8wks until PD
Bone marrow 
aspirate/biopsy
For screening (up to 42 days before randomization) fresh 
aspirate or biopsy preferred. If not available, obtain non-
decalcified tissue according to Section 9.2.1.5 Table 9
and/or FFPE tissue. Fresh biopsy or aspirate (or both) 
required to confirm CR/sCR. Samples for biomarker 
analysis to be sent to central laboratory
X
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, 30, 36, 48, and 60
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 
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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
including timepoints.
Quantitative Ig
See Section 9.2.1.2
X
every 16 weeks
X
Assessment of lytic 
disease
Acceptable for screening if performed within 42 days before 
randomization
X
As clinically indicated, using the same methodology as used at screening
Extramedullary 
plasmacytomas
Subjects with history of plasmacytoma; acceptable for 
screening if performed within 42 days before randomization
X
If applicable, by physical exam every 4 wks, by radiologic exam (if required) 
every 12 wks using same methodology as used at screening; for subjects with 
history of plasmacytoma assessed by physical exam, repeat assessment on 
C1D1 if not done within 14 days prior to randomization
PRO
EORTC-QLQ-30, EQ-5D-5L
Both questionnaires must be administered and completed 
prior to any other study procedures or assessments for that 
study visit.
All PRO measures will be collected via an electronic device 
(ePRO).
X
D1 of Cycle 3, 6, 9, 12 for year 1; every 6th month ± 14 days thereafter until PD. Post-PD 
collect at Wks 8 and 16. 
MRU
Continuous from C1D1 until End of Treatment (see Section 9.6)
Follow-up
Survival, PFS2, second primary malignancy, subsequent anti-myeloma 
therapy
Q16wk
Ongoing Subject Review
Adverse Events
See Section 12 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Concomitant 
Medications
See Section 8 for detailed instructions.
continuous from the time of signing of ICF until 30 days after last dose of last study drug
Abbreviations 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; 
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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
UPEP=urine M-protein quantitation by electrophoresis;  Wk=week
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TIME AND EVENTS SCHEDULE, DOSE ADMINISTRATION
Notes
Cycle 1 and Cycle 2
Cycle 3 to Cycle 6
Cycle 7 and after
EOT
D1
D8
D15
D22
D1
D15
D1
The start of each cycle may occur ±3 days of the scheduled day in order to accommodate the schedule of the site or subject. The start of each cycle should be scheduled relative to Cycle 1 
Day 1 and should not change if visits have shifted within the allowed window.
Hematology
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 days before other infusion days. Results of 
hematology tests must be evaluated before each study drug 
administration. Perform at additional timepoints, as clinically 
indicated. To be done by local lab.
X
X
X
X
X
X
X
X
Clinical 
Chemistry
X
X
X
X
Weight
If a subject’s weight changes by more than 10% from 
baseline, the dose of all study treatments will be re-calculated
X
X
X
Vital Signs
Vital signs (blood pressure, temperature, pulse/heart rate)
measured in sitting position. On Cycle 1 Day 1 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. For all other infusions, vital signs will be measured 
before infusion start and at end of dara infusion.
X
X
X
X
X
X
X
Diary review
Accountability/exposure check
X
X
X
X
X
X
X
X
Pre-infusion Medications, Arm B only
Dexamethasone
Administer approximately 1 hour before dara infusion. PO 
preinfusion medications may be administered within 3 hours 
before the infusion.

Dexamethasone 40 mg weekly IV (preferred) or PO. 
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) 

Acetaminophen (paracetamol) 650-1000 mg IV or PO
X
X
X
X
X
X
X
Antihistamine
X
X
X
X
X
X
X
Acetaminophen 
(paracetamol)
X
X
X
X
X
X
X
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Notes
Cycle 1 and Cycle 2
Cycle 3 to Cycle 6
Cycle 7 and after
EOT
D1
D8
D15
D22
D1
D15
D1
Study Drug Administration, Arm A and Arm B
Lenalidomide
Dispense on Day 1 for self-administration.  In Arm B, on 
daratumumab infusion days, lenalidomide will be 
administered either prior to or at the same time (preferred) as 
the pre-infusion medications.
25 mg daily, Day 1-21 of each cycle
(until PD or unacceptable toxicity)
Dexamethasone
Dispense on Day 1 for self-administration.
40mg weekly PO; Day 1, 8, 15, 22 of each cycle. 
(until PD or unacceptable toxicity)
Not required in Arm B on daratumumab infusion days. 
Study Drug Administration, Arm B Only
Daratumumab
Refer to SIPPM for recommendations on daratumumab 
infusion rate. For windows see Table 3.
X
X
X
X
X
X
X
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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
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
IRB
Institutional Review Board
ITT
intent-to-treat
IUD
intrauterine device
IV
intravenous
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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
REMS
Risk Evaluation and Mitigation Strategy
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
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 
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(ADCC) is slower in its action, with maximal ADCC by daratumumab observed at 4 hours in 
vitro (de Weers 2011).6 Daratumumab has also been shown to induce antibody-dependent 
cellular phagocytosis (ADCP) in the presence of macrophages within 4 hours in vitro 
(Overdijk 2013).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.
1.3.
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 
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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.
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).
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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
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 
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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. 
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
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
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. 
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.
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.
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Figure 2:
Schematic Overview of the Study
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 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 cytokine release syndrome will include preinfusion medication with 
dexamethasone, acetaminophen (paracetamol), and an antihistamine before each daratumumab 
infusion. 
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 
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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 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.
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 (ie, when 260 deaths have occurred) subject monitoring
will be conducted according to Section 9.1.6. Investigators will be informed when each interim 
analysis is to occur.
The end of the study will occur when 330 subjects have died, or 7 years after the last subject is 
randomized, whichever comes first. The sponsor will ensure that subjects benefiting from 
treatment with daratumumab will be able to continue treatment after the end of the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to 
review efficacy and safety results at the 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 
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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.
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.
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 
toxicity in 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.
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Rationale for Daratumumab Dose
CD38, the target for daratumumab, is expressed on NK cells and clinical data has shown NK cell 
suppression to be a marker of on target drug activity. Clinical pharmacokinetic data have shown 
the 16 mg/kg dose to be the lowest dose that results in 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.
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 cutoff date of 24 January 2014. In Study GEN501, the ORRs (ie, PR or greater) 
were 11% and 40% for the 8 mg/kg (n=28) and 16 mg/kg (n=15) dose regimens, respectively. 
For Study MMY2002, the unconfirmed ORRs for the 8 mg/kg and 16 mg/kg dose regimens were 
similar to those observed in GEN501. In addition, VGPRs were observed for 7 of 30 subjects 
treated with the 16 mg/kg dose in the 2 studies. VGPR had not been observed at lower dose 
levels. These preliminary data support that full target saturation at the 16 mg/kg dose is needed 
to achieve higher and deeper response rates. 
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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.
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 
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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);
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
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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.
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.
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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.
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 
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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).
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 
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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
must continue during the Treatment Phase, during any dose interruptions, for 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, for 4 weeks after the last dose of 
lenalidomide, and for 3 months after the last dose of daratumumab.
2.
During the Treatment Phase, pregnancy tests are required weekly during Cycle 1 and 
then monthly in subsequent cycles in women with regular menstrual cycles or every 
2 weeks in women with irregular menstrual cycles. A pregnancy test is also required at 
the End-of-Treatment Visit. Additional pregnancy tests may be required, as specified in 
the 
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).
3.
A man who is sexually active with a woman of childbearing potential must always use a 
latex or synthetic condom during the study, for 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 sperm during the study, 
for 4 weeks after the last dose of lenalidomide, and for 3 months after the last dose of 
daratumumab.
4.
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).
5.
Subjects must not donate blood during therapy and for at least 4 weeks following 
discontinuation of lenalidomide.  
6.
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, 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 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 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
The infusion solution will be prepared on the day of the planned infusion. Detailed instructions 
for preparation and administration of daratumumab will be supplied in the Site Investigational 
Product Procedures Manual (SIPPM) or equivalent document.
6.1.2.
Daratumumab Administration
Daratumumab (16 mg/kg) will be administered 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. After the end of the study, the 
sponsor will ensure that subjects benefiting from treatment with daratumumab will be able to 
continue treatment.
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 6.1.3.
Every effort should be made to keep subjects on the planned dosing schedule. Time windows for 
daratumumab administration are outlined in Table 3.
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
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subject experiences any significant medical event, then the investigator should assess whether 
the subject should stay overnight for observation. 
6.1.3.
Prevention of Infusion Reactions
6.1.3.1.
Preinfusion Medication 
Preinfusion medications for subjects receiving daratumumab will be administered as described in 
the Time and Events Dose Administration Schedule. 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 but avoid IV use of 
promethazine) approximately 1 hour prior to infusion (see Attachment 9 for list of 
antihistamines that may be used); 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.

Dexamethasone 40 mg IV (preferred) or PO, 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.
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.
6.1.3.2.
Postinfusion 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 postinfusion 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)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their FEV1 should be measured before discharge. If 
these subjects are not hospitalized, then a follow up telephone call should be made to monitor 
their condition within 48 hours after all infusions. If the subject has not experienced a significant 
medical event but is hospitalized overnight only for observation, then the hospitalization should 
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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 postinfusion 
medications may be waived after 4 full doses at the investigator’s discretion.
6.1.4.
Management of Infusion-related Reactions
Subjects in Arm B should be carefully observed during daratumumab infusions. Trained study 
staff at the clinic should be prepared to intervene in case of any infusion reactions occurring, and 
resources necessary for resuscitation (eg, agents such as epinephrine and aerosolized 
bronchodilator, also medical equipment such as oxygen tanks, and a defibrillator) must be 
available. Attention to staffing should be considered when multiple subjects will be dosed at the 
same time.
If an infusion-related reaction develops, then the infusion should be paused. Subjects who 
experience adverse events during the infusion must be treated according to the investigator’s 
judgment and best clinical practice. The following guidelines may apply:

Subjects should be treated with acetaminophen, antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, 
subjects may require vasopressors.

In the event of a life-threatening infusion-related reaction (which may include pulmonary or 
cardiac events), or anaphylactic reaction, daratumumab should be discontinued and no 
additional daratumumab should be administered to the subject. Aggressive symptomatic 
treatment should be applied. 
If an infusion is paused, then a longer-than-anticipated infusion time may occur. Overnight stays 
at the hospital because of slow infusion times should not be reported as a serious adverse event.
However, if the underlying cause of the delayed infusion time is an adverse event or serious 
adverse event, then that should be reported as such.
6.1.4.1.
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses an adverse event to be related to the daratumumab infusion, then the 
infusion should be paused. When the subject’s condition is stable, the infusion may be restarted 
at the investigator’s discretion. Upon restart, the infusion rate should be half of that used before 
the interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion. 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from the onset, then the subject must be withdrawn from treatment.
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6.1.4.2.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related adverse events that are Grade 4, the infusion should be stopped and 
treatment with daratumumab will be discontinued for that subject.
For infusion-related adverse events that are Grade 3, the daratumumab infusion must be stopped, 
and the subject must be observed carefully until the resolution of the adverse event or until the 
intensity of the event decreases to Grade 1, at which point the infusion may be restarted at the 
investigator’s discretion. Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the investigator’s discretion.
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the 
procedure described in this section may be repeated at the investigator’s discretion. Should the 
intensity of the adverse event increase to Grade 3 for a third time, then treatment with 
daratumumab will be discontinued for that subject.
6.2.
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 infusion 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 an infusion 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 infusion.
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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.
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 6.1.3 for details on management of infusion-related reactions. ONLY if any of 
the following criteria are met and the event cannot be ascribed to lenalidomide, the daratumumab 
infusion must be held to allow for recovery from toxicity. The criteria for a dose delay are:

Grade 4 hematologic toxicity

Grade 3 thrombocytopenia with bleeding

Febrile neutropenia 

Neutropenia with infection, of any grade

Grade 3 or higher 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 administration does not commence within the 
prespecified window (Table 3) of the scheduled administration date, then the dose will be 
considered a missed dose. Administration may resume at the next planned dosing date. 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
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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.
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.
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.
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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.
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.
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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.
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 infusions.
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 
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sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
Routine systemic use of the following concomitant medications will be collected in the eCRF 
and recorded in the source documents beginning with signing of the ICF to 30 days after the last 
dose of the last study treatment or until the start of subsequent anti-myeloma treatment, if earlier: 
growth factors, transfusions, anti-infectives (antibacterials, antivirals, and antimycotics), steroids, 
anti-arrhythmics and other cardiac supportive therapy, anti-epileptics, centrally acting psychiatric 
medication, anti-histamines and other medications targeting postinfusion 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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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 6.1.3.2 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. 
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. 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.
After sponsor confirmation of PD, 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 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 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.
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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.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, 
pharmacokinetic, immunogenicity, biomarker, patient reported outcomes, and safety 
measurements applicable to this study.
All visit-specific PRO assessments should preferably be conducted/completed before any tests, 
procedures, or other consultations for that visit to prevent influencing subject perceptions. Refer 
to Section 9.7 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.
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.
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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 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.
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.
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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. 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.
If the information is obtained via telephone contact, written documentation of the 
communication must be available for review in the source documents. If the subject has died, the 
date and cause of death will be collected and documented in the eCRF. 
The end of the study occurs after 330 subjects have died, or for a maximum of 7 years after the 
last subject is randomized, whichever occurs first. The sponsor will ensure that subjects 
benefiting from treatment with daratumumab will be able to continue treatment after the end of 
the study.
9.1.5.
Assessments Following the Positive Second Interim Analysis of PFS
Following the positive second interim analysis of PFS, subjects remaining in the study will
continue to be monitored as follows until the next interim analysis of OS (ie, when 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).
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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 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 study end (ie, when 330 deaths have
occurred, or 7 years after the last subject is randomized, whichever comes first):

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).

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, disease 
evaluations are to be performed locally per the site’s standard of care. Sponsor confirmation 
of disease progression will no longer be required prior to initiation of subsequent anti-
myeloma therapy.

