Clinical trial NCT03277105
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC
Start date: 2017-10-27; Completion date: 2024-01-12
Enrollment: 522 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant human hyaluronidase PH20 (Dara SC) is non-inferior to intravenous (IV) administration of daratumumab (Dara IV) in terms of the overall response rate (ORR) and maximum trough concentration (Ctrough).

Detailed description:
The study population will consist of adults diagnosed with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD. The study consists of 3 phases: a screening phase (up to 28 days), a treatment phase, and a follow-up phase. Efficacy, pharmacokinetics, immunogenicity, biomarkers and safety will be assessed at scheduled time. Follow-up will continue until the end of the data collection period, approximately 24 months after the last participant was randomized or when the median overall survival for both arms has been reached, whichever occurs first. The primary hypotheses is that the ORR and maximum Ctrough for Dara SC 1800 milligram (mg) are not inferior to the ORR and maximum Ctrough, respectively, for Dara IV 16 mg per kilogram (mg/kg) in participants with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a PI and an IMiD.

Arms: arm 1: Participants will receive a fixed dose of daratumumab as 1800 milligram (mg) subcutaneously (Dara SC) co-formulated with recombinant human hyaluronidase (rHuPH20) 2000 Unit per milliliter (U/mL), once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks. arm 2: Participants will receive daratumumab for intravenous infusion (Dara IV) 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks on Day 1 in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. The duration for each cycle is 4 weeks. For Participants still receiving treatment with Dara-IV at the time of Protocol Amendment 4 the duration of infusion may be shortened to a 90-minute infusion or participants will have the option to switch to Dara 1800 mg subcutaneous (SC) on Day 1 of any cycle, at the discretion of the investigator.
Interventions: intervention 1: Dara SC intervention 2: Dara IV
Intervention descriptions: intervention 1: Participants will receive a fixed dose of Dara SC as 1800 mg daratumumab with rHuPH20 2000 U/mL, once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study. intervention 2: Participants will receive Dara IV 16 mg/kg once weekly in Cycle 1 and 2, every 2 weeks in Cycle 3 to 6, every 4 weeks in Cycle 7 and thereafter until disease progression, unacceptable toxicity or the end of study.

Protocol documents:
Prot_002.pdf: 
1
Status: Approved, Date: 1 April 2020
Janssen Research & Development *
Clinical Protocol
A Phase 3 Randomized, Multicenter Study of Subcutaneous vs. Intravenous 
Administration of Daratumumab in Subjects With Relapsed or Refractory 
Multiple Myeloma 
Protocol 54767414MMY3012; Phase 3
AMENDMENT 4
JNJ-54767414  (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen 
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout 
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information 
page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER:         2017-000206-38
Status:
Approved
Date:
1 April 2020
Prepared by:
Janssen Research & Development, LLC 
EDMS number:
EDMS-ERI-137065766, 8.0
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.
NCT03277105


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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.................................................................................................................................................. 18
TIME AND EVENTS SCHEDULES ............................................................................................................ 21
ABBREVIATIONS ...................................................................................................................................... 26
1.
INTRODUCTION................................................................................................................................ 28
1.1.
Multiple Myeloma ........................................................................................................................... 28
1.2.
Daratumumab for Intravenous Infusion.......................................................................................... 28
1.2.1.
Clinical Studies ........................................................................................................................... 29
1.2.1.1.
Single-agent Studies ............................................................................................................... 29
1.2.1.2.
Combination Therapy Studies ................................................................................................. 30
1.3.
Daratumumab for Subcutaneous Injection..................................................................................... 30
1.3.1.
Nonclinical Studies ..................................................................................................................... 30
1.3.2.
Clinical Studies ........................................................................................................................... 31
1.4.
Overall Rationale for the Study...................................................................................................... 32
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES.......................................................................... 33
2.1.
Objectives and Endpoints .............................................................................................................. 33
2.1.1.
Objectives ................................................................................................................................... 33
2.1.2.
Endpoints.................................................................................................................................... 33
2.2.
Hypothesis ..................................................................................................................................... 34
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 34
3.1.
Overview of Study Design.............................................................................................................. 34
3.2.
Study Design Rationale.................................................................................................................. 36
4.
SUBJECT POPULATION.................................................................................................................. 41
4.1.
Inclusion Criteria ............................................................................................................................ 41
4.2.
Exclusion Criteria ........................................................................................................................... 43
4.3.
Prohibitions and Restrictions ......................................................................................................... 45
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 45
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 46
6.1.
Preparation..................................................................................................................................... 46
6.1.1.
Subcutaneous Preparation ......................................................................................................... 46
6.1.2.
Intravenous Preparation ............................................................................................................. 46
6.2.
Treatment Schedule and Administration........................................................................................ 46
6.2.1.
Subcutaneous Dosing................................................................................................................. 47
6.2.2.
Intravenous Administration ......................................................................................................... 47
6.3.
Predose and Postdose Medications .............................................................................................. 48
6.3.1.
Predose Medications .................................................................................................................. 48
6.3.2.
Postdose Medications................................................................................................................. 48
6.4.
Management of Injection-site and Infusion-related Reactions....................................................... 49
6.4.1.
Local Injection-site Reactions..................................................................................................... 49
6.4.2.
Infusion-related Reactions.......................................................................................................... 49
6.5.
Dose Delays and Modification ....................................................................................................... 50


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7.
TREATMENT COMPLIANCE............................................................................................................ 51
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 52
8.1.
Recommended Therapies.............................................................................................................. 52
8.1.1.
Bisphosphonate Therapy............................................................................................................ 52
8.1.2.
Therapy for Tumor Lysis Syndrome ........................................................................................... 52
8.1.3.
Therapy for Pneumocystis carinii/jirovecii .................................................................................. 52
8.1.4.
Prophylaxis for Herpes Zoster Reactivation ............................................................................... 53
8.1.5.
Prevention of Steroid Induced Gastritis...................................................................................... 53
8.1.6.
Management of Hepatitis B Virus Reactivation .......................................................................... 53
8.2.
Permitted Therapies....................................................................................................................... 53
8.3.
Prohibited Therapies...................................................................................................................... 54
9.
STUDY EVALUATIONS .................................................................................................................... 54
9.1.
Study Procedures........................................................................................................................... 54
9.1.1.
Overview..................................................................................................................................... 54
9.1.2.
Screening Phase ........................................................................................................................ 55
9.1.3.
Treatment Phase ........................................................................................................................ 55
9.1.4.
Follow-Up Phase ........................................................................................................................ 56
9.1.5.
Post Data Collection Period to End of Study.............................................................................. 56
9.2.
Efficacy Evaluations....................................................................................................................... 57
9.2.1.
Response Categories ................................................................................................................. 57
9.2.2.
Myeloma Protein Measurements in Serum and Urine................................................................ 59
9.2.3.
Serum Calcium Corrected for Albumin....................................................................................... 60
9.2.4.
β2-microglobulin and Albumin .................................................................................................... 60
9.2.5.
Bone Marrow Examination.......................................................................................................... 61
9.2.6.
Assessment of Lytic Bone Disease ............................................................................................ 61
9.2.7.
Documentation of Extramedullary Plasmacytomas.................................................................... 61
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 62
9.3.1.
Evaluations ................................................................................................................................. 62
9.3.2.
Analytical Procedures................................................................................................................. 62
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 63
9.3.4.
Immunogenicity Assessments .................................................................................................... 63
9.4.
Biomarkers ..................................................................................................................................... 64
9.5.
Patient-reported Outcomes............................................................................................................ 65
9.6.
Medical Resource Utilization.......................................................................................................... 65
9.7.
Safety Evaluations ......................................................................................................................... 66
9.8.
Sample Collection and Handling.................................................................................................... 69
10.
SUBJECT DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL FROM THE 
STUDY............................................................................................................................................... 69
10.1.
Discontinuation of Study Treatment............................................................................................... 69
10.2.
Withdrawal From the Study............................................................................................................ 70
10.3.
Withdrawal From the Use of Samples in Future Research............................................................ 70
11.
STATISTICAL METHODS................................................................................................................. 71
11.1.
Subject Information ........................................................................................................................ 71
11.2.
Sample Size Determination ........................................................................................................... 71
11.3.
Co-primary Endpoints .................................................................................................................... 72
11.4.
Secondary Endpoints..................................................................................................................... 72
11.5.
Pharmacokinetic Analyses............................................................................................................. 73
11.6.
Immunogenicity Analyses .............................................................................................................. 73
11.7.
Biomarker Analyses ....................................................................................................................... 74
11.8.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 74
11.9.
Patient-reported Outcomes............................................................................................................ 74
11.10.
Medical Resource Utilization Analyses.......................................................................................... 74
11.11.
Safety Analyses ............................................................................................................................. 74
11.12.
Safety Data Monitoring................................................................................................................... 75