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.
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.
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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 
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 of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24 hours

If the serum and urine M-protein are not measurable, a decrease of ≥50% in the difference between 
involved and uninvolved FLC levels is required in place of the M-protein criteria

In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft tissue 
plasmacytomas is also required.
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 
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≥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.
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 the end of study, whichever occurs first. Disease evaluations 
scheduled for treatment days should be collected before study treatment is administered. 
9.2.1.2.
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a 
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the 
central laboratory to perform the following tests. 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 
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this study as long as it was sent to the central lab for analysis after the informed consent was 
obtained.

Serum quantitative immunoglobulins (QIgs)

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.
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Measurement of free ionized calcium is an acceptable alternative to corrected serum calcium for 
determining hypercalcemia. Free ionized calcium levels greater than the ULN (local laboratory 
reference ranges) are considered to be hypercalcemic for this study.
9.2.1.4.
β2-microglobulin and Albumin
Blood samples for β2 microglobulin and albumin are to be collected at Screening, and will be 
analyzed by the central laboratory.
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.
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*. 
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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 of the 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 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.
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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 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
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
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.

Proportion of subjects who achieve VGPR or better, defined as the proportion of subjects 
achieving VGPR and CR (including sCR) according to the IMWG criteria during or after the 
study treatment at the time of data cutoff.

Time to response, defined as the time between 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.
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Exploratory Endpoints

Biomarkers predictive of response or resistance to daratumumab.

Durability of MRD negativity.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations
For all subjects in Arm B, pharmacokinetic samples to determine serum concentration of 
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 assessments 8 weeks 
after the last dose of daratumumab, regardless of whether there has been confirmed disease 
progression. 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. 
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.
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).
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9.3.4.
Immunogenicity Assessments (Antibodies to daratumumab)
Venous blood samples drawn from all subjects in the DRd arm will be assessed for the 
generation of antibodies to daratumumab (immunogenicity), according to the Time and Events 
Schedule. In the Follow-up Phase, for all subjects in Arm B (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 progression.
All samples collected for immunogenicity analysis will also be evaluated for daratumumab 
serum concentration to ensure appropriate interpretation of immunogenicity data. At each time 
point, immunogenicity and serum daratumumab concentration analyses will be performed on 
aliquots from the same blood draw and no additional sampling is required. Procedures for sample 
collection, preparation, identification, storage, and shipment will be provided in the Laboratory 
Manual or equivalent document. 
Serum samples will be screened for antibodies binding to daratumumab and serum titer will also 
be determined from confirmed positive samples using validated assay methods by or under the 
supervision of the sponsor. Other immunogenicity analyses (eg, assessment of neutralizing 
capabilities) may be performed to further characterize the immune responses that are generated. 
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab 
any time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety 
or efficacy aspects that address concerns arising during or after the study period or for the 
evaluation of relevant biomarkers by the sponsor or sponsor’s designee.
9.4.
Pharmacokinetic/Pharmacodynamic Evaluations
If sufficient data are available, then other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy. If these analyses are performed, then the details and results 
will be presented in a separate report.
9.5.
Biomarkers
Biomarker assessments will focus on 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 
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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 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.
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, 
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or other 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 end 
of the study/early withdrawal will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached.
Based on the previous human experience with daratumumab, in vitro studies, and animal 
toxicological 
findings, 
infusion-related 
reactions/allergic 
reactions, 
hemolysis, 
and 
thrombocytopenia will be closely monitored. As a biologic agent, immunogenicity also will be 
monitored. Any of the safety monitoring assessments may be performed more frequently, and 
adverse events should be evaluated by the investigator according to the standard practice, if 
clinically indicated.
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 
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representative) for the duration of the study. Adverse events will be followed by the investigator 
as specified in Section 12, Adverse Event Reporting.
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 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 6.1.3.2 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.
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 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.
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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he or she has finished all 
protocol-specified procedures before the end of the study, has not been lost to follow up, or has 
not withdrawn consent for study participation before the end of the study. The study end is 
defined as when 330 deaths have occurred, or 7 years after the last subject is randomized, 
whichever comes first.
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 should be discontinued if:

The investigator believes that for safety reasons (eg, adverse event) it is in the best interest 
of the subject to discontinue study treatment

The subject becomes pregnant 

The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study treatment

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for multiple myeloma

The subject experiences unacceptable toxicity, including infusion-related reactions described 
in Section 6.1.4

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)

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 
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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.
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 
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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 will continue until 330 deaths have been observed or 7 years after
the last subject is randomized. Therefore, this study will achieve approximately 80% power to 
detect a 27% reduction in the risk of death (hazard ratio = 0.73) with a log-rank test (two-sided 
alpha = 0.05).
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.
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 330 deaths have been observed. Earlier analyses, in which overall 
survival is analyzed, will be considered as interim analyses. Even though the significance of PFS 
has already been established at the second interim analysis, testing of OS will continue as 
planned until a definitive conclusion on OS is reached. The details about testing of OS over time 
are specified in Section 11.10. The analysis of OS may be confounded by subjects from Arm A 
receiving daratumumab after 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% 
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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 postinfusion 
sample. All serum concentrations below the lowest quantifiable concentration or missing data 
will be labeled as such in the concentration data presentation. Concentrations below the lowest 
quantifiable concentration will be treated as zero in the summary statistics. All subjects and 
samples excluded from the analysis will be clearly documented in the study report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling time point and pharmacokinetic parameters of daratumumab such as Cmin and Cmax. 
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.
11.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab will be summarized for all subjects who receive a 
dose of daratumumab and have appropriate samples for detection of antibodies to daratumumab.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then population pharmacokinetic analysis 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 
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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 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 
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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.
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 
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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 
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.
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Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious.
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
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An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI CTCAE Version 4. Any adverse event or serious adverse event not listed in the 
NCI CTCAE Version 4 will be graded according to investigator clinical judgment by using the 
standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening of disabling adverse event
Grade 5: Death related to the adverse event
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
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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, unless the subject withdraws consent for study participation, or starts subsequent 
anti-myeloma therapy. For subjects who have received subsequent treatment with therapeutic 
intent for multiple myeloma during the adverse event reporting period, only adverse events that 
are considered to be possibly, probably, or definitely related to daratumumab need to be 
reported. Serious adverse events, including those spontaneously reported to the investigator 
within 30 days after the last dose of study treatment, must be reported using the Adverse Event 
Form. The sponsor will evaluate any safety information that is spontaneously reported by an 
investigator beyond the time frame specified in the protocol.
Expected progression of disease should not be considered an AE (or SAE). However, if 
determined by the investigator to be more likely related to the study treatment than the 
underlying disease, the clinical signs or symptoms of progression and the possibility that the 
study treatment is enhancing disease progression, should be reported per the usual reporting 
requirements (see Section 12.1). 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.
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 
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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)
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:
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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following infusion of daratumumab, then the hospitalization should not 
be reported as a serious adverse event.

Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered serious adverse events. Any adverse event that results in a prolongation of 
the originally planned hospitalization is to be reported as a new serious adverse event.
12.3.3.
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 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 
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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.
Because the effect of the study drug on sperm is unknown, pregnancies 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
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 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.
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14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The daratumumab supplied for this study is a colorless to yellow liquid and sterile concentrate of 
20 mg/mL in a vial. It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator's Brochure for a list of excipients.
14.2.
Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 
20 mg/mL.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage
All study drug vials must be stored in the original carton in a refrigerator ranging from 2°C to 8°C 
and must not be utilized after the expiry date printed on the label. The product must be protected 
from light and must not be frozen. Daratumumab does not contain preservatives; therefore any 
unused portion remaining in the vial must be discarded. 
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl) 
prior to IV administration. Refer to the Investigational Product Preparation Instructions and 
Investigational Product Procedures Manual for details regarding dose preparation, storage, and 
handling of diluted solutions.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug, or used returned study drug for destruction, will be documented on the drug return form. 
When the study site is an authorized destruction unit and study drug supplies are destroyed 
on-site, this must also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
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Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Study drug may not be relabeled or reassigned for use by 
other subjects. The investigator agrees neither to dispense the study drug from, nor store it at, 
any site other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for daratumumab

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 6.1.3 for prevention details. Based on the mode of action of daratumumab, a potential risk 
could be infection; therefore the protocol requires the review of hematological laboratory results 
prior to daratumumab infusion. CD38 is distributed in erythrocytes and platelets. A significant 
reduction of platelets was reported in an animal study. In a human clinical study (Study GEN501), 
thrombocytopenia was also reported. However, safety laboratory monitoring did not show a 
clinically meaningful reduction of platelets. Anemia was also reported in Study GEN501. Free 
hemoglobin was mildly elevated, but other parameters did not support hemolysis. No bleeding 
events were observed. Routine safety laboratory measurement of RBCs and platelets will be 
closely monitored in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The 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 
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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.
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.
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During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of 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 
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the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, including permission to obtain information about his or 
her survival status, and agrees to allow his or her study physician to recontact the subject for the 
purpose of obtaining consent for additional safety evaluations, if needed, and subsequent 
disease-related treatments, or to obtain information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
When prior consent of the subject is not possible and the subject's legally acceptable 
representative is not available, enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and 
well-being of the subject and to ensure compliance with applicable regulatory requirements. The 
subject or legally acceptable representative must be informed about the study as soon as possible 
and give consent to continue.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
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disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for 
study-related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker/PK/immunogenicity research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand daratumumab, to 
understand multiple myeloma, to understand differential drug responders, and to develop 
tests/assays related to daratumumab and multiple myeloma.  The research may begin at any time 
during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Study (Withdrawal From the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
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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 
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)
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
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. 
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 
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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:

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).
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
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.
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.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
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17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the hospital or clinic records 
(source documents). The nature and location of all source documents will be identified to ensure 
that all sources of original data required to complete the eCRF are known to the sponsor and 
study-site personnel and are accessible for verification by the sponsor study-site contact. If 
electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed after 330 deaths have occurred or 7 years after the last subject 
is randomized, whichever is first. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject at that study site, in the time frame specified in the 
Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
biomarker analyses performed after the Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
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 
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and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months after study end date, or the sponsor 
confirms there will be no multicenter study publication. Authorship of publications resulting 
from this study will be based on the guidelines on authorship, such as those described in the
ICMJE Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical Journals, which state that the named authors must have made a significant 
contribution to the conception or design of the work; or the acquisition, analysis, or interpretation 
of the data for the work; and drafted the work or revised it critically for important intellectual 
content; and given final approval of the version to be published; and agreed to be accountable for 
all aspects of the work in ensuring that questions related to the accuracy or integrity of any part 
of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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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.
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Chapuy C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility 
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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 
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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 
an ddexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous 
stem-cell transplant (SWOG S0777): a randomized, open-label, phase 3 trial. Lancet. 2017;389:519-527.
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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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October 21, 2013 vol. 122 no. 21 2. ASH 2013 Meeting Abstract. 
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Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J 
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Gay F and Palumbo A. Management of older patients with multiple myeloma. Blood Reviews. 2011;25:65-73.
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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, 
excluding Transplantation. American Society of Hematology (ASH) 2013 meeting. Abstract 1960.
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Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of 
the EQ-5D (EQ-5D-5L). Qual Lif Res. 2011;20:1727-1736.
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Hulin C, Belch A, Shustik C, et al. Updated outcomes and impact of age with lenalidomide and low-dose 
dexamethasone or melphalan, prednisone, and thalidomide in the randomized, Phase III FIRST trial. J Clin 
Oncol. 2016;34:3609-3617.
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Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. 
J Hematol Oncol. 2009;2:36.
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Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response 
and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-346.
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Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. 
Mayo Clin Proc. 2003;78(1):21-33. 
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Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple 
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Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) 
multiple myeloma. N Engl J Med. 2007;356(25):2582-2590.
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Ladetto M, Bruggemann M, Monitello L, et al. Next-generation sequencing and real-time quantitative PCR for 
minimal residual disease detection in B-cell disorders. Leukemia. 2014. doi: 10.1038/leu.2013.375.
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Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal 
residual disease detection in multiple myeloma. Blood, prepublished online March 19, 2014: 10.1182/blood-
2014-01-55020.
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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.
23.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines): Multiple Myeloma, version 2.2013. Fort Washington, PA: National Comprehensive Cancer 
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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. 
13 May 2013. 
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 of multiple 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, Wisloff F, 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 of pregnancy

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.
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.
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
Female patients should not donate blood during therapy and for at least 28 days following 
discontinuation of study drug.

Male patients should not donate blood, semen or sperm during therapy or 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 
while taking lenalidomide. The teratogenic potential of lenalidomide in humans cannot be 
ruled out. FCBP must agree not to become pregnant while taking lenalidomide. 
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
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 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.