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12.
ADVERSE EVENT REPORTING ...................................................................................................... 75
12.1.
Definitions ...................................................................................................................................... 76
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 76
12.1.2.
Attribution Definitions.................................................................................................................. 77
12.1.3.
Severity Criteria .......................................................................................................................... 77
12.2.
Special Reporting Situations.......................................................................................................... 78
12.3.
Procedures..................................................................................................................................... 78
12.3.1.
All Adverse Events...................................................................................................................... 78
12.3.2.
Serious Adverse Events ............................................................................................................. 80
12.3.3.
Disease-Related Events or Outcomes Not Qualifying as Adverse Events ................................ 81
12.3.4.
Pregnancy................................................................................................................................... 81
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 81
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 81
13.1.
Procedures..................................................................................................................................... 82
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 82
14.
STUDY DRUG INFORMATION......................................................................................................... 82
14.1.
Physical Description of Study Drugs.............................................................................................. 82
14.2.
Packaging ...................................................................................................................................... 82
14.3.
Labeling.......................................................................................................................................... 83
14.4.
Preparation, Handling, and Storage............................................................................................... 83
14.5.
Drug Accountability ........................................................................................................................ 83
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 84
16.
ETHICAL ASPECTS ......................................................................................................................... 84
16.1.
Study-Specific Design Considerations........................................................................................... 84
16.2.
Regulatory Ethics Compliance....................................................................................................... 85
16.2.1.
Investigator Responsibilities ....................................................................................................... 85
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 86
16.2.3.
Informed Consent ....................................................................................................................... 87
16.2.4.
Privacy of Personal Data ............................................................................................................ 88
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 89
16.2.6.
Country Selection ....................................................................................................................... 89
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 89
17.1.
Protocol Amendments.................................................................................................................... 89
17.2.
Regulatory Documentation ............................................................................................................ 90
17.2.1.
Regulatory Approval/Notification ................................................................................................ 90
17.2.2.
Required Prestudy Documentation............................................................................................. 90
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 91
17.4.
Source Documentation................................................................................................................... 91
17.5.
Case Report Form Completion ...................................................................................................... 92
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 92
17.7.
Record Retention ........................................................................................................................... 93
17.8.
Monitoring ...................................................................................................................................... 93
17.9.
Study Completion/Termination....................................................................................................... 94
17.9.1.
End of Data Collection/Study Completion .................................................................................. 94
17.9.2.
Study Termination....................................................................................................................... 94
17.10.
On-Site Audits ................................................................................................................................ 95
17.11.
Use of Information and Publication................................................................................................ 95
REFERENCES............................................................................................................................................ 97
INVESTIGATOR AGREEMENT ............................................................................................................... 115


JNJ-54767414  (daratumumab)
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LIST OF ATTACHMENTS
Attachment 1:
International Myeloma Working Group Diagnostic Criteria ........................................ 99
Attachment 2:
Prior Cancer Therapy for Multiple Myeloma............................................................. 100
Attachment 3:
Eastern Cooperative Oncology Group Performance Status Score.......................... 101
Attachment 4:
Modified Diet in Renal Disease Formula.................................................................. 102
Attachment 5:
Serum Calcium Corrected for Albumin..................................................................... 103
Attachment 6:
Conversion Table for Glucocorticosteroid Dose....................................................... 104
Attachment 7:
Asthma Guidelines ................................................................................................... 105
Attachment 8:
New York Heart Association (NYHA) Functional Classification ............................... 107
Attachment 9:
Antihistamines That May Be Used Predose............................................................. 108
Attachment 10: 
Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE Interference 
Test........................................................................................................................... 109
Attachment 11:
Modified Cancer Therapy Satisfaction Questionnaire.............................................. 110
Attachment 12:
Anticipated Events.................................................................................................... 112
Attachment 13:
Continuation of Treatment After Clinical Cutoff for the Final Analysis (End of 
the Data Collection Period)....................................................................................... 113
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule – Overview.................................................................................... 21
Table 2:
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection 
Times ........................................................................................................................................ 25
Table 3:
Study Drug (Dara-SC or Dara-IV) Administration Schedule..................................................... 46
Table 4:
Daratumumab Administration Schedule ................................................................................... 51
Table 5:
International Uniform Response Criteria Consensus Recommendations ................................ 57
Table 6:
Bone Marrow Testing................................................................................................................ 61
FIGURES
Figure 1:
Schematic Overview of Study Design....................................................................................... 35
Figure 2:
Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800 mg 
(subcutaneous administration) and Dara-IV 16 mg/kg (intravenous administration) ............... 39
Figure 3:
Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (ratio 
of trough concentrations and median trough concentration for overall population at 
each dose) for Dara-MD 1800 mg (subcutaneous administration) and Dara-IV 16 
mg/kg (intravenous administration)........................................................................................... 39


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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
23 May 2017
Amendment 1
7 December 2017
Amendment 2
13 August 2018
Amendment 3
Amendment 4
21 January 2020
01 April 2020
Amendments below are listed beginning with the most recent amendment.
Amendment 4 (01 April 2020)
The overall reason for the amendment: The overall reason for the amendment is to provide flexibility for study 
investigators to prioritize the safety of their patients during the global coronavirus (COVID-19) pandemic. To 
ensure continuity of study treatment, while limiting subjects’ time spent at the study center, subjects who were 
randomized to receive Dara-IV (16 mg/kg) will be given the option to switch to Dara-SC (1800 mg), at the 
discretion of the investigator. Alternatively, for subjects who continue to receive Dara-IV, the duration of infusion 
may be shortened to a 90-minute infusion for subjects without a history of infusion related reactions after the third 
dose, at the discretion of the investigator. Detailed information regarding Dara-IV administration, including infusion 
rates and duration, has been removed and will only be provided in the Site Investigational Product Procedures 
Manual (SIPPM).
Applicable Section(s)
Description of Change(s)
Rationale: To allow subjects currently receiving Dara-IV the option to switch to Dara-SC, at the discretion of the 
investigator.
Synopsis; Table 1; 3.1.Overview 
of Study Design; Figure 1; 
3.2.Study Design Rationale; 
6.2.1.Subcutaneous Dosing; 
9.1.1.Overview
Text was added to allow subjects the option to switch from Dara-IV to Dara-SC.
Table 2 (Time and Events 
Schedule –
Pharmacokinetic/Immunogenicity 
Sample Collection Times); 
3.2.Study Design Rationale; 
9.3.1.Evaluations; 
9.3.4.Immunogenicity 
Assessments
Text was added to clarify that rHuPH20 immunogenicity sampling was not required 
for subjects who switch from Dara-IV to Dara-SC.
9.3.1.Evaluations; 
9.3.4.Immunogenicity 
Assessments
Text was added regarding the sampling requirements for detection of antibodies to 
daratumumab for subjects who switch from Dara-IV to Dara-SC.
3.1.Overview of Study Design;
6.2.1.Subcutaneous Dosing
Text was added to clarify that subjects with allergy/intolerance to sorbitol cannot 
switch from Dara-IV to Dara-SC.
6.2.2.Intravenous Administration;
6.4.2.Infusion-related Reactions;
Table 4 removed (Dara-IV 
Intravenous Infusion Rates)
Detailed information regarding Dara-IV administration, including infusion rates and 
duration was removed; text was added that information is provided in the SIPPM; and
text related to accelerated infusion rates was added.
6.3.2.Postdose Medications
Text was added to clarify that postdose medications may be offered for the first and 
subsequent doses of Dara-SC for subjects who switch from Dara-IV to Dara-SC.


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Applicable Section(s)
Description of Change(s)
Rationale: To clarify the sponsor’s standard operating procedures.
12.3.1.All Adverse Events
The following text was added: The sponsor will evaluate any safety information that 
is spontaneously reported by an investigator beyond the time frame specified in the 
protocol.
Rationale: To clarify which events should be reported expeditiously and to align with the sponsor’s standard operating 
procedures.
12.1.1.Adverse Event Definitions 
and Classifications
The following text was added: Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that to do not result in hospitalization; or development of 
drug dependency or drug abuse or malignancy.
Rationale: To provide additional clarity on safety laboratory assessments after the end of the data collection period.
Attachment 13
The following text was added: 
Safety Laboratory Assessments
Once the data collection period has ended, local hematology labs, chemistry labs, and 
assessment of vital signs should still be performed on Day 1 of each dosing cycle for 
consistency with previous cycles and in accordance with good clinical practice. These 
local laboratory results do not need to be reported to the sponsor.
Rationale: To provide additional clarity on data reporting.
3.1.Overview of Study Design
Bolded text was added; strikethrough text was removed: Data collected through the 
end of the data collection period will be included in the final study analysis and 
reported in a separate Clinical Study Report. Data collected following the data 
collection period up to the study end will be reported as an addendum to the 
CSR.
Rationale: Minor errors, editorial issues, or changes for clarity/consistency noted in the protocol were corrected.
Abbreviations
Abbreviations added: SIPPM, IPPI
6.Dosage and Administration
Bold text was added; strikethrough text was removed: The Investigational Product 
and Procedures Manual SIPPM and Investigational Product Preparation Instructions 
(IPPI) contain detailed descriptions for preparation and administration of 
daratumumab and will be supplied to each pharmacy and site.
15.Study-Specific Materials
Bold text was added; strikethrough text was removed: Site Investigational Product
and Procedures Manual
Throughout the protocol
Minor edits, editorial changes, abbreviations, and other changes have been applied 
throughout.