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.
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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 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 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 about lenalidomide?
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 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 of Asthma Severity
Intermittent
Persistent
Mild
Moderate
Severe
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Impairment
Normal FEV1/FVC :
8-19 yr 85%
20-39 yr 80%
40-59 yr 75%
60-80 yr 70%
Symptoms
≤2 days/week
> 2 days/week but not daily
Daily
Throughout the day
Nighttime 
awakenings
0
≤2x/month
1-2x/
month
3-4x/month
3-4x/
month
> 1x/week but not nightly
> 1x/
month
Often 7x/week
SABA use for 
symptom control 
(not prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/ 
week but not 
daily, and
not more 
than 1x on
any day
Daily
Several time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% Normal
N/A
60-80%
75-80%
60-80% 
Reduced 5%
N/A
< 60%
< 75%
< 60% 
Reduced 5%
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 
exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year
lasting >1 day
and risk factors
for persistent 
asthma
≥ 2/year
Relative annual
risk may be 
related to 
FEV1.
≥ 2/year
Relative annual
risk may be 
related to 
FEV1.
≥ 2 
exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day
and risk factors
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be related
to FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 
exacerbations in
6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 year 
lasting >1 day 
and risk factors 
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be related
to FEV1.
≥ 2/year
Relative annual
risk
may be related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
Recommended Step for
Initiating Treatment
Step 1
Step 2
Step 3 and 
consider 
short course 
of oral 
steroids
Step 3: 
medium dose 
ICS and 
consider
short course of
oral steroids
Step 3 and 
consider short 
course of oral 
steroids
Step 3 and 
consider short 
course of oral 
steroids
Step 3: medium
dose ICS OR
Step 4 and
consider short
course of oral
steroids
Step 4 or 5 and
consider short 
course
of oral steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy.  5-11 and 12+ years: adjust therapy accordingly.
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Components of 
Control
Classification of Asthma Control
Well Controlled
Not Well Controlled
Very Poorly Controlled
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Symptoms
≤ 2 days/week but not 
more than once on
each day
≤ 2 days/
week
> 2 days/week or 
multiple times on 
≤2 days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime 
awakenings
≤ 1x/month
≤ 2x/month
> 1x/month
≥ 2x/month
1-3x/week
> 1x/week
≥ 2x/week
≥ 4x/week
Interference with 
normal activity
None
Some limitation
Extremely limited
SABA use for symptom 
control (not prevention of
EIB)
≤2 days/week
> 2 days/week
Several times per day
Lung function
FEV1 or peak flow
FEV1/FVC
N/A
> 80%
> 80%
> 80%
N/A
60-80%
75-80%
60-80%
N/A
< 60%
< 75%
< 60%
Validated questionnaires
ATAQ
ACQ
ACT
0
≤ 0.75
≥ 20
1-2
≥ 1.5
16-19
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral 
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung 
function
Evaluation requires long-term follow-up
• Maintain current step
• Regular follow-up every 
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 
of oral 
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Recommended Action for
Treatment
1-6 months
• Consider step down if well 
controlled for at least 3 
months
• Before step up:
Review adherence to medication,
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred
treatment for that step.
• Reevaluate the level of asthma
control in 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative 
diagnoses or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.
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 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative diagnoses
or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.
steroids
• Step up 1-2 
steps
• Reevaluate 
in 2 weeks
• For side
effects, 
consider 
alternative 
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 preinfusion 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:

Anaemia

Bleeding

Bone diseases

Hypercalcaemia

Hyperuricemia

Hyperviscosity syndrome

Infection

Neutropenia

Renal failure or insufficiency

Thrombocytopenia
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated events 
and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor as described in 
Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from expedited reporting as 
individual single cases to Health Authorities. However, if based on an aggregate review, it is determined 
that an anticipated event is possibly related to study drug, the sponsor will report these events in an 
expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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NCT02252172

SAP_000.pdf: 
1
Approved, Date: 3 October 2018
Janssen Research & Development
Statistical Analysis Plan
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 Amendment INT-4 Phase 3
JNJ-54767414  (daratumumab)
Status:
Approved
Date:
3 October 2018
Prepared by:
Janssen Research & Development
Document No.: EDMS-ERI-120250925, 3.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
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JNJ-54767414  (daratumumab)
Statistical Analysis Plan 54767414MMY3008
2
Approved, Date: 3 October 2018
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Overview of Trial Design.................................................................................................................. 7
1.2.
Statistical Hypotheses for Trial Objectives....................................................................................... 8
1.3.
Sample Size Determination ............................................................................................................. 8
1.4.
Interim Analyses............................................................................................................................... 9
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 9
2.1.
Visit Windows................................................................................................................................... 9
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 9
2.3.
Study Treatment and Study Drug .................................................................................................. 10
2.4.
Study Treatment Dosing Date........................................................................................................ 10
2.5.
Baseline Measurement .................................................................................................................. 10
2.6.
Unique Lab Value........................................................................................................................... 10
2.7.
Imputation of Partial Dates............................................................................................................. 10
2.7.1.
Missing/Partial Adverse Event Onset Date................................................................................. 11
2.7.2.
Missing/Partial Adverse Event End Date.................................................................................... 11
2.7.3.
Partial Concomitant Medication Start/End Date ......................................................................... 11
2.7.4.
Partial Multiple Myeloma Diagnosis Date................................................................................... 12
2.7.5.
Partial Subsequent Anticancer Therapy Start Date .................................................................... 12
2.8.
General Analysis Method............................................................................................................... 12
2.9.
Analysis Sets.................................................................................................................................. 12
2.10.
Definition of Subgroups.................................................................................................................. 14
2.11.
Other General Definitions............................................................................................................... 14
2.11.1.
Treatment Emergent Adverse Events ........................................................................................ 14
2.11.2.
Linking of Treatment Emergent Adverse Events........................................................................ 14
3.
SUBJECT INFORMATION................................................................................................................ 15
3.1.
Demographics and Baseline Characteristics ................................................................................. 15
3.2.
Disposition Information................................................................................................................... 15
3.3.
Extent of Exposure......................................................................................................................... 16
3.4.
Protocol Deviations ........................................................................................................................ 17
3.5.
Prior, Concomitant and Subsequent Therapies............................................................................. 17
4.
EFFICACY ......................................................................................................................................... 17
4.1.
Analysis Specifications................................................................................................................... 18
4.1.1.
Level of Significance................................................................................................................... 18
4.1.2.
Data Handling Rules................................................................................................................... 19
4.2.
Primary Efficacy Endpoint .............................................................................................................. 19
4.2.1.
Definition..................................................................................................................................... 19
4.2.2.
Analysis Methods........................................................................................................................ 19
4.2.3.
Sensitivity Analysis of PFS ......................................................................................................... 20
4.2.3.1.
Progressive Disease Based on Investigator Assessment....................................................... 20
4.2.3.2.
Not Censored for Start of Subsequent Anticancer Therapies ................................................. 20
4.2.3.3.
Censored for Death/PD after Missing More Than One Disease Evaluation ........................... 21
4.2.3.4.
Per-protocol Analysis of PFS................................................................................................... 21
4.2.3.5.
Unstratified Analysis of PFS .................................................................................................... 21
4.3.
Secondary Endpoints ..................................................................................................................... 21
4.3.1.
CR or Better Rate ....................................................................................................................... 22
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4.3.1.1.
Definition.................................................................................................................................. 22
4.3.1.2.
Analysis Methods .................................................................................................................... 22
4.3.2.
VGPR or Better Rate .................................................................................................................. 22
4.3.2.1.
Definition.................................................................................................................................. 22
4.3.2.2.
Analysis Methods .................................................................................................................... 22
4.3.3.
MRD Negativity Rate .................................................................................................................. 22
4.3.3.1.
Definition.................................................................................................................................. 22
4.3.3.2.
Analysis Methods .................................................................................................................... 23
4.3.4.
Overall Response Rate (ORR) ................................................................................................... 23
4.3.4.1.
Definition.................................................................................................................................. 23
4.3.4.2.
Analysis Methods .................................................................................................................... 23
4.3.5.
Overall Survival........................................................................................................................... 23
4.3.5.1.
Definition.................................................................................................................................. 23
4.3.5.2.
Analysis Methods .................................................................................................................... 23
4.3.6.
Time to Disease Progression (TTP) ........................................................................................... 24
4.3.6.1.
Definition.................................................................................................................................. 24
4.3.6.2.
Analysis Methods .................................................................................................................... 24
4.3.7.
Progression-free Survival on Next Line of Therapy (PFS2) ....................................................... 25
4.3.7.1.
Definition.................................................................................................................................. 25
4.3.7.2.
Analysis Methods .................................................................................................................... 25
4.3.8.
sCR Rate .................................................................................................................................... 25
4.3.8.1.
Definition.................................................................................................................................. 25
4.3.8.2.
Analysis Methods .................................................................................................................... 25
4.3.9.
Time to Subsequent Antimyeloma Treatment ............................................................................ 25
4.3.9.1.
Definition.................................................................................................................................. 25
4.3.9.2.
Analysis Methods .................................................................................................................... 26
4.3.10.
Time to Response....................................................................................................................... 26
4.3.10.1.
Definition.................................................................................................................................. 26
4.3.10.2.
Analysis Methods .................................................................................................................... 26
4.3.11.
Duration of Response................................................................................................................. 26
4.3.11.1.
Definition.................................................................................................................................. 26
4.3.11.2.
Analysis Methods .................................................................................................................... 26
4.4.
Subgroup Analysis of Efficacy Endpoints ...................................................................................... 26
4.5.
Functional Status and Well-being .................................................................................................. 27
4.5.1.
Definition..................................................................................................................................... 27
4.5.2.
Analysis Methods........................................................................................................................ 27
5.
SAFETY............................................................................................................................................. 29
5.1.
Adverse Events .............................................................................................................................. 29
5.1.1.
Overview of TEAEs..................................................................................................................... 29
5.1.2.
All TEAEs.................................................................................................................................... 30
5.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 30
5.1.4.
Study Treatment-Related TEAEs ............................................................................................... 30
5.1.5.
Serious Adverse Events (SAEs) ................................................................................................. 30
5.1.6.
TEAEs Leading to Dose Modifications ....................................................................................... 30
5.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment ...................................................... 30
5.1.8.
TEAEs Leading to Discontinuation of All Study Treatment......................................................... 31
5.2.
Deaths............................................................................................................................................ 31
5.2.1.
Death Due to TEAEs................................................................................................................... 31
5.2.2.
Deaths......................................................................................................................................... 31
5.2.3.
Adverse Events by Subgroups ................................................................................................... 31
5.3.
Adverse Events of Clinical Interest ................................................................................................ 32
5.3.1.
Infusion-Related Reactions (IRR)............................................................................................... 32
5.3.2.
Infections and infestations .......................................................................................................... 32
5.3.2.1.
Opportunistic Infections ........................................................................................................... 33
5.3.3.
Cytopenia.................................................................................................................................... 33
5.3.4.
Hemorrhage................................................................................................................................ 33
5.3.5.
Second Primary Malignancies .................................................................................................... 33
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5.4.
Clinical Laboratory Tests................................................................................................................ 33
5.5.
Vital Signs and Physical Examination Findings ............................................................................. 34
5.6.
Electrocardiogram (ECG)............................................................................................................... 34
5.7.
ECOG Performance Score ............................................................................................................ 34
6.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS .......................................... 35
6.1.
Pharmacokinetics........................................................................................................................... 35
6.1.1.
Sampling Timepoints .................................................................................................................. 35
6.1.2.
Pharmacokinetic Parameters ..................................................................................................... 35
6.1.3.
Analysis Methods........................................................................................................................ 35
6.2.
Immunogenicity.............................................................................................................................. 36
6.2.1.
Sampling Timepoints .................................................................................................................. 36
6.2.2.
Analysis Methods........................................................................................................................ 36
6.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 36
7.
BIOMARKER..................................................................................................................................... 36
7.1.
Minimal Residual Disease (MRD) .................................................................................................. 36
7.1.1.
Sampling Timepoints .................................................................................................................. 37
7.1.2.
Analysis Methods........................................................................................................................ 37
7.2.
Molecular Subtyping....................................................................................................................... 37
7.2.1.
Sample collection and characterization...................................................................................... 37
7.2.2.
Molecular Subtypes .................................................................................................................... 37
7.2.3.
High-risk/Standard-risk Molecular Subgroup Analysis ............................................................... 37
8.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 38
REFERENCES............................................................................................................................................ 39
ATTACHMENTS......................................................................................................................................... 40
ATTACHMENT 1:
Additional Exploratory Analysis to Support HEMAR .................................................. 40
ATTACHMENT 2:
Multiple Myeloma IMWG Algorithm............................................................................ 44
LIST OF IN-TEXT TABLES
Table 1:
Subgroup Analyses of Efficacy and Safety Endpoints.............................................................. 14
Table 2:
PFS Event and Censoring Method ........................................................................................... 19
Table 3:
PFS Event and Censoring Method ........................................................................................... 21
Table 4:
TTP Event and Censoring Method ........................................................................................... 24
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AMENDMENT HISTORY
Unique Identifier
for SAP Version
Date of 
SAP Version
Author
Changes from the Previous Version
1.0
24 February 2016
The initial version for the first interim analysis
2.0
3 October 2018
1. Updated per the latest protocol
2. Added the efficacy part
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ASCT
Autologous Stem Cell Transplant
AST
aspartate aminotransferase
BSA
body surface area
CI
confidence interval
CR
complete response
CrCL
creatinine clearance
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DOR
duration of response
DPS
data presentation specification
DRd
Daratumumab, lenalidomide, dexamethasone
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FISH
fluorescence in situ hybridization
FLC
free light chain
IA
interim analysis
ICF
informed consent form
IDMC
Independent Data Monitoring Committee
IMWG
International Myeloma Working Group
IRR
infusion-related reaction
ISS
International Staging System
ITT
intent-to-treat
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
M-protein
monoclonal protein, monoclonal paraprotein
MRD
minimal residual disease
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
ORR
overall response rate
OS
overall survival
PD
progressive disease
PBMC
peripheral blood mononuclear cell
PFS
progression-free survival
PP
per-protocol
PR
partial response
Rd
lenalidomide, dexamethasone
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
sCR
stringent complete response
SD
stable disease
SD
standard deviation 
SOC
system organ class
SPEP
serum protein electrophoresis
TEAEs
treatment-emergent adverse events
TTR
time to response
TTP
time to disease progression
UPEP
urine protein electrophoresis
VGPR
very good partial response
WBC
white blood cells
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables, and 
statistical methods for the planned analyses as specified in the protocol JNJ-
54767414MMY3008, Amendment INT-4.
1.1.
Overview of Trial Design
This is a randomized, open-label, active controlled, parallel-group, multicenter study in subjects 
at least 18 years of age with previously untreated multiple myeloma who are not candidates for 
high dose chemotherapy and ASCT. The primary objective is to evaluate if daratumumab in 
combination with Rd prolongs progression-free survival (PFS) compared with Rd alone. The
secondary objectives are to compare the 2 treatment groups with respect to time to disease 
progression (TTP), complete response (CR) or better rate, MRD negativity rate, progression-free 
survival on next line of therapy (PFS2), overall survival (OS), time to next treatment, overall 
response rate (ORR), very good partial response (VGPR) or better rate, sCR rate, time to 
response, duration of response  as well as to assess the safety and tolerability of daratumumab 
when administered in combination with Rd.
Approximately 730 subjects will be randomized in this study with 365 subjects planned per 
treatment arm (DRd or Rd). Randomization will be stratified by International Staging System 
(I vs II vs III), region (North America vs Other), and age (<75 vs ≥75). Within each stratum, 
subjects will be randomized using an equal allocation ratio of 1:1.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 21 days before Cycle 1 Day 1. 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 25 mg or 10 mg orally (PO) on Days 1 through 21 of 
each 28-day cycle, and dexamethasone will be administered at a dose of 40 mg or 20 mg once a 
week for both treatment arms (per age, for more detail refer to protocol Section 6. Dosage and 
Administration). Those in the Rd arm will receive lenalidomide will be administered at a dose of 
25 mg or 10 mg orally (PO) on Days 1 through 21 of each 28-day cycle, and dexamethasone will 
be administered at a dose of 40 mg or 20 mg once a week until disease progression or 
unacceptable toxicity. Subjects in both treatment 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.
The Follow-up Phase will begin once a subject discontinues all study treatments. Subjects who 
discontinue for reasons other than disease progression must continue to have disease evaluations 
according to the Time and Events Schedule which will continue until confirmed progression 
disease (PD), death, lost to follow up, consent withdrawal, subsequent anticancer therapy, or 
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study end, whichever occurs first. After the clinical cut-off (see below for definition), data 
collection will be reduced as per protocol Section 9.1.4.
Two interim analyses are planned (for detail refer to Section 1.4).
The primary PFS analysis will occur when approximately 390 PFS events have been observed. 
The date established for the primary PFS analysis will serve as the clinical cut-off date, after 
which data collection in the study will be reduced. Investigators will be informed when each 
interim analysis is to occur. All available data prior to that time will be included in each of the 
respective analyses.
The end of the study will occur when 330 subjects have died, or 7 years after the last subject is 
randomized, whichever comes first. The sponsor will ensure that subjects benefiting from 
treatment with daratumumab will be able to continue treatment after the end of the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to 
review efficacy and safety results at the planned interim analyses (more detail information
including the timing refer to section 1.4). 
After the interim reviews, they will make 
recommendations regarding the continuation of the study. In addition, the IDMC may also 
review cumulative safety data every 6 months besides the 2 interim analyses.
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will 
be conducted on bone marrow samples. Safety evaluations will include adverse event 
monitoring, physical examinations, electrocardiogram (ECG) monitoring, clinical laboratory 
parameters (hematology and chemistry), vital sign measurements, and Eastern Cooperative 
Oncology Group (ECOG) performance status. Blood samples will be drawn for assessment of 
pharmacokinetic parameters.
1.2.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint of this study is PFS. The null hypothesis is that there is no
difference in PFS between daratumumab in combination with Rd and Rd alone in subjects with
newly diagnosed multiple myeloma who are ineligible for high dose chemotherapy and 
autologous stem cell transplant.
The secondary endpoints such as ORR, VGPR or better rate, CR or better rate, MRD negativity 
rate, OS, TTP, PFS2, sCR rate, time to next treatment, time to response and duration of response 
will be evaluated as well.
1.3.
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 the addition of daratumumab can reduce the risk of the disease progression or death 
by 25%, i.e., 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 
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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 will continue until 330 deaths have been observed or 7 years after 
the last subject is randomized, whichever is first. Therefore, this study will achieve 
approximately 80% power to detect a 27% reduction in the risk of death (hazard ratio = 0.73) 
with a log-rank test (two-sided alpha = 0.05) if 330 death events are observed at the study end.
1.4.
Interim Analyses
Two interim analyses are planned. The first interim analysis, with a purpose to evaluate safety, 
has been 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 
approximately 234 PFS events, which is 60% of the total planned events (390 PFS events), have 
been accumulated to evaluate the cumulative interim safety and efficacy of daratumumab in 
combination with Rd. 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.
More details about the conduct of these interim analyses can be found in a stand-alone IDMC 
charter. 
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
For analyses of data by cycle, if data are collected by date (e.g., AE onset), the corresponding
study evaluations will be assigned to actual sequential cycles, which are derived from the study
treatment administration data. The start date of a particular cycle is defined as the date of the first
scheduled dose of any component of the study treatment, and the end date of a cycle is the start
date of the next cycle minus 1. For the last cycle, the end date is defined as the end of treatment
visit date or the minimum of last study treatment date plus 30 days and subsequent
antimyeloma therapy minus 1 day, if the end of treatment visit date is not available.
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal cycle
will be used to summarize data. However, due to possible cycle delays, assessment performed
in the same cycle may not be well aligned in time scale for different subjects.
2.2.
Pooling Algorithm for Analysis Centers
All participating centers in the study will be pooled together for analyses.
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2.3.
Study Treatment and Study Drug
In this study, study treatment refers to lenalidomide, dexamethasone, and/or daratumumab.
Study drug refers to daratumumab.
2.4.
Study Treatment Dosing Date
Study treatment dosing date is the date on which a subject actually receives study treatment
(partial or complete) and will be recorded in the study treatment administration dataset.
For subjects who receive DRd treatment, the first study treatment date is defined as the earliest
date of non-zero dose of the following administration: lenalidomide, dexamethasone or
daratumumab. The last study treatment date is defined as the latest date of non-zero dose of the
following administration: lenalidomide, dexamethasone or daratumumab.
For subjects who receive Rd treatment, the first study treatment date is defined as the earliest
date of non-zero dose of the following administration: lenalidomide or dexamethasone. The
last study treatment date is defined as the latest date of non-zero dose of the following
administration: lenalidomide or dexamethasone.
2.5.
Baseline Measurement
Baseline measurement is defined as the closest non-missing measurement taken on or prior to the 
first study treatment administration (including time if time is available, with exception of 
parameters associated with disease-related efficacy assessment such as SPEP, UPEP, kappa, 
lambda, kappa/lambda ratio, serum calcium, and albumin).
2.6.
Unique Lab Value
In general, in instances when there are multiple records at a given visit date for lab parameters 
associated with disease assessment, the following rules will be applied to select the unique lab 
value for analysis: a) multiple records from both central and local lab, central lab value always 
takes precedence over local lab value; b) multiple records from central lab, select the latest value
by time, visit number, or sequence number as the unique lab value; c) multiple records from local 
lab, select the latest lab value by time, visit number, or sequence number as the unique local lab 
value.
2.7.
Imputation of Partial Dates
Unless specified otherwise, no data imputation will be applied for missing safety and efficacy 
evaluations. For analysis and reporting purpose, partial dates in adverse event (AE onset date; 
AE end date), concomitant therapies (start date; end date), MM diagnosis date, and start date of 
subsequent antimyeloma therapy will be imputed.
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2.7.1.
Missing/Partial Adverse Event Onset Date
If the onset date of an adverse event is missing completely or partially, the following imputation 
rules will be used.