JNJ-54767414  (daratumumab)
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Amendment 3 (21 January 2020)
The overall reason for the amendment: The overall reason for the amendment is to define the end of the data 
collection period and to clarify access to drug treatment after data collection in the study eCRF has ended. Updates 
to the Anticipated Events sections and minor adjustments to study assessments in the Follow-Up Phase are also 
included.
Applicable Section(s)
Description of Change(s)
Rationale: To allow subjects benefitting from treatment to continue receiving treatment, the end of the study has 
been revised. A data collection period has been defined, after which only limited data collection will occur, as 
described in new Attachment 13.
Table 1 Time and Events
Schedule -Overview; Table 2 
Time and Events Schedule -
Pharmacokinetic/ 
Immunogenicity Sample 
Collection Times
The following note was added to the front of each Time and Events table: 
Refer to Attachment 13 for a description of study procedures for subjects 
who continue to receive study drug provided by the sponsor after the data 
collection period has ended.
3.1 Overview of Study Design 
The study is considered completed approximately 18 months after the last 
subject is randomized. The data collection period will end and the clinical 
database will be closed approximately 24 months after the last subject was 
randomized or when median overall survival for both arms has been 
reached, whichever occurs first.
9.1.4 Follow-Up Phase
Clarification was added that follow-up will continue until the end of the data 
collection period, which has been defined.
17.9.1 End of Data Collection/ 
End of Study (old)
The section heading has been revised: End of Data Collection/Study 
Completion/End of Study.
The end of the data collection period will be approximately 24 months 
after the last subject was randomized or when median overall survival for 
both arms has been reached, whichever occurs first.
The end of the study has been redefined: The study is considered completed 
approximately 18 months after the last subject is randomized or when the 
sponsor decides to stop the study The study will be considered complete 
when all subjects still receiving study drug have commercial or alternative 
access to the appropriate formulation of daratumumab, have stopped 
receiving daratumumab treatment, or at approximately 5 years after the 
last subject was randomized, whichever occurs first.
Attachment 13
Added Attachment 13 summarizing procedures, data collection, and data 
reporting methods to be followed after clinical cutoff for the final study 
analysis (end of the data collection period) has been reached.
9.1.1 Overview; 9.1.5 Post Data 
Collection Period to End of 
Study; 9.2.1 Response Categories; 
9.7 Safety Evaluations (Adverse 
Events, HBV DNA Tests); 9.8 
Sample Collection and Handling; 
17.5 Case Report Form 
Completion; 17.9.1 End of Data 
Collection/Study Completion
Cross-reference was added to Attachment 13 for detail on the scope of study 
procedures required after the end of the data collection period.
Rationale: Daratumumab will be provided by the sponsor to allow continued treatment for subjects benefitting from 
either the IV or SC formulation.


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Applicable Section(s)
Description of Change(s)
3.1 Overview of Study Design; 
9.1.5 Post Data Collection Period 
to End of Study; 17.9.1 End of 
Data Collection/ Study 
Completion
Detail was added regarding the sponsor’s commitment to provide 
daratumumab to responding subjects. The sponsor will ensure that the IV or 
SC formulation of daratumumab is available so that subjects still on treatment
may receive the appropriate daratumumab treatment after the end of the data 
collection period. Daratumumab will be provided until the applicable 
formulation is commercially available or becomes available from another 
source, or until the study is complete.
9.1.4 Follow-up Phase; 9.1.5 Post 
Data Collection Period to End of 
Study
Section 9.1.5 was added to describe continuation of study treatment and 
procedures to be followed after the end of the data collection period. Relevant 
text previously included in Section 9.1.4 was moved to Section 9.1.5.
Rationale: The clinical database will be closed at the end of the newly defined data collection period, and the final 
study analysis will be performed. 
3.1 Overview of Study Design; 
17.9.1 End of Data Collection/ 
Study Completion
Clarification was added that the clinical database will be closed once the data 
collection period has ended and no additional data will be collected in the 
eCRF. The final study analysis will include data collected during the data 
collection period.
9.1.4 Follow-up Phase
New text added: Continuation of Follow-up Phase study procedures is not 
required once the end of the data collection period is reached, and the End 
of Trial page of the eCRF should be completed at that time for subjects 
ongoing in the Follow-up Phase.
Rationale: Once the data collection period has ended, subsequent safety reporting will be limited to serious adverse 
events and pregnancy, which will occur only through the sponsor’s global medical safety database.
12.3.1 All Adverse Events
The following text was deleted: The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
12.3.2 Serious Adverse Events
New text added: Refer to Attachment 13 for details on serious adverse 
event reporting after the end of the data collection period.
12.3.4 Pregnancy
New text added: Pregnancy reporting will continue as described above 
after the end of the data collection period. 
Rationale: A data collection period has been defined that is distinct from the end of the study.
3.1 Overview of Study Design
The Follow up Phase begins immediately following the End-of-Treatment 
Visit, and will continue until death, loss to follow up, withdrawal of consent 
for study participation, or end of the study data collection period, whichever 
occurs first.
8 Prestudy and Concomitant 
Therapy
Clarification was added that collection of concomitant therapy information is 
only required during the data collection period. 
9.1.4 Follow-Up Phase
Information on all new second primary malignancies will also be collected 
until the end of the study data collection period.
9.2.1 Response Categories
For subjects who discontinue study treatment before disease progression, 
disease evaluations should continue to be performed as described in the Time 
and Events Schedule, until confirmed disease progression, death, start of a new 
treatment for multiple myeloma, withdrawal of consent for study participation, 
or the end of the study data collection period.
9.5 Patient-reported Outcomes
The schedule for completion of the modified-CTSQ will be completed per is 
outlined in the Time and Events Schedule until the end of the data collection 
period.


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Description of Change(s)
9.7 Safety Evaluations (Adverse 
Events)
Adverse events will be reported by the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject's legally acceptable representative) from the 
time a signed and dated informed consent is obtained until at least 30 days 
after the last dose of study treatment during the data collection period, unless 
the subject withdraws consent for study participation or starts subsequent 
anticancer therapy… After the data collection period has ended, only 
serious adverse events will be collected, as described in Attachment 13.
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 final dose of study drug during the data collection period.
Rationale: The text for hepatitis B serology testing for any subject with unknown hepatitis B serology and 
monitoring and managing of hepatitis B virus (HBV) reactivation was added for consistency across daratumumab 
protocols.
Table 1: Time and Events 
Schedule - Overview
Identified that the HBV DNA test will be performed during survival 
assessment in the Follow-up Phase.
Also identified in newly added footnote ‘b’ that the HBV DNA test will be 
performed only for subjects with serologic evidence of resolved HBV 
infection; will be performed locally, every 4 weeks during treatment, end of 
treatment visit, and every 4 weeks for up to 6 months after the last dose of 
study treatment.
8.1.6 Management of Hepatitis B 
Virus Reactivation
Added a new section for information on the management of HBV reactivation.
9.7 Safety Evaluations (HBV 
DNA Tests)
Removed the reference (no. 7) to the Japan society of hepatology guidelines 
for the management of HBV infection. Additional guidance provided for 
subjects with serologic findings suggestive of prior HBV vaccination and 
known history of prior HBV vaccination.
References
Deleted reference no. 7 and renumbered subsequent references.
Rationale: To eliminate the possibility of inconsistency between the NCI-CTCAE version number being referenced 
in the protocol and the standard grade descriptions included in the protocol.
12.1.3. Severity Criteria
Removed definitions of severity criteria as they are specified in the NCI-
CTCAE Version 4.03.
Rationale: Modified the list of anticipated events to remove any events that are known adverse drug reactions of 
daratumumab. Clarification that after unblinding of aggregate safety data by the sponsor’s study team, there is no 
need for independent SAC review of anticipated events. Additional clarification of the reporting responsibilities for 
anticipated events to Health Authorities and IRBs/IECs. Changed name of committee to be in alignment with 
company procedures.
Attachment 12 Anticipated Events
Anemia, neutropenia, and thrombocytopenia were deleted from the anticipated 
events list.
The review and reporting requirements for anticipated events were clarified.
Revised “Anticipated Event Review Committee” (ARC) to “Safety 
Assessment Committee” (SAC).
Rationale: Medical resource utilization data collected during the Follow-up Phase will not be analyzed.
Table 1: Time and Events 
Schedule - Overview
Medical resource utilization information will not be collected during the 
Follow-up Phase.
Rationale: To clarify when IDMC review was performed.