When month and year are present and the day is missing,

If the onset month and year are the same as the month and year of first study treatment, 
the day of first study treatment or the day-component of the AE end date (possibly 
imputed) is imputed, whichever is earlier

If the onset month and year are not the same as the month and year of first study 
treatment, then the first day of the month is imputed

When only a year is present,

If the onset year is the same as the year of first study treatment. If AE end date is 
available and is prior to first study treatment, the day and month of AE end date are 
imputed. Otherwise, the day and month of first study treatment are imputed

If the onset year is different from the year of first study treatment, the 1st of January is 
imputed

If the onset date is completely missing, the earlier one of the date of first study treatment and 
the AE end date is imputed as the onset date.
No imputation will be done for partial or missing AE onset time.
2.7.2.
Missing/Partial Adverse Event End Date
If the end date of an adverse event is missing completely or partially, the following imputation 
rules will be used.

If month and year are present and the day of the month is missing, the last day of the month 
is imputed.

If only a year is present, the 31st of December is used.

If the imputed date is later than the date of death (if available), the date of death will be used 
as the imputed date instead.

If the year of end date is missing, no imputation will be applied.
No imputation will be done for partial or missing AE end time.
2.7.3.
Partial Concomitant Medication Start/End Date
In case of partially missing concomitant medication start/end dates, the following imputation 
rules will be applied. If the date is completely missing, no imputation will be performed.

If only the day is missing, the 15th day of the month will be used

If both the day and month are missing, the 30th of June will be used. 
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
If the medication was taken prior to study start, and the imputed start date is after first 
treatment date, further adjust of the imputed start date as the day prior to first dosing date; If 
the medication was taken after study start, and the imputed start date is prior to first dosing 
date, further adjust the imputed start date as first dosing date. Also adjust the imputed 
medication end date so that it is on or after first dosing date.
2.7.4.
Partial Multiple Myeloma Diagnosis Date
For partial date of original multiple myeloma diagnosis, the following imputation rules will apply:

If only the day is missing, set to 15th (as imputed date), and pick minimum of imputed date, 
date of collection and date of randomization

If both the day and month are missing, set to January 1, and pick minimum of imputed date, 
date of collection and date of randomization 

If year is missing, no imputation will be applied.
If the imputed date of original diagnosis is after the randomization date, further adjust the 
imputed start date as the day before the randomization date.
2.7.5.
Partial Subsequent Anticancer Therapy Start Date
If year or month of subsequent anticancer therapy start date is missing or no components of the 
start date are present, no imputation will be performed.
If only the day is missing, the following steps apply:

If the month and year of the start date are the same as the month and year of last dosing
date, the day of last dosing date or the day-component of the stop date of subsequent
anticancer therapy is imputed, whichever is earlier.

If the start month and year are not the same as the month and year of last dosing date, the 
first day of the month is imputed.
No imputation will be applied for missing or partial subsequent anticancer therapy end date.
2.8.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation (SD), median and range. Categorical variables will be summarized using 
frequency and percentage. For time-to-event variables, which is defined as from randomization 
to the date of the event, the Kaplan-Meier method will be used for descriptive summaries. For 
the calculation of time-to-event and duration-of-event variables, the difference between the start 
date and the end date plus 1 day will be used.
2.9.
Analysis Sets
The following analysis sets are defined.
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
Intent-to-treat (ITT): defined as subjects who have been randomly assigned to the DRd or
Rd group. Analyses of demographics, baseline characteristics and efficacy endpoints will 
be primarily analyzed based on this population.

Safety population: defined as subjects who have received at least 1 administration of any
study treatment (partial or complete). This population will be used for all safety analyses.
The safety analyses grouping will be according to treatment actually received.

Response-evaluable: defined as subjects who have a confirmed diagnosis of multiple
myeloma and measurable disease at baseline or screening visit. In addition, subjects must
have received at least one administration of study treatment and have adequate post-
baseline disease assessments. Measurable disease is defined as follows:

IgG myeloma: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine 
M-protein level ≥200 mg/24 hours; or 

IgA, IgD, IgE or IgM multiple myeloma: serum M-protein level ≥0.5 g/dL or urine 
M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in serum or urine: Serum 
immunoglobulin free light chain (FLC) level ≥10 mg/dL and abnormal serum 
immunoglobulin kappa lambda free light chain ratio.
This population will be used as sensitivity analyses for selective response-related secondary 
endpoints such as CR or better rate.

Per-protocol (PP) population: defined as subjects who are randomized and meet all 
eligibility criteria.

Pharmacokinetics-evaluable: is defined as subjects assigned to DRd group who received at 
least 1 administration of daratumumab and have at least 1 pharmacokinetic sample 
concentration value after the first infusion. All pharmacokinetics analyses are based on the 
pharmacokinetic evaluable population.

Immune response-evaluable: is defined as subjects assigned to DRd group who have at least 
1 immunogenicity sample obtained after their first daratumumab administration.

Molecular genetic evaluable: defined as subjects who meet one of the following biomarker 
criteria for risk assessment based on the next generation sequencing (NGS) data: 

Standard risk: subjects that are negative (=molecular aberration absent) for all del17p, 
t(14;16), t(4;14).

High risk: subjects that are positive (=molecular aberration present) for any of del17p, 
t(14;16), t(4;14).

Cytogenetic evaluable: defined as subjects who meet one of the following cytogenetic risk 
categories: 

Standard risk: subjects that are negative for del17p, t(14;16), t(4;14) by 
FISH/Karyotype.