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Applicable Section(s)
Description of Change(s)
3.1 Overview of Study Design
The following text was added: The IDMC will no longer review study data 
after primary analysis has been completed.
Rationale: To clarify how study data collected through the end of the data collection period will be reported. 
3.1 Overview of Study Design
Data collected through the end of the study data collection period will be 
included in the final study analysis and reported in a separate an addendum 
to the Clinical Study Report.
Rationale: To reiterate the sponsor’s option to end the study at any time. 
3.1 Overview of Study Design
The following text was added: The sponsor may decide to end the study at 
any time, as described in Section 17.9.2.
Rationale: Text not relevant to study design.
10 Subject Discontinuation of 
Study Treatment/ Withdrawal 
From the Study
The heading for Section 10 was changed as follows: SUBJECT 
COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ 
WITHDRAWAL FROM THE STUDY
10.1 Completion
Section 10.1 was deleted. Subsequent sections were renumbered.
Rationale: For consistency across daratumumab protocols.
6.2.1 Subcutaneous Dosing
Text was revised: Doses will be administered by manual push over 
approximately 3-5 minutes in the abdominal SC tissue…
6.5 Dose Delays and Modification
•
Grade 3 or higher thrombocytopenia with bleeding
The following text was added to the last paragraph of the section: Infusion-
related reactions may occur upon re-initiation of daratumumab after a 
prolonged delay in treatment. Investigators should consider the applicable 
infusion reaction guidance provided in Section 6.4.2 when restarting 
treatment after a long delay.
Rationale: To allow flexibility for some study procedures.
6.3.1 Predose Medications
Text was revised: In an effort to prevent IRRs, all subjects will start the 
following medications approximately 1 to 3 hours prior to each study drug 
administration…
Rationale: Minor errors were noted
Table 1: Time and Events 
Schedule - Overview
For the assessment: Subsequent therapy, survival, secondary second primary
malignancy information
Abbreviations
The abbreviations list has been updated.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 2 (13 August 2018)
The overall reason for the amendment: In order to meet a health authority commitment, an update to the
regulatory strategy, including an update to the statistical plan, is being implemented to allow Japan to enroll beyond 
the initially planned 480 subjects. Clarifications have also been made to ensure accuracy and clarity throughout the 
protocol.


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Applicable Section(s)
Description of Change(s)
Rationale: The data cutoff and primary analysis strategy has been updated to allow Japan to enroll beyond the 
initially planned 480 subjects.
3.1 Overview of Study Design 
The data cutoff for the primary analysis will occur approximately 6 months 
after the last subject has 480 subjects have been randomized.
11.3 Co-primary Endpoints
The primary analysis will occur approximately 6 months after the last subject 
has 480 subjects have been randomized.
Rationale: The Time and Events Schedules have been updated for flexibility (Table 1) and clarity (Table 2)
regarding assessment timing and sample collections, respectively. 
Table 1, Time and Events 
Schedule - Overview
Study day windows have been added to the Follow-up phase assessments. 
Table 2, Time and Events 
Schedule 
Pharmacokinetic/Immunogenicity 
Sample Collection Times -
Footnote d has been added to the Follow-up phase assessments to clarify that 
PK/immunogenicity samples should be collected even if subsequent therapy 
has been initiated.
Rationale: Further information added to ensure clarity in the protocol study design and conduct requirements.
6.4.2 Infusion-related Reactions
Clarified language in the Infusion-Related Reactions of Grade 3 or Higher 
subsection to specify requirements for restarting the infusion after an IRR is 
reported, as follows “Once reaction symptoms resolve, if continuing 
treatment is deemed appropriate by the investigator, consider restarting the 
infusion at no more than half the rate at which the reaction occurred.”
6.5 Dose Delays and 
Modification; 
Clarified that dose modification is not permitted: “Dose modification of 16 
mg/kg Dara-IV or 1800 mg Dara-SC (increase or decrease) is not permitted.”
Clarification has been made for when there is a dose delay: “Grade 3 pain 
associated with symptoms of multiple myeloma (bone/joint pain)” has been 
added as an exception to the criterion to hold study treatment. 
9.1.4 Follow-Up Phase
Clarification made that “Beyond the 30-days End of Treatment Visit after the 
last dose, serious adverse events considered related to study treatment will 
continue to be collected.”
9.2.2 Myeloma Protein 
Measurements in Serum and 
Urine
Text has been revised regarding the conditions for when UPEP assessments can 
stop after C1D1.
9.7 Safety Evaluations
Subjects who are positive for antiHBc or antiHBs will undergo testing for 
hepatitis B DNA by PCR every 4 weeks (each cycle). Subjects who are 
positive for antiHBs antibodies due to prior immunization are not required 
to be monitored by HBV DNA by PCR. During and following study 
treatment, subjects who have history of HBV infection will be closely 
monitored for clinical and laboratory signs of reactivation of HBV according to 
the JSH Guidelines for Prevention of HBV reactivation in patients receiving 
Immunosuppressive Therapy or Chemotherapy (JSH Guidelines for the 
Management of Hepatitis B Virus Infection7). Where required by local law, 
the result of HBV testing may be reported to the local health authorities.
Attachment 4: Modified Diet in 
Renal Disease Formula
An error in the modified diet in renal disease formula calculation has been 
corrected.
Rationale: Updated Attachment 10 to include SEBIA Hydrashift 2/4 Daratumumab IFE Interference assay.


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Applicable Section(s)
Description of Change(s)
Updated Attachment 10: 
Interpretation of the SEBIA 
Hydrashift 2/4 Daratumumab IFE
Interference Assay
Text updated to delete reference to the DIRA assay and include the three 
outcomes of the SEBIA Hydrashift 2/4 Daratumumab IFE Interference assay.
Rationale: Minor changes made to the protocol.
4.3 Prohibitions and Restrictions;
8.3 Prohibited Therapies
The following text related to IV contrast being used in CT in subjects with 
multiple myeloma has been deleted from the protocol. 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.
4.2 Exclusion Criteria, Criterion 
#5.2; 
4.2 Exclusion Criteria, Criterion 
#8.2;
6.2.2 Intravenous Administration, 
Table 4; 
6.3.1 Predose medications; 
6.3.2 Postdose medications; 
Minor editorial and grammatical changes made to the text of the protocol for 
clarifications.
Amendment 1 (7 December 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: The overall reason for the amendment is to address feedback from 
regulatory health authorities including updating inclusion criteria for measurable disease and HBV status, to provide 
additional instruction in the event of infusion-related reactions, and to clarify methodology of local bone marrow 
testing.
Applicable Section(s)
Description of Change(s)
Rationale: Clarification that chest x-rays obtained as part of the skeletal survey can be accepted as the screening 
chest X-ray.
Time and Event Schedule, Table 
1, Chest X-ray
Text added that chest x-rays are acceptable if performed as part of standard of 
care within 28 days before randomization or if performed as part of the skeletal 
survey
Rationale: To provide operational flexibility for study sites, ECOG assessment no longer specified to be done prior 
to other assessments.
Time and Event Schedule, Table 
1, ECOG performance status; 9.7. 
Safety Evaluations, Physical 
Examination and ECOG 
Performance Status
Text outlining that ECOG performance status be obtained prior to other study 
activities on scheduled days removed.
Rationale: To align with regional guidelines for management of HBV infection, safety follow-up timepoints added 
for subjects who are positive for antiHBc or antiHBs.