High risk: subjects that are positive for any of del17p, t(14;16), t(4;14) by 
FISH/Karyotype.
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2.10.
Definition of Subgroups
The following pre-specified subgroup analyses are to be performed at the 2nd IA for the efficacy 
and safety endpoints (Table 1). Additional subgroup analyses may be performed, if requested 
and deemed necessary by IDMC for making their decision.
Table 1:
Subgroup Analyses of Efficacy and Safety Endpoints
Subgroup 
Definition 
Analysis Type 
Sex 
Male, Female 
E, S 
Age 
<75 years, ≥75 years 
E, S 
Race 
White, Others 
E, S 
Baseline renal function (CrCl)
E: >60 mL/min, ≤60 mL/min
S: <30, 30 to <60, 60 to <90, ≥90 mL/min
E, S
Baseline hepatic function 
Normal, Impaired a
E, S 
Region 
North America, Others
E, S 
International Staging System (ISS) 
I, II, III 
E 
Type of MM 
IgG, Non-IgG 
E 
Cytogenetic risk 
High risk b, Standard risk 
E 
ECOG performance score 
0, 1, ≥2
E
E: efficacy (PFS, ORR, CR or better rate); S: TEAE 
a Includes mild (total bilirubin ≤ ULN and AST > ULN or ULN < total bilirubin ≤ 1.5×ULN), moderate (1.5×ULN < 
total bilirubin ≤ 3×ULN), severe (total bilirubin > 3×ULN).
b. High risk is defined as positive for any of del17p, t(14;16) or t(4;14) by FISH/Karyotype.
2.11.
Other General Definitions
2.11.1.
Treatment Emergent Adverse Events
Treatment emergent adverse events (TEAEs) are defined as any AE with onset date and time on 
or after that of the first dose of study drug infusion through 30 days after the last dose of study 
drug or the day prior to start of subsequent therapy, whichever is earlier; or any AE that is 
considered related to (probably, possibly, or very likely) study drug regardless of the start date of 
the event. AEs with missing or partial onset date and time will be considered as treatment-
emergent unless the onset date and time of an AE can be determined as earlier than that of the 
first dose, or later than 30 days after last dose.
2.11.2.
Linking of Treatment Emergent Adverse Events
All event records of the same preferred term from the same subject are to be linked by the onset 
date and the end date. If an event is followed by another event of the same preferred term with an 
onset date (or date/time) the same as or 1 day (or 1 minute if applicable) after the end date 
(or date/time) of the previous record and any features of the adverse event (i.e.: toxicity 
grades/seriousness/action taken) are different between these two records, these 2 records should 
be linked together and considered as 1 event, the maximal toxicity grade of the 2 records would 
be used for the analysis.
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3.
SUBJECT INFORMATION
3.1.
Demographics and Baseline Characteristics
Unless specified otherwise, all demographic and baseline characteristics variables will be
summarized for the ITT population. No statistical comparison between the 2 treatment groups is
planned.
The distribution of subject enrollment will be presented for each treatment group according to 
region and country. 
Subject demographic and baseline characteristic variables: age (<65 years, 65 to <70 years, 70 to
<75 years, and ≥75 years), sex, ethnicity, race, weight (kg), height (cm), body surface area
(BSA, m2) and ECOG performance status will be summarized by treatment group and
overall. A listing of subject demographic and baseline characteristics will be provided as 
well.
Baseline disease characteristics including type of multiple myeloma (IgG, IgA, IgM, IgD,
IgE, light chain only, biclonal, or negative immunofixation), type of measurable disease
(Serum only (IgG, IgA, Other - IgD, IgM, IgE and biclonal), Serum and urine, Urine only, 
Serum FLC only, or not evaluable), ISS staging at baseline (I, II, III), time since initial MM
diagnosis
(months), number of lytic bone lesions (None, 1-3, 4-10, more than 10),
presence
of
diffuse
myeloma-related osteopenia (Yes, No), number of extramedullary 
plasmacytomas (0, ≥1), presence of extramedullary plasmacytomas (Yes, No), bone marrow 
biopsy/aspirate 
% 
plasma 
cells 
(<10, 10 – 30, >30), bone marrow biopsy % plasma cells (<10, 10 – 30, >30), bone marrow 
aspirate % plasma cells (<10, 10 – 30, >30), standard-risk and high-risk cytogenetic 
abnormalities 
(del17p, t(4;14), t(14;16)), will be summarized and tabulated by treatment group and overall.
A descriptive summary of selected hematology and biochemistry laboratory analytes at baseline
will be provided for each treatment group and overall. In addition, baseline toxicity grade of
each selected laboratory analyte in hematology and chemistry panel will be summarized by
treatment group using frequency based on the safety population.
Medical history collected at baseline or screening visit will be summarized by system-organ
class and preferred term for each treatment group and overall.
A summary of stratification factors (ISS staging, region, and age) used in the randomization 
based on IWRS will be provided to evaluate whether or not randomization process was 
appropriately executed in the study. The stratified log-rank test and stratified cox model use 
these stratification factors in randomization.
3.2.
Disposition Information
An overview of subject disposition in the study will be provided. The overview includes a 
summary of total number of subjects who are randomized to each treatment group, the number 
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and percentage of subjects who are randomized but not treated in each treatment group, and total 
number of subjects who are treated in each treatment group. For all treated subjects (defined as 
subjects who have received at least 1 administration of any study treatment), the number and 
percentage of subjects who discontinued treatment including reason for discontinuation as 
indicated by the investigators will be summarized. The similar summaries will be presented for 
all randomized subjects who discontinued from study.
A list of subjects who discontinued study treatment will be provided for safety subjects. This 
listing will include subject ID, treatment group, date of treatment discontinuation, study day of 
last dose, reason for discontinuation as well as the specific adverse events (MedDRA preferred 
term/verbatim term) if discontinuation due to AEs and primary cause of death if discontinuation 
due to death. A similar list of subjects who discontinued study will be provided for ITT subjects.
3.3.
Extent of Exposure
Extent of exposure to study treatments will be summarized and presented based on the safety
population.
The number and percentage of subjects treated within each cycle will be summarized by
treatment group. The maximum number of treatment cycles received for each subject will be
summarized by frequency and descriptive statistics.
Duration of study treatment, defined as the number of months from the date of the first
administration of study treatment to the date of the last administration of study treatment, will be
summarized.
The number of daratumumab administrations will be summarized for subjects treated with
DRd. The total dose administered for daratumumab
(mg/kg), lenalidomide (mg), and
dexamethasone (mg) will be summarized overall, by cycle of daratumumab treatment.
The dose intensity, which is defined as the sum of total dose administered in all cycles
divided by the number of treatment cycles, will be calculated for each study treatment and
summarized accordingly. Additionally, the daratumumab dose intensity will be summarized
by cycles of daratumumab treatment.
The relative dose intensity (%) defined as the ratio of total actually received dose and total
planned dose (planned dose level times the number of administered infusions/medications) will
be calculated for each study treatment and summarized by treatment group using descriptive
statistics.
The number of subjects with treatment dose delay within the cycle, dose reduced, dose re-
escalated per protocol, or dose skipped for lenalidomide and dexamethasone will be summarized 
for each treatment group. The reasons (AE or other) for treatment dose delay within the cycle, 
dose reduced, dose re-escalated per protocol, or dose skipped for lenalidomide and 
dexamethasone will be reported. In addition, a summary of study treatment dose modifications 
by cycle will be provided.
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3.4.
Protocol Deviations
Major protocol deviations will be summarized for the ITT population by the following types (not 
limited) of deviation for each treatment group:

Developed withdrawal criteria but not withdrawn

Entered but did not satisfy criteria

Received a disallowed concomitant treatment

Received wrong treatment or incorrect dose

Efficacy assessment deviation

Safety assessment deviation
A listing of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided.
3.5.
Prior, Concomitant and Subsequent Therapies
With the study population of newly diagnosed multiple myeloma subjects who are not candidates 
for high dose chemotherapy and ASCT, prior systemic use of corticosteroids is limited to a short 
course (equivalent of dexamethasone 40mg/day for 4 days) for purposes other than multiple 
myeloma. If any, a listing of all prior systemic use of corticosteroids will be provided. 
Concomitant medications collected in the CRF page during the study will be summarized by 
therapeutic class, pharmacologic class, and drug name for each treatment group. A similar 
summary will be provided for subjects who received growth factor support, pre-infusion 
medication and post-infusion medication, respectively. In addition, systemic steroids as 
concomitant medication use during the study will be summarized. Additionally, prophylactic 
antiviral medication use will be tabulated.
The total number of subjects who received subsequent antimyeloma therapy will be reported for 
subjects in safety population in each treatment group. A summary of subsequent antimyeloma 
therapy will be presented by therapeutic class, pharmacologic class and drug name. In addition, 
for subjects who received subsequent antimyeloma therapy, their best response to the first 
subsequent antimyeloma therapy will be summarized.
4.
EFFICACY
A validated computerized algorithm, which is based on the IMWG response criteria (Durie 2006, 
Rajkumar 2011)1, 2 and has been used and validated by an independent review committee (IRC) 
in Study MMY2002, will be used to determine response and disease progression for each 
subject. As a sensitivity analysis, investigator assessment of response and disease progression 
using the IMWG response criteria will also be performed.
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4.1.
Analysis Specifications
4.1.1.
Level of Significance
All statistical hypothesis tests and 95% confidence interval presented will be 2-sided.
The primary hypothesis is to be tested at the 0.05 significance level (overall). The exact
significance level at the second interim analysis is to be determined by the observed number of
events per the O’Brien-Fleming alpha spending function. Assuming 234 PFS events are
observed at the second interim analysis, the alpha to be spent will be 0.0076 (2-sided) for the 
interim analysis and 0.0476 (2-sided) for the primary PFS analysis (390 PFS events occur). If
the observed two-sided p-value is smaller than this significance level as specified above, the
superiority of DRd versus Rd with respect to PFS will be established.
If the primary endpoint of PFS is statistically significant, the following secondary endpoints
ordered below will be sequentially tested, each with an overall two-sided alpha of 0.05, by
utilizing a hierarchical testing approach as proposed by Tang and Geller (1999) that strongly
controls Type I error rate:
1)
CR or better rate
2)
VGPR or better rate 
3)
MRD negativity rate (10-5)
4)
Overall response rate (ORR)
5)
Overall survival (OS)
These secondary endpoints will be tested at the 2nd IA and the primary PFS analysis. The 
primary PFS analysis will be skipped if PFS is positive at the 2nd IA. If this is the case, the 
protocol will be amended to add an analysis for secondary endpoints at a similar timing as the 
planned primary PFS analysis (note that OS will also be tested at its protocol-specified final 
analysis). The significance level at the second interim and the primary PFS analyses will be 
determined by the alpha-spending function specific to endpoints: 

For ORR, VGPR or better rate, CR or better rate, and MRD negativity rate (10-5), the 
information fraction is expected to be 80% at the 2nd IA. The O’Brien-Fleming alpha-
spending function as implemented by the Lan-DeMets method will be used for alpha 
spending: 0.0244 (two-sided) at the 2nd IA and 0.0428 (two-sided) at the primary PFS 
analysis.