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Applicable Section(s)
Description of Change(s)
Time and Event Schedule, Table 
1, HBV DNA test
Timepoints for HBV DNA tests for subjects who are positive for antiHBc or 
anti-HBs added at Screening, Cycle 1 Day 1, at Day 1 of each subsequent 
cycle, and at EOT.
Rationale: To investigate biomarkers response and resistance to daratumumab, additional longitudinal blood 
collections were added. Additional text included to clarify biomarker activities.
Time and Event Schedule, Table 
1, Whole blood (biomarker)
Sample collections for biomarkers added on Cycle 6 Day 1 and Cycle 13 Day 
1.
3.2. Study Design Rationale
Added text to clarify that biomarkers samples will be used to evaluate 
pharmacodynamic biomarkers and to evaluate the role of the 
immunomodulatory mechanism of action of daratumumab in response and 
development of resistance.
9.4. Biomarkers
Added text to clarify that biomarkers samples will be used to evaluate 
pharmacodynamic biomarkers and to evaluate the role of the 
immunomodulatory mechanism of action of daratumumab in response and 
development of resistance. Text added that testing may include the evaluation 
of specific subsets of immune cells. 
Rationale: Correction of methodology for bone marrow testing
Time and Event Schedule, Table 
1, Bone marrow aspirate/biopsy; 
Added text to table to indicate that FISH was the preferred method of testing 
and to clarify that if a fresh aspirate bone marrow sample was obtained, a 
portion was to be sent to the central lab for biomarker evaluation; DNA/RNA 
sequencing replaced with biomarker evaluation. A typographical error “and 
phenotyping” was corrected to read “or karyotyping”.
9.2.5. Bone Marrow 
Examination, Table 7
Text “Cytogenetics by FISH (preferred) or karyotyping” added under Local 
Testing. Text under Central Testing revised to indicate that if a fresh bone 
marrow aspirate is collected at Screening, a portion will be sent to a central 
laboratory for biomarker evaluation; DNA/RNA sequencing replaced with 
biomarker evaluation.
Rationale: To provide operational flexibility for study sites, MRI added as an option for skeletal survey.
Time and Event Schedule, Table 
1, Skeletal survey
Added text that x-ray or MRI may be used as alternatives for skeletal surveys if 
applicable in local practice. 
Rationale: Corrections and clarifications for PK sample collection.
Time and Event Schedule, Table 
2
PK sample collection windows on dosing days changed from ±1 day or ±3 days 
(depending on cycle) to ±0 days. Footnote “a” modified to indicate that samples 
collected on dosing days must be collected on the day of study drug 
administration. Text indicating collection of samples ±4 hours of the time of 
study drug administration on non-dosing days deleted.
Samples obtained at non-dosing days Cycle 1 Day 4, Cycle 3 Day 4, Follow-up 
post-treatment Week 4 and Follow-up post-treatment Week 8 moved to “After 
dose” line in table for clarity.
New footnote “c” added that end of dose samples (Dara-IV) should be collected 
after the end of infusion (up to 2 hours after the end of infusion).
Rationale: Inclusion criterion for measurable disease revised to align with current IMWG criteria


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Applicable Section(s)
Description of Change(s)
4.1. Inclusion Criteria 2
Text revised to define documented multiple myeloma as serum M-protein level 
≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours. Text defining 
measurable disease for IgA, IgD, IgE, and IgM multiple myeloma as serum M-
protein level ≥0.5 g/dL or urine M-protein level ≥200 mg/24 hours deleted.
Rationale: Exclusion criteria revised to align with ASCO recommendations
4.2. Exclusion Criteria 5
Revised exclusion text to history of malignancy (other than multiple myeloma) 
if all treatment of that malignancy was completed at least 2 years before 
consent and the patient has no evidence of disease (exceptions are squamous 
and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or 
breast, or other non-invasive lesion, that in the opinion of the investigator, with 
concurrence with the sponsor's medical monitor, is considered cured with 
minimal risk of recurrence within 3 years.)
Rationale: Exclusion criteria and safety follow-up for HBV revised to align with regional guidelines for 
management of HBV infection.
4.2. Exclusion Criteria 8b
Revised exclusion text to define hepatitis B as hepatitis B surface antigen 
[HBsAg] positive, or antibodies to hepatitis B surface or core antigens [antiHBs 
or antiHBc] with hepatitis B virus [HBV]-DNA quantitation positive). In 
addition, subjects who are positive for antiHBs or antiHBc must have a 
negative polymerase chain reaction (PCR) for HBV-DNA quantitation result at 
screening, PCR positive subjects are to be excluded.
9.7. Safety evaluations
Added a new section for safety follow-up for subjects who are positive for 
antiHBc or anti-HBs. During the study, subjects who are positive for antiHBc 
or antiHBs will undergo testing for hepatitis B DNA by PCR every 4 weeks 
(cycle). During and following study treatment, subjects who have history of 
HBV infection will be closely monitored for clinical and laboratory signs of 
reactivation of HBV. Added reference: JSH Guidelines for the Management of 
Hepatitis B Virus Infection 2014.
Rationale: Clarification to ensure study site alignment with IPPI in the event of drug administration interruption due 
to an adverse event related to the study drug. 
6.4.2. Infusion-related Reactions
Added text that the investigator/study coordinator should review the 
information of the dispensed study drug on the Investigational Product 
Preparation Form and ensure the correct drug product is being used before 
restarting the administration.
Rationale: Clarification of Day 1 dosing schedule delays and subsequent drug administration.
6.5 Dose Delays and 
Modification
Added text that the delay of Day 1 drug dosing in any given cycle should not 
result in a skipped dose but should lead to a delay of the entire cycle instead. A 
minimum of 4 days between daratumumab doses must be observed.
Rationale: Clarification of herpes zoster prophylaxis recommendations.
8.1.4. Prophylaxis for Herpes 
Zoster Reactivation
Text revised that antiviral prophylaxis within 1 week after starting study 
treatment and continuing for 3 months following study treatment is 
recommended
Rationale: Modification of disease evaluable intervals from ±3 days to ±7 days to align with other daratumumab 
studies.
9.1.1 Overview; 9.2.1. Response 
Categories
Text revised that disease evaluations must be performed every 28 days 
(±7days).
Rationale: Update of estimated blood volumes to be collected to align with current Covance laboratory manual and 
additional biomarker samples.


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Applicable Section(s)
Description of Change(s)
9.1.1 Overview; 16.1. 
Study-Specific Design 
Considerations
Text updated to indicate the maximum blood volume for a subject who 
completes 8 cycles and the post-treatment assessments is approximately 490
mL. The total blood volume to be collected is estimated at approximately 34 
mL for Screening, 100 mL for Cycles 1 and 2, 161 mL for Cycles 3-6, 21 mL at 
each subsequent cycle… 
Rationale: Clarification of study success as requested by Health Authority.
11.3. Co-primary endpoints
Text revised that once the null non-inferiority hypothesis is rejected for both 
the ORR and maximum Ctrough, non-inferiority of Dara-SC to Dara-IV will be 
established….
Rationale: Based on oncology studies, overall survival substituted for time to next treatment in the evaluation of 
secondary endpoints.  
11.3. Co-primary endpoints
Text updated to indicate that hierarchical procedure for superiority testing will 
be implemented to control familywise Type I error rate at a two-sided 
significance level of 0.05 for secondary endpoints including incidence of IRR, 
PFS, rate of VGPR or better, and overall survival. Time to next therapy (TNT) 
deleted.
Rationale: Clarification of adverse event reporting to align with variations based on individual country health 
authority requirements.
12.3.1. All Adverse Events
Text added that while some countries require reporting of all adverse events to 
the health authorities, others will not identify anticipated events for the health 
authorities.
Rationale: Clarification of exceptions to expedited reporting to align with Health Authority request.
12.3.3. Disease-Related Events or 
Outcomes Not Qualifying as 
Adverse Events
Text added that known consequences of the underlying disease and events 
common in the study population independent of drug therapy are considered 
adverse events. Text revised that drug-related adverse events will be recorded 
and reported (if appropriate) as per current legislation to Health Authorities and 
ECs. Disease-related or adverse events not related to the study drug will be 
exempt from expedited reporting.
Previous text noting that events that are part of the natural course of the disease 
under study should not be recorded as an adverse event or serious adverse event 
and that clinical sequelae resulting from disease progression is to be reported if 
the serious event definition is fulfilled deleted. 
Rationale: Text with exception to mandatory termination of pregnant subjects from the study provided to align with 
current daratumumab considerations.
12.3.4. Pregnancy
Added text that pregnant subjects can continue the study if the subject (or the 
subject's legally acceptable representative), investigator, and sponsor agree the 
benefits outweigh the risks to the fetus and continuation of study treatment is in 
the best interests of the subject.
Rationale: Modification of template text to align with recent protocol template changes.
10.3. Withdrawal from Study 
Revised the text related to subjects withdrawing from the study.
12.3.1. All Adverse Events
Added text related to sponsor's responsibility for reporting anticipated events
and SUSARs.
17.3. Subject Identification. 
Enrollment, and Screening Logs
Added ‘(as allowed by local regulations)’ following 2 instances of ‘date of 
birth’.


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Applicable Section(s)
Description of Change(s)
17.11 Use of Information and 
Publications
Changed the time for submitting study results for publication from ‘within 
12 months of the availability of the final data (tables, listings, graphs)’ to 
‘within 18 months after study end date’.
Revised the text beginning ‘Authorship of publications...’
Previous text related to uniform requirements for manuscripts submitted to 
Biomedical journals deleted.
Rationale: Removal of non-applicable text.
Attachment 10
Text identifying subjects assigned to the daratumumab, lenalidomide, and 
dexamethasone group deleted.
Rationale: Attachment update
Attachment 11
PRO attachment replaced with current version.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.


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SYNOPSIS
A Phase 3 Randomized, Multicenter Study of Subcutaneous vs. Intravenous Administration of 
Daratumumab in Subjects With Relapsed or Refractory Multiple Myeloma 
EudraCT NUMBER: 2017-000206-38
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a 
transmembrane glycoprotein, in a variety of hematological malignancies including multiple myeloma.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objectives

To show that subcutaneous (SC) administration of daratumumab co-formulated with recombinant 
human hyaluronidase PH20 (Dara-SC) is non-inferior to intravenous (IV) administration of 
daratumumab (Dara-IV) in terms of the overall response rate (ORR)

To show that Dara-SC is non-inferior to Dara-IV in terms of the maximum trough concentration 
(Ctrough)
Secondary Objectives

To assess the pharmacokinetics and immunogenicity of Dara-SC and Dara-IV

To evaluate the safety of Dara-SC and Dara-IV

To evaluate the clinical benefit of Dara-SC and Dara-IV

To evaluate the immunogenicity of recombinant human hyaluronidase (rHuPH20) following Dara-
SC administration

To evaluate patient-reported satisfaction with Dara-SC and Dara-IV
Endpoints
Primary Endpoints
The co-primary endpoints of this study are:

ORR

Maximum Ctrough (Cycle 3 Day 1 predose)
Secondary Endpoints

Rate of infusion-related reactions (IRRs)

Progression-free survival (PFS)

Rate of very good partial response (VGPR) or better

Rate of complete response (CR) or better

Time to next therapy (TNT)

Overall survival (OS)


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
Patient-reported satisfaction with therapy

Duration of response

Time to response
Hypothesis
The ORR and maximum Ctrough (defined as the serum predose concentration on Cycle 3 Day 1) for 
Dara-SC 1800 mg are not inferior to the ORR and maximum Ctrough, respectively, for Dara-IV 16 mg/kg 
in subjects with multiple myeloma who have received at least 3 prior lines of therapy including a 
proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or whose disease is refractory to both a 
PI and an IMiD.
OVERVIEW OF STUDY DESIGN
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to demonstrate that the 
efficacy and pharmacokinetics of Dara-SC are not inferior to those of Dara-IV. The study population 
consists of adults diagnosed with multiple myeloma who have received at least 3 prior lines of therapy 
including a PI and an IMiD, or whose disease is refractory to both a PI and an IMiD. Approximately 
480 subjects will be assigned randomly to the Dara-SC group or the Dara-IV group in a 1:1 ratio. The 
randomization will be stratified by body weight at baseline (65 kg, 66 kg to 85 kg, >85 kg), number of 
prior lines of therapy (4 prior lines versus >4 prior lines), and type of myeloma (IgG versus non-IgG).
As of Protocol Amendment 4 and in response to the coronavirus (COVID-19) pandemic in 2020, subjects 
currently receiving Dara-IV treatment may switch to Dara-SC at the discretion of the investigator.
SUBJECT POPULATION
Key eligibility criteria include the following: 18 years of age; a multiple myeloma diagnosis according 
to the International Myeloma Working Group (IMWG) diagnostic criteria; achieved a response (partial 
response [PR] or better based on investigator’s determination of response by IMWG criteria) to at least 1 
prior treatment regimen; evidence of relapsed or refractory disease on the most recent prior treatment; 
have received at least 3 prior lines of therapy including a PI and an IMiD, or disease that is refractory to 
both a PI and an IMiD; and an Eastern Cooperative Oncology Group (ECOG) Performance Status score 
of 0, 1, or 2.
DOSAGE AND ADMINISTRATION
Each treatment cycle is 28 days. Study drug will be administered once weekly in Cycles 1 and 2, every 
2 weeks in Cycles 3 to 6, and every 4 weeks thereafter. All doses will be administered at outpatient visits.
In the Dara-SC group, a fixed dose of Dara-SC 1800 mg will be administered by SC injection. In the 
Dara-IV group, a weight-based dose of Dara-IV 16 mg/kg will be administered by IV infusion. As of 
Amendment 4 and in response to the coronavirus (COVID-19) pandemic in 2020, subjects who currently
receive Dara-IV treatment may switch to Dara-SC at the discretion of the investigator.
EFFICACY EVALUATIONS
Assessment of disease will be conducted in accordance with the IMWG response criteria. Disease 
evaluations will include the following: measurements of myeloma proteins, bone marrow examinations, 
skeletal surveys and other imaging studies, and serum calcium corrected for albumin.
OTHER EVALUATIONS
Blood samples will be drawn from all subjects to characterize the pharmacokinetics of daratumumab and 
to assess for the generation of antibodies to daratumumab. In the Dara-SC group (excluding those subjects 
who may switch from Dara-IV to Dara-SC), additional blood samples will be assessed for the generation 
of antibodies to rHuPH20. Blood and bone marrow aspirate samples will be used to better understand the 


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mechanism of action of daratumumab and to obtain information about potential markers of clinical 
response and resistance.
SAFETY EVALUATIONS
Safety evaluations include adverse event monitoring, physical examinations, electrocardiograms (ECGs), 
SC injection site evaluations, clinical laboratory parameters (hematology and chemistry), vital sign 
measurements, and ECOG performance status.
STATISTICAL METHODS
In a previous clinical study (MMY2002), of 106 subjects with relapsed or refractory multiple myeloma 
who had received at least 3 prior therapies and who were treated with Dara-IV 16 mg/kg, an ORR of 
29.2% (95% CI: 20.8%, 38.9%) was observed. Non-inferiority of Dara-SC to Dara-IV in the current study 
is defined using a 60% retention of the lower bound (20.8%) of the 95% CI from Study MMY2002. With 
a planned 1:1 randomization, 480 subjects (n=240 in the Dara-SC group and n=240 in the Dara-IV group) 
will be needed to demonstrate non-inferiority with a power of 80% and a one-sided alpha=0.025, 
assuming that the true ORR is the same for both groups.
The study is also designed to establish non-inferiority of maximum Ctrough between Dara-SC and Dara-IV. 
Dara-SC will be considered non-inferior to Dara-IV if the lower bound of the 90% confidence interval for 
the ratio of the geometric means of Ctrough on Cycle 3 Day 1 is at least 80% (non-inferiority margin of 
20%). A one-sided test is selected based on previous analyses that demonstrated a strong relationship 
between maximum Ctrough and efficacy. However, there is no apparent relationship between drug exposure 
in the therapeutic dose range and adverse events of interest. With the planned 1:1 randomization, 
480 subjects, and a one-sided alpha of 0.05, the power will be >95%. This assumes a true ratio of the 
maximum Ctrough of 1 and a coefficient of variation of 0.6.


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TIME AND EVENTS SCHEDULES
Table 1:
Time and Events Schedule – Overview
Note: Refer to Attachment 13 for a description of study procedures for subjects who continue to receive study drug provided by the sponsor
after the data collection period has ended.
Study Visits
Screening Phase
Treatment Phase (1 Cycle = 28 days)
Follow-up Phase
Cycles 1 & 2
Cycles 3-6
Cycles 7+
EOT
FUPa
Survivala
Study Day
Notes
-28 to -1
D1
D8
D15
D22
D1
D15
D1c
Post-
Treatment
Week 4
+7 days
Post-
Treatment
Week 8
±7 days
q16wks
After PD
±14 days
The start of Cycles 2 and 3 may occur ±1 day of the scheduled day. The start of each subsequent cycle may occur ±3 days of the scheduled day. Day 1 of subsequent cycles should be adjusted accordingly 
to maintain the 28-day cycle duration. Unless otherwise stated, all blood and urine samples must be obtained before administration of study drug (Dara-SC or Dara-IV). Blood samples must not be taken from 
the same arm as IV drug administration, if applicable.
Informed consent
Subjects must sign the informed consent form before any study-specific procedures are performed
Eligibility criteria, 
demography, height, 
medical history
X
Forced expiratory 
volume test
Subjects with known or suspected COPD
X
Chest x-ray
Acceptable if performed as part of 
standard of care within 28 days before 
randomization or if performed as part of 
the skeletal survey
X
Physical examination
X
Symptom-directed physical examination only
Weight
Prior to drug administration
X
X
X
Pulse, temperature, 
and blood pressure
After ~5 minutes of rest
X
C1D1 - For Dara-SC: immediately before administration; at end 
of administration; and at 0.5 and 1 hour after end of 
administration. For Dara-IV: immediately before administration; 
at 0.5, 1, 1.5, 2, and 3.5 hours after the start of administration; 
at end of administration; and at 0.5 and 1 hour after end of 
administration.
All other doses - immediately before administration and at the 
end of administration.
X
ECOG performance 
status 
X
X
X
X
X
Electrocardiogram
(ECG)
After ~5 minutes of rest,
prior to any blood draw
X
As clinically indicated
X