For OS, a modified linear alpha spending function will be used to determine the alpha level 
at three looks (2nd IA, primary PFS analysis, and final OS analysis). The alpha level will be 
0.0001 for the first OS look, and linear spending function will be used to determine the 
alpha level for the second and last looks. For example, if 59% targeted OS events are 
observed at the second look, the corresponding alpha level will be 0.0295.
If the null hypothesis for any of these endpoint fails to be rejected at the second interim analysis, 
then any subsequent endpoint(s) listed above will not be tested until the next analysis time point 
(e.g., primary PFS analysis), if applicable. If the null hypothesis for an endpoint is rejected at the 
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second interim analysis, it will remain being rejected and will not be re-tested at any subsequent 
time points, if any.
4.1.2.
Data Handling Rules
There is no imputation planned for missing efficacy endpoint values.
4.2.
Primary Efficacy Endpoint
The primary efficacy endpoint is progression-free survival (PFS) based on the computerized 
algorithm.
4.2.1.
Definition
PFS is defined as the duration from the date of randomization to either progressive disease, 
according to the IMWG response criteria, or death, whichever occurs first. Subjects who start 
subsequent antimyeloma therapies for multiple myeloma without disease progression will be 
censored at the last disease assessment before the start of subsequent therapies. Subjects who 
withdrew consent from the study before disease progression will be censored at the last disease 
assessment before withdrawal of consent to study. Subjects who are lost to follow-up will be 
censored at the last disease assessment before subjects are lost to follow-up. Subjects who have 
not progressed and are still alive at the cutoff date for analysis will be censored at the last disease 
assessment. Subjects without any post-baseline disease assessment will be censored at the 
randomization.
Determination of dates of PFS event and dates for censoring is summarized in Table 2 as 
follows.
Table 2:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Disease progression prior to start of
subsequent antimyeloma therapy
Earliest date that indicates disease progression
PFS event
Death without subsequent antimyeloma
therapy
Date of death
PFS event
No post-baseline disease assessment
Randomization
Censored
Other (e.g., withdrawal of consent to study
participation, lost to follow-up, start of subsequent
antimyeloma therapy etc.)
Date of last disease assessment prior to
withdrawal of consent to study participation, lost to 
follow-up, or subsequent antimyeloma treatment
Censored
4.2.2.
Analysis Methods
Analysis of PFS will be based on the ITT population. The Kaplan-Meier method will be used to
estimate the distribution of overall PFS for each treatment group. The median PFS with 95% CI
will be provided. In addition, the number and percentage of subjects who had a PFS event or
were censored will be reported. The Kaplan-Meier PFS curve will also be plotted by treatment
group.
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The primary treatment comparison of the distribution of overall PFS will be based on a stratified 
log-rank test. The p-value from a stratified log-rank test will be reported. Hazard ratio and its 
95% confidence interval will be estimated based on a stratified Cox’s regression model with 
treatment as the sole explanatory variable. Stratification factors used in the analyses include ISS
staging (I, II, III), region (North America vs other), and age (<75 years vs ≥75 years).
In addition, 12, 24 and 36-months of PFS rate with 95% CI will be estimated by Kaplan-
Meier method and reported for each treatment group.
Additionally, reasons for PFS event and censoring will be summarized for ITT population.
4.2.3.
Sensitivity Analysis of PFS
The following sensitivity analysis is planned to evaluate the robustness of the primary endpoint 
analysis of PFS.
4.2.3.1.
Progressive Disease Based on Investigator Assessment
A sensitivity analysis of PFS, in which progressive disease is based on investigator assessment
according to the IMWG response criteria, will be performed in a similar manner as described
in the Section 4.2.2.
The PFS definition used in the sensitivity analysis is similar to that defined in the
Section 4.1.2, except for date of progressive disease and date of censoring. The date of
progressive disease is
the date of initial disease progression recorded in the Disease
Progression CRF page or earliest date of confirmed progressive disease recorded in the
Evaluation of Response CRF page, based on investigator assessment. Similarly, the censoring
date is the latest date of disease response recorded in the Evaluation of Response CRF page,
based on investigator assessment.
In addition, reasons for PFS and censoring based on investigator assessment will be summarized
for ITT population.
4.2.3.2.
Not Censored for Start of Subsequent Anticancer Therapies
A sensitivity analysis of PFS derived from the algorithm by not censoring data due to start
of subsequent anticancer therapies for subjects, who have not developed a confirmed
progressive disease, will be performed in a similar manner as described in Section 4.2.2.
The PFS definition used in the sensitivity analysis is similar to that defined in Section 4.2.1,
except for censoring data due to start of subsequent anticancer therapies. Subjects who start
subsequent anticancer therapies for multiple myeloma without disease progression will NOT
be censored at the last disease assessment before the start of subsequent therapies. If there
is no confirmed progressive disease, the subjects will be
censored at the last disease 
assessment before subjects are lost to follow-up or withdrawal of consent to study.
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Determination of dates of PFS event and dates for censoring is summarized in Table 3 as
follows.
Table 3:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
Disease progression
Earliest date that indicates disease progression
PFS event
Death
Date of death
PFS event
No post-baseline disease assessment
Randomization
Censored
Other (e.g., withdrawal of consent to study
participation, lost to follow-up, start of
subsequent anticancer therapy etc.)
Date of last disease assessment
Censored
4.2.3.3.
Censored for Death/PD after Missing More Than One Disease
Evaluation
A sensitivity analysis of PFS derived from the algorithm by censoring for death or
progression after missing consecutive evaluations will be performed in a similar manner as
described in Section 4.2.2.
The PFS definition used in the sensitivity analysis is similar to that defined in Section 4.2.1,
except for death or progression after missing more than one disease evaluation. For any PFS
(death or progression) event identified by the computer algorithm, if the event date and the
latest date of scheduled disease evaluation (includes serum M-protein, urine M-protein, serum
FLC and corrected calcium only) immediately preceding the event differs more than 2.5
disease evaluation intervals, which indicates that subject missed at least one scheduled disease
evaluation, then this event will not be considered as a PFS event in the sensitivity analysis.
Instead, the subject will be censored at the date of last disease evaluation (includes serum
M-protein, urine M-protein, serum FLC and corrected calcium only) prior to the PFS event
originally identified.
4.2.3.4.
Per-protocol Analysis of PFS
A sensitivity analysis of PFS derived from the algorithm based on Per-protocol population will 
be performed in a similar manner as described in Section 4.2.2.
4.2.3.5.
Unstratified Analysis of PFS
A sensitivity analysis of PFS by using unstratified log-rank test and unstratified Cox’s regression 
model will be performed in a similar manner as described in Section 4.2.2.
4.3.
Secondary Endpoints
Secondary efficacy endpoints include overall response rate (ORR), VGPR or better rate, CR or 
better rate, MRD negativity rate, OS, TTP, PFS2, sCR rate, time to subsequent antimyeloma 
treatment, time to response and duration of response.
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4.3.1.
CR or Better Rate
4.3.1.1.
Definition
CR or better rate is defined as the proportion of subjects with a response of CR or better 
(i.e., CR or sCR) based on the computerized algorithm, according to IMWG response criteria, 
during or after the study treatment.
4.3.1.2.
Analysis Methods
CR or better rate will be calculated for each treatment group based on the ITT and
response-evaluable population. The number and percentage of subjects in the following response 
categories will be presented by treatment group: stringent complete response (sCR), complete 
response (CR), sCR+CR, very good partial response (VGPR), VGPR or better 
(sCR+CR+VGPR), partial response (PR), overall response (sCR+CR+VGPR+PR), stable 
disease (SD), progressive disease (PD), and not evaluable (NE). The corresponding 95% exact
CI will be provided.
Stratified CMH test will be used to test treatment difference in ORR, VGPR or better rate, CR or 
better rate and sCR rate. The CMH estimate of odds ratio and its 95% confidence interval and 
p-value for testing treatment difference will be reported. Stratification factors used in the analysis 
include 
ISS
staging 
(I, 
II, 
III), 
region 
(North 
America 
vs. 
Other), 
and 
age 
(<75 years vs. ≥75 years).
A sensitivity analysis, which disease response is based on investigator assessment according
to the IMWG response criteria, will be performed in a similar manner as described above.
4.3.2.
VGPR or Better Rate
4.3.2.1.
Definition
VGPR or better rate is defined as the proportion of subjects with a response of VGPR or better 
(i.e., VGPR, CR or sCR) based on the computerized algorithm, according to IMWG response 
criteria, during or after the study treatment.
4.3.2.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.3.1.2for CR or better rate
analysis.
4.3.3.
MRD Negativity Rate
For this study, three threshold values, 10-4, 10-5 and 10-6, will be used to evaluate MRD
negativity status and its predictive value for PFS.
4.3.3.1.
Definition
MRD negativity rate is defined as the proportion of subjects who have negative MRD at any
time point after the date of randomization and prior to subsequent antimyeloma therapy. MRD 
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positive subjects include subjects of which all tested results were found to be MRD positive, or 
indeterminate, or unavailable (calibration failure or missing). 
4.3.3.2.
Analysis Methods
The MRD negativity rate will be calculated for each treatment group based on the ITT
population. The corresponding 95% exact CI will be provided.
For each threshold value, Fisher’s exact test will be used to test if the MRD negativity rate is the
same between the two treatment groups in the previously untreated myeloma setting.
For the purpose of hierarchical testing (Section 4.1.1), the threshold value of 10-5 will be 
employed using ITT populations.
The durability of MRD negativity may be examined for each treatment group by the proportion 
of subjects remaining MRD negative 12 months after initial MRD negativity if data becomes 
available.
4.3.4.
Overall Response Rate (ORR)
4.3.4.1.
Definition
ORR is defined as the proportion of subjects who achieve a partial response or better (i.e., PR, 
VGPR, CR or sCR) based on the computerized algorithm, according to IMWG response criteria, 
during or after the study treatment.
4.3.4.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.3.1.2 for CR or better rate
analysis.
4.3.5.
Overall Survival
4.3.5.1.
Definition
Overall survival (OS) is measured from the date of randomization to the date of death due to any 
cause. Subjects who are lost to follow-up will be censored at the time of lost to follow-up. 
Subjects who are still alive at the clinical cut-off date for the analysis will be censored at the last 
known alive date. The date of last known alive will be determined by the maximum 
collection/assessment date from among selected data domains within the clinical database.
4.3.5.2.
Analysis Methods
OS, including 12, 24 and 36-months survival rate, will be analyzed for the ITT population.
The Kaplan-Meier method will be used to estimate the distribution of OS for each treatment
group. Median OS with 95% CI will be provided. In addition, the number and percentage of
subjects who had died or were censored will be reported. Additionally, the survival rate with
95% CI at 12, 24 and 36-months will be estimated using Kaplan-Meier method for each
treatment group.
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Due to the expected small number of death events at the second interim analysis, the
distribution of OS for the 2 treatment groups will be compared based on an un-stratified log-
rank test. A p-value from an un-stratified log-rank test will be reported. Hazard ratio and its
95% confidence interval will be estimated based on an un-stratified Cox’s regression model
with treatment as the sole explanatory variable.
In addition, a summary of reasons for censoring of overall survival will be provided.
If the null hypothesis of OS is not rejected at the second interim analysis, for OS at the primary 
PFS analysis when 360 PFS events observed, the alpha to be spent will be determined by a linear 
alpha spending function based on the observed number of deaths at that time, i.e., the cumulative 
alpha to be spent will be the total alpha (0.05) multiplied by the proportion of the observed 
number of deaths out of the total planned number of deaths (330, expected at time of the final 
OS). See Section 4.1.1 for more details on alpha spending and type I error control.
4.3.6.
Time to Disease Progression (TTP)
4.3.6.1.
Definition
TTP is defined as the time between the date of randomization and the date of first documented 
evidence of confirmed PD, as defined in the IMWG response criteria, or death due to PD, 
whichever occurs first. Subjects who start subsequent antimyeloma therapies for multiple 
myeloma without disease progression will be censored at the last disease assessment before the 
start of subsequent therapies. Subjects who withdraw consent to study or are lost to follow-up or 
die without disease progression will be censored at the last disease assessment. Subjects who 
have not progressed at the cutoff date for analysis will be censored at the last disease assessment. 
Subjects without any post-baseline disease assessment will be censored at the randomization.
Determination of dates of TTP event and dates for censoring is summarized in Table 4 as 
follows.
Table 4:
TTP Event and Censoring Method
Situation 
Date of Progression or Censoring 
Outcome 
Disease progression prior to start of subsequent 
anticancer therapy 
Earliest date that indicates disease 
progression 
TTP event 
Death due to disease progression prior to start of 
subsequent anticancer therapy 
Date of death 
TTP event 
No post-baseline disease assessment 
Randomization 
Censored 
Other (e.g., withdrawal of consent to study 
participation, lost to follow-up, start of subsequent 
anticancer therapy etc.) 
Date of last disease assessment prior 
to subsequent anticancer treatment 
Censored 
4.3.6.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.2.2for PFS analysis, 
including descriptive and comparison of the distribution of overall TTP.
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4.3.7.
Progression-free Survival on Next Line of Therapy (PFS2)
4.3.7.1.
Definition
Progression-free survival on next line of therapy (PFS2) is defined as the time from 
randomization to progression on next line of therapy or death, whichever comes first. Any deaths 
are considered as PFS2 events. Subjects who start next line of therapy without disease 
progression on study treatment will be censored at the last disease assessment before starting 
next line of therapy. For subjects who start next line of therapy after progression on study 
treatment, are still alive and not yet progress on next line of therapy, they will be censored on the 
last date of follow-up. Subjects without any post-baseline follow-up will be censored at the 
randomization.
Determination of dates of PFS2 event and dates for censoring is summarized in Table 5 as 
follows.
Table 5:
PFS2 Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No post-baseline disease assessment 
Randomization
Censored
Alive and no disease progression on study 
treatment 
Date of last disease assessment prior to start of 1st 
line on next therapy 
Censored
Disease progression on study treatment 
and progress on the 1st line of next 
therapy or any death 
Minimum of earliest date that indicates 
progression on the 1st line of next therapy and date 
of death
PFS2 event
Other
Minimum of start date of 2nd line of next therapy 
minus 1 and last date of follow-up
Censored
4.3.7.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.2.2 for PFS analysis.
4.3.8.
sCR Rate
4.3.8.1.
Definition
sCR rate is defined as the proportion of subjects with a response of sCR based on the 
computerized algorithm, according to IMWG response criteria, during or after the study 
treatment.
4.3.8.2.
Analysis Methods
Similar statistical methods will be applied as described in Section 4.3.3.2 for CR or better rate
analysis.
4.3.9.
Time to Subsequent Antimyeloma Treatment
4.3.9.1.
Definition
Time to subsequent antimyeloma treatment is defined as the time from randomization to the
start of subsequent antimyeloma treatment. Death due to PD without start of subsequent
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therapy will be considered as event. Subjects who withdrew consent to study or are lost to
follow, or die due to causes other than disease progression will be censored at the date of death
or the last date known to be alive.
4.3.9.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of time to subsequent 
antimyeloma treatment for the ITT population. Median time to subsequent antimyeloma 
treatment with 95% CI will be tabulated for each treatment group. In addition, a Kaplan-Meier 
curve for time to subsequent antimyeloma treatment will be plotted. The hazards ratio and its 
95% CI will be obtained through a stratified Cox’s regression model with treatment as the sole 
explanatory variable. Treatment comparison will be made via a stratified log-rank test.
4.3.10.
Time to Response
4.3.10.1.
Definition
Time to response (i.e., time to first response) is defined as the time between the date of 
randomization and the first efficacy evaluation that the subject has met all criteria for PR or 
better based on the computerized algorithm for patients who had PR or better as their best 
response. 
4.3.10.2.
Analysis Methods
For subjects who achieve a confirmed response, descriptive statistics (n, mean, standard 
deviation, median, and range) will also be provided to summarize time to response, time to first 
response, time to VGPR or better response and time to CR or better response.
4.3.11.
Duration of Response
4.3.11.1.
Definition
Duration of response (DOR) is defined for subjects with a confirmed response (PR or better) as 
the time between first documentation of response and disease progression based on the 
computerized algorithm, according to IMWG response criteria, or death due to PD, whichever 
occurs first. Responders without disease progression will be censored at the censoring time point 
for TTP.
4.3.11.2.
Analysis Methods
No formal statistical comparison of DOR between the 2 treatment groups is planned. Analysis of 
DOR will be based on subjects who achieved a confirmed response of PR or better. Median 
DOR with 95% CI will be estimated based on the Kaplan-Meier method for each treatment 
group. The Kaplan-Meier duration of response curve will be plotted by treatment group.
4.4.
Subgroup Analysis of Efficacy Endpoints
For assessment of internal consistency and investigation of homogeneity of the treatment effect 
across subgroups, subgroup analyses of the primary and selected secondary efficacy endpoints 
will be conducted based on pre-specified subgroups defined in Section 2.10.
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A forest plot of subgroup analysis on PFS and selected secondary endpoints (e.g. ORR) will be 
generated, respectively.
Additionally, the primary endpoint of PFS and secondary endpoint of TTP may be explored by 
responder vs non-responder for each treatment group.
4.5.
Functional Status and Well-being
4.5.1.
Definition
Functional status and well-being will be assessed using 2 PRO measures, the EORTC 
QLQ-C30 and the EQ-5D-5L.
The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales (physical functioning,
role functioning, emotional functioning, cognitive functioning, and social
functioning), 1
Global Health Status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6
single
items
(dyspnea,
insomnia,
appetite
loss,
constipation,
diarrhea, and financial 
difficulties). The recall period is 1 week (the past week).
The instrument contains 28 items using a verbal rating scale with 4 response options: “Not at 
All,” “A Little,” “Quite a Bit,” and “Very Much” (scored 1 to 4). Two additional items use 
response options (1 to 7): 1 = Very Poor, to 7 = Excellent. All scale and item scores will be 
linearly transformed to be in the range from 0 to 100 according to the algorithm in EORTC 
QLQ-C30 scoring manual, version 3.0 (Fayers et al, 2001). A higher score represents a higher 
("better") level of functioning, or a higher ("worse") level of symptoms.
The EQ-5D-5L is a generic measure of health status. For purposes of this study, the
EQ-5D-5L will be used to generate utility scores for use in cost effective analyses.
The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care,
usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating
“health today” with anchors ranging from 0 (worst imaginable health state) to 100 (best
imaginable health state). The scores for the 5 separate questions are categorical and cannot
be analyzed as cardinal numbers. However, the scores for the 5 dimensions are used to
compute a single utility score ranging from zero (0.0) to 1 (1.0) representing the general health 
status of the individual (but allows for values less than 0 by UK scoring algorithm).
4.5.2.
Analysis Methods
Compliance rates for completion of EORTC QLQ-C30 and EQ-5D-5L at each time point will be 
generated based on number of expected.
Key PRO endpoints