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Study Visits
Screening Phase
Treatment Phase (1 Cycle = 28 days)
Follow-up Phase
Cycles 1 & 2
Cycles 3-6
Cycles 7+
EOT
FUPa
Survivala
Study Day
Notes
-28 to -1
D1
D8
D15
D22
D1
D15
D1c
Post-
Treatment
Week 4
+7 days
Post-
Treatment
Week 8
±7 days
q16wks
After PD
±14 days
Medication Administration
Study drug (Dara-SC or 
Dara-IV)
X
X
X
X
X
X
X
Predose and postdose 
medications
X
X
X
X
X
X
X
Laboratory Assessments
Blood group and type 
assessment and 
indirect antiglobulin test 
(IAT) results
Obtained before start of dose; includes 
ABO, Rh, and indirect antiglobulin test 
results. Results placed on subject 
identification wallet card
X
Urine or serum 
pregnancy test 
Women of childbearing potential only
Study day
-14 to -1
As clinically indicated
Chemistry
May be performed up to 3 days before 
study drug administration day. Results 
must be evaluated before each study drug 
administration. At Cycle 1 Day 1, tests do 
not need to be repeated if they were 
performed within the previous 5 days.
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
HBV DNA test
Only for subjects who are positive for anti-
HBc or anti-HBs
X
X
X
X
X
Xb
Whole blood
(biomarker)
Predose collection for immunophenotyping
C1
C4
Whole blood 
(biomarker)
Predose plasma and PBMC collection
C1
C4
and 
C6 
C13
X
Pharmacokinetics and Immunogenicity Blood Samples
Pharmacokinetics, 
immunogenicity
Pharmacokinetics of daratumumab; 
immunogenicity of daratumumab and 
rHuPH20
See Table 2
Disease Evaluations (Blood/Urine) Samples must be sent to the central laboratory.
Serum 2-microglobulin
SPEP and UPEP are to be performed 
within 14 days before Cycle 1 Day 1.
See Section 9.2.2 for details.
X
QIg (IgA, IgM, IgG, IgD, 
IgE)
X
Every 3 months (±1 month) during treatment
X
SPEP
X
X
X
X
X
Xa
UPEP (24-hr urine 
sample)
X
X
X
X
X
Xa


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Study Visits
Screening Phase
Treatment Phase (1 Cycle = 28 days)
Follow-up Phase
Cycles 1 & 2
Cycles 3-6
Cycles 7+
EOT
FUPa
Survivala
Study Day
Notes
-28 to -1
D1
D8
D15
D22
D1
D15
D1c
Post-
Treatment
Week 4
+7 days
Post-
Treatment
Week 8
±7 days
q16wks
After PD
±14 days
Serum calcium 
corrected for albumin
X
X
X
X
X
Serum FLC & 
serum/urine 
immunofixation
X
Serum FLC and serum/urine immunofixation are to be performed for any subject when CR is suspected or 
maintained; for light chain MM subjects, serum FLC will also be performed on Day 1 of every cycle, at end 
of treatment and at follow-up until PD.
Disease Evaluations (Other)
Bone marrow 
aspirate/biopsy
Disease characterization (morphology and 
either immunohistochemistry, 
immunofluorescence, or flow cytometry), 
FISH (preferred), or karyotyping. 
Performed locally.
Up to 42 days before 
randomization; if a 
fresh aspirate, send 
portion to central lab 
for biomarker 
evaluation
To confirm CR (including sCR) and if feasible, at the time of disease 
progression. A portion of aspirate collected at PD will be sent to a central lab 
for evaluation of biomarkers of resistance to daratumumab.
Skeletal survey
Low-dose whole body CT is preferred. 
Depending on local practice, a skeletal 
survey by x-ray or MRI may be used as an 
alternative.
Up to 42 days before 
randomization
As clinically indicated and per the local standard of care for imaging (X-ray, 
CT, or MRI). The same methodology used at Screening should be used 
throughout the study for comparison purposes.
Extramedullary 
plasmacytomas
For subjects with a history of 
extramedullary plasmacytomas, lesions 
should be assessed by PET-CT or MRI.
Up to 42 days before 
randomization
To confirm MR, PR, VGPR, CR, or sCR; as well as at suspected PD and as 
clinically indicated per the local standard of care
Modified-CTSQ
To be completed prior to any other study 
procedures at that visit.
C2
X
X
X
X
X
X
Medical resource 
utilization
See Section 9.6 for details
X
X
X
X
X
X
X
Ongoing Subject Review
Adverse event 
monitoring
See Section 12 for details.
Continuous from time of ICF signature until 30 days after last study drug 
dose
Treatment-related 
serious adverse events
Concomitant 
medication recording
See Section 8 for details.
Continuous from time of ICF signature until 30 days after last study drug 
dose
Subsequent therapy, 
survival, second
primary malignancy 
information
Continuous from first dose of study drug until end of study


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Study Visits
Screening Phase
Treatment Phase (1 Cycle = 28 days)
Follow-up Phase
Cycles 1 & 2
Cycles 3-6
Cycles 7+
EOT
FUPa
Survivala
Study Day
Notes
-28 to -1
D1
D8
D15
D22
D1
D15
D1c
Post-
Treatment
Week 4
+7 days
Post-
Treatment
Week 8
±7 days
q16wks
After PD
±14 days
Abbreviations: Anti-HBc=antibodies to hepatitis B core antigen; Anti-HBs=antibodies to hepatitis B surface antigen; C=Cycle; COPD=chronic obstructive pulmonary disease; CR=complete response; 
CT=computed tomography; d/D=day(s); Dara-SC=daratumumab and recombinant human hyaluronidase for subcutaneous injection; Dara-IV=daratumumab for intravenous formulation; ECOG=Eastern 
Cooperative Oncology Group; EOT=End of Treatment; FISH=fluorescence in situ hybridization; FLC=free light chain; FUP=Follow-up Phase; HBV=hepatitis B virus; ICF=informed consent form; 
IV=intravenous; QIg=quantitative immunoglobulin; MM=multiple myeloma; modified-CTSQ=modified Cancer Therapy Satisfaction Questionnaire; MR=minimal response; MRI=magnetic resonance imaging; 
PBMC=peripheral blood mononuclear cells; PCR=polymerase chain reaction; PD=progressive disease; PET=positron emission tomography; PR=partial response; rHuPH20=recombinant human 
hyaluronidase; sCR=stringent CR; SPEP=Serum M-protein quantitation by electrophoresis; UPEP=urine M-protein quantitation by electrophoresis; VGPR=very good partial response; w=weeks.
a.
For subjects who discontinue study treatment before PD, disease evaluations should continue to be performed at the frequency specified below until confirmed PD, death, start of a new treatment for 
multiple myeloma, withdrawal of consent to study participation, or end of the study whichever occurs first. Once PD is confirmed subsequent disease assessment time points are not required. 
-
Every 4 weeks: SPEP and 24-hour UPEP assessments, and serum calcium corrected for albumin
-
When CR is suspected or maintained: serum FLC, serum and urine immunofixation
-
As clinically indicated: skeletal survey
Evidence of clinical relapse will also be documented at the time at which it is first detected.
After PD is documented, survival status, subsequent anticancer treatment, response to subsequent anticancer treatment, date of progression, and information on all new second primary malignancies 
will be recorded (interview may be conducted by telephone) for all subjects until the end of the data collection period.
b.
To be performed only for subjects with serologic evidence of resolved HBV infection (ie, positive anti-HBs or positive anti-HBc) at Screening, HBV DNA testing by PCR must be performed locally. 
Performed locally every 4 weeks during treatment, end of treatment visit, and every 4 weeks for up to 6 months after the last dose of study treatment.
c.
Following implementation of Protocol Amendment 4, subjects still receiving Dara-IV treatment will have the option to switch to Dara-SC on Day 1 of any cycle, at the discretion of the investigator.