EORTC QLQ-C30 global health status/quality of life subscale

EQ-5D-5L utility score

EQ-5D-5L visual analog scale (VAS)
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The change from baseline at each time point will be summarized descriptively by treatment 
group. 
A distribution based method will be used to define worsening/improvement in scores, i.e., half
standard deviation away from the mean score at baseline combining both treatment groups.
Time to worsening and time to improvement will be derived. Death due to disease
progression will be considered as worsening. Subjects who have not met the definition of
worsening/improvement will be censored at the last PRO assessment. Subjects without baseline
assessment or post-baseline assessment will be censored at date of randomization.
Time to improvement will be descriptively reported. Time to worsening will be estimated using
Kaplan-Meier methods. The hazard ratio for DRd relative to Rd and its associated 95%
confidence interval (CI) will be calculated based on the stratified Cox proportional hazards
model by the stratification factor at randomization.
A mixed effects model with repeated measures analysis will be conducted estimating
change from baseline at each time point between two treatments. ITT subjects who have a
baseline value and at least one post-baseline value are included in the analysis. Change from
baseline will be fitted to a mixed effects model including subjects as a random effect, and
baseline value, treatment group, time in week, treatment-by-time interaction, and stratification 
factors as fixed effects. Line plot of LS mean of change from baseline with standard error over 
time will be displayed by treatment arm.
Secondary PRO endpoints
These may include other QLQ-C30 scales:

functional scales: physical, role, cognitive, emotional, and social

symptom scales: fatigue, pain, and nausea and vomiting

single-item score: dyspnea, loss of appetite, insomnia, constipation, diarrhea, and
financial difficulties
The change from baseline at each time point may be summarized descriptively by treatment
group.
Time to worsening/improvement and mixed effect model analysis, as described for the key
PRO endpoints, may be performed as appropriate. Line plot of LS mean of change from baseline 
with standard error over time may be displayed by treatment arm.
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5.
SAFETY
Safety assessment will be evaluated through AEs and clinical hematology and chemistry 
laboratory tests. Safety analyses will be based on the safety population and presented by the 
treatment actually received.
5.1.
Adverse Events
All adverse events whether serious or non-serious, will be reported from the time a signed and
dated informed consent form (ICF) is obtained until 30 days after the last dose of study
treatment, until the subject withdraws consent for study participation, or until the subject
starts subsequent antimyeloma therapy, whichever occurs first. AEs will be recorded in
standard
medical
terminology and
graded according to the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. For AE
reporting, the verbatim term used in the CRF by investigators to identify adverse events will
be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA)
coding dictionary.
Unless otherwise specified, at each level (e.g., system organ class and/or preferred term)
of subject summarization in reporting the incidence of the AE, a subject is counted once if
one or more events were recorded. For summarizing new onset events, all event records of the 
same preferred term from the same subject are to be linked by the onset date and the end date. If 
an event is followed by another event of the same preferred term with an onset date (or 
date/time) the same as or 1 day (or 1 minute if applicable) after the end date (or date/time) of the 
previous record and any features of the adverse event (i.e.: toxicity grades/seriousness/action 
taken) are different between these two records, these 2 records should be linked together and 
considered as one event. A Grade 5 event will be linked to previous event of the same preferred 
term if the onset date of grade 5 record is the same or one day after the end date of previous 
record.
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs), which
are defined as any AE that occurs after start of the first study treatment through 30 days after
the last study treatment; or the day prior to start of subsequent antimyeloma therapy,
whichever is earlier; or any AE that is considered drug-related (very likely, probably, or
possibly related) regardless of the start date of the event; or any AE that is present at baseline
but worsens in toxicity grade or is subsequently considered drug-related by the investigator.
The incidence of TEAEs will be summarized overall, by MedDRA system organ class (SOC)
and
preferred
term,
by
toxicity
grade,
and
by
relationship,
to
study
treatment
administration. Specifically, the following AE summaries will be presented by treatment group.
5.1.1.
Overview of TEAEs
An overview of TEAEs reported through the study will be provided for each treatment group. 
The overview will include summaries of subjects with TEAEs, with TEAEs related to study 
treatment, with TEAEs of maximum toxicity grade of 1 to 5, SAEs, TEAEs leading to 
discontinuation of all study treatment.
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5.1.2.
All TEAEs

Incidence of TEAEs by MedDRA SOC and preferred term.

Most commonly reported (>10%) TEAE by MedDRA SOC and preferred term.
5.1.3.
Toxicity Grade 3 or 4 TEAEs

Incidence of toxicity Grade 3 or 4 TEAEs, by MedDRA SOC and preferred term

List of subjects with any toxicity Grade 3 or 4 TEAEs

Most commonly reported (>5%) Grade 3 or 4 TEAE by MedDRA SOC and preferred term 
5.1.4.
Study Treatment-Related TEAEs

Incidence of TEAEs considered by the investigator to be related to study treatment, by
MedDRA SOC, preferred term and relationship to study treatment

Incidence of TEAEs with toxicity Grade 3 or 4 considered by the investigator to be related
to study treatment, by MedDRA SOC and preferred term and relationship to study treatment
5.1.5.
Serious Adverse Events (SAEs)

Incidence of treatment-emergent SAEs, by MedDRA SOC and preferred term

Incidence of treatment-emergent SAEs considered by the investigator to be related to study
treatment, by MedDRA SOC, preferred term and relationship to treatment

Most commonly reported (>2%) SAEs by MedDRA SOC and preferred term 

List of subjects with any treatment-emergent SAEs
5.1.6.
TEAEs Leading to Dose Modifications
Incidence of TEAEs leading to dose modifications will be summarized by MedDRA SOC and 
preferred term. The summaries will be presented by all grades and Grade 3 or 4 for each 
treatment. This table will include TEAEs leading to cycle delays or dose modification of at least 
1 of the study treatments, the dose modifications include dose delay within the cycle, dose 
reduced (not applicable to daratumumab), dose re-escalated per protocol (not applicable to 
daratumumab), or dose skipped.
5.1.7.
TEAEs Leading to Discontinuation of Any Study Treatment
A summary of number of subjects who discontinued any study treatment because of 1 or more
TEAEs by MedDRA system-organ class and preferred term will be provided. The summaries
will be presented by all grades and Grade 3 or 4 for each treatment group. The AEs leading
to discontinuation of any study treatment are based on AEs recorded in the AE CRF page
with an action taken of drug withdrawal for any study treatment.
A listing of subjects who discontinued any study treatment because of TEAEs will be provided
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5.1.8.
TEAEs Leading to Discontinuation of All Study Treatment
A summary of number of subjects who discontinued all study treatment because of 1 or more
TEAEs by MedDRA system-organ class and preferred term will be provided. A listing of 
subjects who discontinued all study treatment because of TEAEs will be provided, this listing 
includes TEAEs leading to discontinuation of all study treatment for those subjects indicated as 
having discontinued study treatment due to an adverse event on the end of treatment CRF page.
5.2.
Deaths
5.2.1.
Death Due to TEAEs
The number of subjects who died due to treatment-emergent adverse events will be summarized 
by preferred term and relationship to study treatment for each treatment group. The TEAEs 
included in this table are AEs with outcome death or toxicity grade of 5 recorded in the AE CRF 
page.
A listing of subjects who died due to treatment-emergent adverse events will be provided.
5.2.2.
Deaths
A summary of all deaths and cause of death will be tabulated overall and by treatment group. 
Specifically, the number of subjects who died during the study will be summarized for the ITT 
population. The primary cause of death collected on the death information CRF page will be 
reported. If the primary cause of death is AE, the number of subjects who have related AE and 
unrelated AE will be further reported. 
Subjects who died within 30 days of last study treatment dose and within 60 days of first study 
treatment dose, respectively, based on the safety population.
A listing of all deaths will be provided.
5.2.3.
Adverse Events by Subgroups
The following subgroup analysis of adverse events will be performed based on subgroups 
specified in Section 2.10:

Overview of TEAEs

All TEAEs

Toxicity Grade 3 or 4 TEAEs

SAEs.
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5.3.
Adverse Events of Clinical Interest
The adverse events of clinical interest would be focus on below items (detail would be defined 
on the DPS or below sections),

IRR

Infections and Infestations 

Opportunistic infections

Virus infections

Hemorrhage events

Interferences for blood typing

Tumor lysis syndromes

Intravascular hemolysis

Cytopenia

Neutropenia events

Thrombocytopenia events

Anaemia

Lymphopenia

Second Primary Malignancies
5.3.1.
Infusion-Related Reactions (IRR)
Subjects with any IRR associated with daratumumab administration will be summarized by
MedDRA system-organ class and preferred term. The summaries will be presented by all
grades, Grade 3, 4, and 5. In addition, the total number of subjects with IRR in more than 1
infusion will be reported. Additionally, the timing of IRR associated with daratumumab
administration will be evaluated through a summary of IRR by event onset time.
A listing of subjects with Grade 3 or higher treatment-emergent infusion-related reactions
associate with daratumumab administration will be provided. In addition, subjects with 
treatment-emergent infusion-related reactions results in discontinuation of daratumumab will be 
listed. 
5.3.2.
Infections and infestations
Infections and infestations refer to adverse events with SOC of infections and infestations. A 
summary of number of subjects with 1 or more toxicity Grade 3 or 4 treatment-emergent 
infections and infestations by MedDRA preferred term and relationship to treatment will be 
provided. Additional summary analyses may include by onset time (i.e., ≤ 6 months vs. 6-≤12 
months vs. 12-≤24 months vs. >24 months) and/or exposure-adjusted incidence rate of
infections/infestations.
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5.3.2.1.
Opportunistic Infections
Opportunistic Infections to adverse events with PT terms which would be defined on the DPS. 
The summaries will be presented by all grades and Grade 3 or 4 for each treatment group.
5.3.3.
Cytopenia
Cytopenia includes Neutropenia events, Thrombocytopenia events, Anaemia and Lymphopenia.
The four types of Cytopenia to adverse events with PT terms which would be defined on the 
DPS. The summaries will be presented by all grades and Grade 3 or 4 for each treatment
group.
5.3.4.
Hemorrhage
Hemorrhage defined by Standardized MedDRA Queries (SMQ) with the first subcategory SMQ 
of hemorrhage terms (exclude laboratory terms). The summaries will be presented by all grades 
and Grade 3 or 4 for each treatment group.
5.3.5.
Second Primary Malignancies
A listing of subjects who reported second primary malignancies during the study will be 
provided. This listing will include diagnosis, study day of diagnosis, recurrence of a prior 
existing malignancy (yes, no) and pathology diagnosis (biopsy, aspirate etc.) etc. information 
whenever a second primary malignancy is observed. In addition, cumulative study treatment
exposure, the treatment for second primary malignancy and the outcome information will also be 
presented in the listing.
5.4.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes:
Hematology panel:

hemoglobin

platelet count

white blood cell (WBC) count with absolute neutrophils and lymphocytes
Blood chemistry panel: 

alkaline phosphatase

creatinine

uric acid

glucose

bilirubin

aspartate aminotransferase (AST)

alanine aminotransferase (ALT)
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
sodium

potassium

corrected calcium

phosphate

creatinine clearance
Blood samples for serum hematology are taken at the screening visit, on Days 1, 8, 15, and 
22 of Cycles 1-2, Days 1 and 15 of Cycles 3-6, Day 1 of Cycles 7+, and at the End-of-
Treatment visit. Blood sample for biochemistry are taken at the screening visit, on Day 1 of 
each treatment cycle and at the End-of-Treatment visit.
Descriptive statistics (mean, standard deviation, median, range) will be used to summarize
observed laboratory values and change from baseline in observed value at each scheduled visit 
for each treatment group. Line plot of mean with standard error for each laboratory analyte over 
time will be displayed by treatment group for hemoglobin, neutrophils, lymphocytes, platelets, 
WBC, AST, ALT, creatinine, and creatinine clearance.
The worst toxicity grade in hematology and chemistry during the treatment will be summarized
by treatment group and toxicity grade. Shift tables from baseline to worst toxicity grade during
the treatment will be provided for each laboratory analyte listed above. These tables will
summarize the number of subjects with each baseline CTC grade and changes to the maximum
CTC grade.
5.5.
Vital Signs and Physical Examination Findings 
Vital signs (systolic and diastolic blood pressure, heart rate, and temperature) values at baseline 
will be summarized. 
Post baseline physical examination findings were collected as AEs, and therefore will not be 
summarized.
5.6.
Electrocardiogram (ECG)
Electrocardiograms (ECG) will be performed at Screening, Day 1 of Cycle 3 and Cycle 6 
immediately after end of daratumumab infusion, and End-of-Treatment visit. 
The number and percentage of subjects with normal or abnormal 12-lead ECG results will be 
summarized. 
5.7.
ECOG Performance Score
ECOG performance status, which evaluates the effect of the disease status on the activities of 
daily living, will be assessed at Screening, Day 1 of Cycle 3, Cycle 6, Cycle 9 and Cycle 12 for 
the first year, every 6th cycle thereafter until EOT (PD), post-PD collected at Week 8 and 16. 
Descriptive statistics will be used to summarize ECOG performance status at baseline, Day 1 of 
each treatment cycle (including change from baseline), worst score during treatment (including 
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change from baseline), and End-of-Treatment visit (including change from baseline) for each 
treatment group. Shift table from baseline to worst score during the treatment will be provided.
6.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
Unless specified otherwise, descriptive statistics (e.g., number of observations, mean, standard 
deviation, median, and range) will be used to summarize pharmacokinetics and 
pharmacodynamics data. In addition, coefficient variation and geometric mean will be provided 
in the pharmacokinetic concentration summary.
6.1.
Pharmacokinetics
6.1.1.
Sampling Timepoints
For subjects assigned to DRd, blood samples to assess serum concentration (pharmacokinetics) 
of daratumumab will be obtained at Day 1 of Cycle 1, 6 and 12, End-of-Treatment and Post-
Treatment Week 8. On a daratumumab dosing day, blood samples need to be collected before 
(up to 2 hours but not after the start of infusion) and after (up to 2 hours but not before the end of 
infusion) daratumumab administration.
6.1.2.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:

Minimum observed concentration (Cmin) - the concentration observed immediately before 
infusion.

Maximum observed concentration (Cmax) - the concentration observed after the end of 
infusion
For daratumumab, the pharmacokinetic evaluations include Cmin and Cmax. 
6.1.3.
Analysis Methods
Pharmacokinetic analyses will be performed on the pharmacokinetic-evaluable population.
All serum concentrations below the lowest quantifiable concentration or missing data will be
recorded as such in the concentration data set. Concentrations below the lowest quantifiable
concentration will be treated as zero in the summary statistics. All subjects and samples
excluded from the analysis will be clearly documented.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling
time
point.
A plot
of
mean
(±SD)
daratumumab serum peak and trough 
concentrations over time will be provided.
If
sufficient
data
are
available,
population
pharmacokinetic
analysis
of
serum
concentration-time data of daratumumab may be performed using nonlinear mixed-effects
modeling. If population pharmacokinetic analysis is conducted, it may include data from
other clinical studies; details will be provided in a population pharmacokinetic analysis plan 
and results will be presented in a separate report.
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6.2.
Immunogenicity
6.2.1.
Sampling Timepoints
Samples to assess the generation of antibodies to daratumumab (immunogenicity) will be 
obtained from all subjects in the DRd group at Cycle 1 Day 1 predose, End-of Treatment, and 
Post-Treatment Week 8. In addition, any time an infusion-related reaction is observed during the 
study, an unscheduled blood sample should be drawn as soon as possible after the reaction for 
potential immune response analysis.
6.2.2.
Analysis Methods
The incidence of anti-daratumumab antibodies (immunogenicity) will be summarized for all 
subjects who receive a dose of daratumumab and have appropriate samples for detection of 
antibodies to daratumumab. In addition, subjects who are positive for antibodies to daratumumab 
will also be listed.
6.3.
Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy. If analysis is conducted, details and results of the analysis will 
be presented in a separate report.
7.
BIOMARKER
Biomarker studies are designed to identify markers predictive of response (or resistance) to
daratumumab. Planned analyses are based on the availability of clinically valid assays and may
be deferred if emerging study data show no likelihood of providing useful scientific
information. Results of biomarker analyses may be presented in a separate report.
Blood samples will be drawn from all subjects in both treatment groups to better understand
the mechanism of action and mechanism of resistance of daratumumab. Minimal residual
disease (MRD) will be assessed from bone marrow aspirates for all subjects who achieve a
CR/sCR. Molecular subtyping will be done to evaluate daratumumab response rates in high-
risk multiple myeloma subpopulations.
7.1.
Minimal Residual Disease (MRD)
Bone marrow aspirates will be collected to monitor MRD in those subjects who attain or suspect 
to have a CR/sCR. MRD will be monitored using next generation sequencing (NGS) on bone 
marrow aspirate.
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7.1.1.
Sampling Timepoints
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 (for detail timepoint refer to 
protocol Section 9.2.1.5). 
7.1.2.
Analysis Methods
Details on MRD negativity rate analyses are described in Section 4.3.4. 
In addition, to evaluate the relationship between MRD negativity and clinical endpoints (e.g. 
PFS) may be explored.
7.2.
Molecular Subtyping
7.2.1.
Sample collection and characterization
Viable, frozen CD38+ bone marrow aspirate samples were collected at baseline for DNA/RNA 
sequencing analysis. Peripheral blood mononuclear cell (PBMC) samples were collected at 
baseline to use as controls.
7.2.2.
Molecular Subtypes
A portion of the bone marrow aspirate samples collected as specified in the Section 7.2.1 will be 
utilized 
for 
translocation/mutation/genomic 
analysis 
using 
exome-sequencing
and 
RNA-sequencing to assess whether specific molecular subgroups having chromosomal 
aberrations such as del17p, t(4;14), t(14;16), are responsive to daratumumab treatment. PBMC 
samples will be sent for exome sequencing and used as controls for mutation and copy number 
analysis. 
7.2.3.
High-risk/Standard-risk Molecular Subgroup Analysis
High-risk and standard-risk molecular subgroups have been defined in Section 2.9.
To determine if daratumumab combined with Rd (DRd) will lead to improved clinical responses 
in high-risk molecular subgroups, the following exploratory analysis will be conducted by using 
the similar analysis methods specified in Sections 4.3.1.2 and 4.2.2.

To evaluate ORR and MRD negativity rate for subjects in high-risk molecular subgroup and 
subjects with specific molecular subtyping such as del17p, t(14;16), t(4;14)

To evaluate PFS and OS for subjects in high-risk molecular subgroup and subjects with 
specific molecular subtyping such as del17p, t(14;16), t(4;14)
If subgroup size allows, these results will also be compared with the subjects treated with DRd in 
the standard-risk molecular subgroup, to explore whether subjects treated with DRd in high risk 
molecular subgroup will have similar clinical outcome as subjects in standard risk subgroup.
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8.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization (excluding study infusion administration) will be descriptively 
summarized by treatment group. Frequencies of hospitalization, outpatient visits, type of 
hospitalization or outpatient visit, reasons for hospitalization or outpatient visit, durations of 
hospitalization or outpatient visit will be calculated and tabulated.
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REFERENCES
1.
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. 
Leukemia 2006;20:1467–1473. Corrigenda/Erratum in: Leukemia. 2007; 21:1134-1135.
2.
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 4691-4695.
3.
Sonneveld P, Avet-Loiseau H, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus 
of the International Myeloma Working Group. Blood. 2016 Jun 16;127(24):2955-62
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ATTACHMENTS
ATTACHMENT 1:
Additional Exploratory Analysis to Support HEMAR
1.
DEFINITION OF SUBGROUPS
Subgroup analyses will be performed using the criteria listed below to determine whether the 
treatment effect is consistent among subgroups. Analyses will be conducted for the ITT 
population and for the following subgroups:

For subjects who reached CR/sCR as their best response

For subjects who reached VGPR as their best response

For subjects who reached PR as their best response

For subjects who reached PD as their best response

For subjects who had baseline ECOG of 2

For subjects who achieved MRD negativity (10-4, 10-5 and 10-6)
Subgroup analyses will be performed if data warrants.
2.
TIME-TO-EVENT ENDPOINTS FOR SUBGROUP ANALYZES
Kaplan-Meier estimates will be used to estimate distribution of time to event by treatment arm 
based on all ITT population. Data will be calculated and summarized with descriptive statistics. 
The following time-to-event endpoints will be analyzed by pre-defined subgroups as defined in 
section 2.10 and in section 1, Appendix:

PFS

TTP

Time to subsequent antimyeloma treatment

PFS2

OS

Time to best response

DOR
2.1.
Subgroup Analysis by Center for PFS, OS and EQ-5D and EORTC QLQ 
C30
3.
EXPOSURE ADJUSTED INCIDENCE RATES (EAIR)
3.1.
Restriction on the first event
The analysis restricts on the occurrence of the first event per patient and ignores the existence of 
later (multiple) events as these cannot be assumed to occur independent of previous events (e.g.: 
patients suffering from infections may have in general a higher risk of having other 
complications and may even have a higher risk of getting other infections). The occurrence of 
multiple events is subject to another analysis considering the absolute number of adverse events 
per patient.
For these reasons the EAIR should be interpreted as 'rate until the first event occurs'. Rates 
estimated from several patients can be averaged on the level of a preferred term (PT), of a system 
organ class (SOC), or on a global level (see below).
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The interpretation of EAIRs is simple and consistent on the preferred-term level only, and can be 
expressed as "Average number of TEAEs per preferred-term emerging per person-month of 
exposure". 
The aforementioned considerations apply in the same way to EAIRs estimated on the global 
level: when EAIRs are collapsed into the global estimate (first analyses), the estimate can be 
interpreted as the "Average number of TEAEs emerging per person-month and PT", because 
estimation has been performed on a 'per PT'-basis (per average or typical PT among all PTs).
Comparing EAIRs on the level of the SOC or on the global level involves data destruction 
because a patient's information is reduced to the first TEAE only (and possibly to a TEAE of 
marginal relevance among many TEAEs with higher clinical relevance).
The EAIR analysis focuses on the 'speed' by which TEAEs emerge. The analysis restricts on the 
first event of a patient because independence of TEAEs cannot be assumed. The necessity to 
restrict on the first event entails considerable data destruction when deriving SOC-specific 
EAIRs or the EAIR on a global level. To overcome this, the 'per PT'-analysis, which is reported 
in both Tables identically, is preferable. 
Comparing EAIRs between the analyses outlined below on a SOC-specific or a global level 
demonstrates that the 'per PT'- method makes the interpretation of results more difficult.  
However, it can be suggested that this method provides a more robust approach when the two 
treatment arms are to be compared on a SOC-specific or global level. A t-Test like comparison 
of PT-specific estimates between the two treatment arms may provide a more robust, 
comprehensive and easy-to-communicate way of visualizing and comparing results.
3.2.
Duration of exposure: censored & non-censored
The incidence rate for a patient is derived from the duration of exposure to treatment of that 
patient. When averaging incidence rates, a patient's duration of exposure is given either A) by the 
time when the event has occurred (non-censored data), or B) by the total duration of treatment in 
case the patient does not show the adverse event in question (censored data). Depending on 
whether a patient has an adverse event or not, the duration of exposure enters the denominator in 
its non-censored or censored form, respectively. 
3.3.
Incidence rate per patient
The incidence rate for a specific event of a patient i is the reciprocal of time t when the first event 
occurs:
 =

 .
3.4.
Average EAIR
The EAIR averaged over all patients is
 =
∑



∑



,
whereby 
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a) a TEAE enters the sum in the nominator unweighted (TEAEi =1, otherwise TEAEi =0), 
and
b) the 
duration 
of 
exposure 
enters 
the 
denominator 
as 
described 
before: 
 =      if occurring $non-censored data+
  ,- ./0,1  0,1 if no event occurs (censored data) .
3.5.
EAIRs on the level of a SOC and on the global level on a ‘per-PT’ basis
3.5.1.
Average EAIR per PT
The EAIR for a specific PT is an average over all patients, i.e.
5 =
∑
67,


∑
67,


, 
whereby the number of TEAEs and durations of exposure enter the nominator and the 
denominator.
3.5.2.
Average EAIR per SOC
The average EAIR per SOC considers the first event of each patient within the SOC.  The 
denominator includes the exposure time of each adverse event of all PTs within the SOC, per 
patient, i.e.
9:; = ∑
9:;, ∑

67,
< 5= >?@ 9:;
5A
<
A
,
where TEAESOC,i is the first event per patient per SOC and tPT,i is the exposure time for a specific 
preferred term of a given patient. 
Note: This EAIR is an incidence rate per average (or typical) preferred term in that SOC (cf. 
3.6.1). 
3.5.3.
Average EAIR on a global level
The average EAIR on a global level only considers the first event per patient across all events.  
The denominator includes the exposure times of all PTs, i.e.
BCDEFC = ∑
 ∑

67,
< 5=
5A
<
A
,
where TEAEi is the first event of a patient overall and the tPT,i‘s are PT-specific exposure times of 
that patient.
Note: This EAIR is an incidence rate per average (or typical) preferred term. 
3.6.
Second analyses
3.6.1.
Average EAIR per PT
The EAIR for a specific PT is an average over all patients as described before, i.e.
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5 =
∑
67,


∑
67,


, 
whereby the number of TEAEs and durations of exposure enter the nominator and the 
denominator.
3.6.2.
Average EAIR per SOC
The average EAIR per SOC considers the first event per patient per SOC only, and only one (the 
corresponding) exposure time in the denominator (confer before, where the denominator in the 
EAIRSOC depends on the number of PTs per SOC):
9:; =
∑
GHI,


∑
GHI,


,
Note: This EAIR is an incidence rate per SOC. 
3.6.3.
Average EAIR on a global level
The average EAIR on a global level considers the overall first event per patient only, and only 
one (the corresponding) exposure time in the denominator (confer before, where the denominator 
in the EAIRSOC depends on the overall number of PTs):
BCDEFC =
∑



∑



,
whereby TEAEi represents the first TEAE among all TEAEs of patient i and ti as before (time 
when TEAE occurs (non-censored data) or total duration of treatment if no event occurs 
(censored data))
4.
ADDITIONAL TIME TO EVENT ANALYSES
In case of different exposure times, time adjustment for AE is necessary. Hazard Ratio and 
Kaplan-Meier curves will be conducted including number of patients at risk for the following 
safety endpoints: 

Any TEAE 

Any Serious TEAE

Any TEAE leading to death

Any Grade 3 or 4 TEAE

Any Grade 3 or higher TEAE

Any TEAE leading to treatment discontinuation
Detailed description by preferred term:

TEAEs by preferred term with prevalence>=10%/

Grade 3 or 4 TEAEs preferred term with prevalence>=5%

Grade 3 or higher TEAEs by preferred term prevalence>=5%

Serious TEAEs preferred term with prevalence>=2%

TEAEs leading to treatment discontinuation preferred term with prevalence>=1%

TEAE leading to death preferred term without prevalence cut-off
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ATTACHMENT 2:
Multiple Myeloma IMWG Algorithm
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Approved, Date: 3 October 2018
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JNJ-54767414  (daratumumab)
Statistical Analysis Plan 54767414MMY3008
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Statistical Analysis Plan 54767414MMY3008
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
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Approved, Date: 3 October 2018
NCT02252172