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Table 2:
Time and Events Schedule - Pharmacokinetic/Immunogenicity Sample Collection Times
Note: Refer to Attachment 13 for a description of study procedures for subjects who continue to receive study drug provided by the sponsor 
after the data collection period has ended.
Cycle 1
Cycle 2
Cycle 3
Cycle 5
Cycle 7
Cycle 12
Follow-upd
Day
1
4
15
1
1
4
1
1
1
Post-treatment
Week 4
Post-treatment
Week 8
Visit window
d=days, w=weeks
0
±1d
±0d
±0d
±0d
±1d
±0d
±0d
±0d
+1w
±1w
D=study drug administered
D
D
D
D
D
D
D
Daratumumab pharmacokinetics (serum) – both groups
Before dosea
X
X
X
X
X
X
X
After dosec
X
(Dara-IV only)
X
(Dara-SC only)
X
(Dara-IV only)
X
(Dara-SC only)
X
X
Daratumumab immunogenicity (no additional blood draw; serum taken from pharmacokinetic sample) – both groups
Before doseab
X
X
X
X
X
X
rHuPH20 immunogenicity (plasma) – Dara-SC only (excluding subjects who switched from Dara-IV to Dara-SC following Protocol Amendment 4)
Before doseab
X
X
X
X
X
X
Dara-SC=daratumumab and recombinant human hyaluronidase for subcutaneous injection; Dara-IV=daratumumab for intravenous formulation; rHuPH20=recombinant human 
hyaluronidase.
a
On dosing days, sample collection may occur up to 2 hours before but not after the start of drug administration. Samples collected on dosing days must be collected on the day of study 
drug administration
b
In addition, samples for assessment of antibodies to daratumumab (Dara-IV group) or antibodies to daratumumab and rHuPH20 (Dara-SC group) should be drawn, if possible, any 
time an infusion-related reaction is reported (according to the Lab Manual and Section 9.3.4) in association with the second administration or beyond.
c
End of dose samples (Dara-IV) are to be collected after the end of infusion (up to 2 hours after the end of infusion).
d
Samples should be collected even if subsequent therapy has been initiated.


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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
AST
aspartate aminotransferase
CDC
complement-dependent cytotoxicity
CI
confidence interval
Cmin
minimum observed concentration
Cmax
maximum observed concentration
COPD
chronic obstructive pulmonary disease
CR
complete response
CT
computed tomography
CTSQ
Cancer Therapy Satisfaction Questionnaire
Ctrough
trough concentration
CV
coefficient of variation
Dara-CF
daratumumab and recombinant human hyaluronidase for subcutaneous injection: co-formulated
Dara-IV
daratumumab for intravenous infusion
Dara-MD
daratumumab and recombinant human hyaluronidase for subcutaneous injection: mix and 
deliver
Dara-SC
daratumumab administered subcutaneously
DRd
Dara-IV, lenalidomide, and dexamethasone
DVd
Dara-IV, bortezomib, and dexamethasone
ECG
electrocardiogram
ECOG
EOT
Eastern Cooperative Oncology Group
End of Treatment
eCRF
electronic case report form
eDC
electronic data capture
EU
European Union
FEV1
forced expiratory volume in 1 second
FLC
free light chain
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
IAT
indirect antiglobulin test
ICF
informed consent form
ICH
International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFE
immunofixation
IMiD
immunomodulatory drug
IMWG
International Myeloma Working Group 
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
IRR
infusion-related reaction
IV
intravenous
IWRS
interactive web response system
mAb
monoclonal antibody


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maximum Ctrough
serum predose concentration of daratumumab on Cycle 3 Day 1
MID
minimally important differences
modified-CTSQ
modified Cancer Therapy Satisfaction Questionnaire
M-protein
monoclonal paraprotein 
MRI
magnetic resonance imaging
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NK
natural killer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PFS
progression-free survival
PI
proteasome inhibitor
PO
orally 
PQC
Product Quality Complaint
PR
partial response
PRO
patient-reported outcome
QIg
quantitative immunoglobulin
RBC
red blood cells
Rd
lenalidomide and dexamethasone
rHuPH20
recombinant human hyaluronidase
SAC
Safety Assessment Committee
SC
subcutaneous
sCR
stringent complete response
SIPPM
Site Investigational Product Procedures Manual
SPEP
serum M-protein quantitation by electrophoresis
TNT
time to next therapy
ULN
upper limit of normal 
UPEP
urine M-protein quantitation by electrophoresis
US
United States
Vd
bortezomib and dexamethasone
VGPR
very good partial response


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1.
INTRODUCTION
1.1.
Multiple Myeloma
Multiple myeloma is a mostly incurable malignant plasma cell disorder diagnosed annually in 
approximately 86,000 patients worldwide (Becker 2011)2. Treatment choices for multiple 
myeloma vary with age, performance status, comorbidity, aggressiveness of the disease, and 
related prognostic factors (Palumbo 201120). Current treatments include combination 
chemotherapy, proteasome inhibitors (PIs; bortezomib [and carfilzomib in the United States]), 
immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, and pomalidomide), high-dose 
chemotherapy, and stem cell support. Chemotherapy includes the use of alkylating agents 
(melphalan and cyclophosphamide), anthracyclines (doxorubicin), vincristine, glucocorticoids, 
or combinations of these agents.
Patients who are heavily pretreated or refractory to both a PI and an IMiD have a dismal 
prognosis, are difficult to get back into a durable remission, and have a median overall survival 
(OS) of only 8 to 9 months (Kumar 201212; Usmani 201624; Verelst 201525). For patients who are 
refractory to at least 3 of the common PIs (bortezomib or carfilzomib) and IMiDs (lenalidomide 
or pomalidomide), the median OS decreases to only 5 months (Usmani 201624). 
1.2.
Daratumumab for Intravenous Infusion
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress 
CD38, a transmembrane glycoprotein, in a variety of hematological malignancies including 
multiple myeloma. Daratumumab induces lysis of CD38-expressing tumor cells, including 
multiple myeloma tumor cells that were freshly isolated from patients, by a wide spectrum of 
mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent 
cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), 
through activation of complement proteins, natural killer (NK) cells, and macrophages, 
respectively (de Weers 20116; Overdijk 201519). 
In the US, intravenously (IV) administered daratumumab (Dara-IV) is indicated for use as 
follows: (1) in combination with lenalidomide and dexamethasone, or bortezomib and 
dexamethasone, for the treatment of patients with multiple myeloma who have received at least 
one prior therapy; (2) as monotherapy, for the treatment of patients with multiple myeloma who 
have received at least 3 prior lines of therapy including a PI and an IMiD, or whose disease is 
refractory to both a PI and an IMiD. In the EU, Dara-IV is indicated for use as follows: (1) as 
monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, 
whose prior therapy included a PI and an IMiD and who have demonstrated disease progression 
on the last therapy; (2) in combination with lenalidomide and dexamethasone, or bortezomib and 
dexamethasone, for the treatment of adult patients with multiple myeloma who have received at 
least one prior therapy.


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For the most comprehensive nonclinical and clinical information regarding daratumumab, refer 
to the latest version of the Investigator's Brochure (IB Daratumumab10). The term "sponsor" used 
throughout this document refers to the entities listed in the Contact Information page(s), which 
will be provided as a separate document.
1.2.1.
Clinical Studies
1.2.1.1.
Single-agent Studies
Preliminary data as of 30 Jun 2016 from 2 ongoing clinical studies (GEN501 and 
54767414MMY2002 [hereafter referred to as MMY2002]) and 1 completed clinical study 
(54767414MMY1002 [hereafter referred to as MMY1002]) are summarized below. For further 
details and the most up-to-date information about single-agent studies, please refer to the 
Investigator's Brochure (IB Daratumumab10).
Dara-IV as monotherapy induces deep and durable responses in subjects with heavily pretreated 
multiple myeloma. Phase 2 Study MMY2002 and Phase 1/2 Study GEN501 Part 2 (Part 1 was 
the dose-escalation phase of this first-in-human study) are ongoing single-arm, open-label studies 
in which subjects with relapsed and refractory multiple myeloma are administered Dara-IV as 
monotherapy weekly for 8 weeks, every 2 weeks for an additional 16 weeks, and every 4 weeks 
thereafter until disease progression or unacceptable toxicity. One hundred forty-eight (148)
subjects treated with Dara-IV 16 mg/kg monotherapy were included in a combined analysis of 
efficacy in Study GEN501 and Study MMY2002. The overall response rate (ORR) for the 
combined data set was 31.1% (95% confidence interval [CI], 23.7%-39.2%). Responses included 
3 subjects with stringent complete response (sCR; 2.0%), 4 subjects with complete response 
(CR; 2.7%), 13 subjects with very good partial response (VGPR; 8.8%) and 26 subjects with 
partial response (PR; 17.6%). Within the individual studies, the ORR was 35.7% (95% CI, 
21.6%-52.0%) in Study GEN501 and 29.2% (95% CI, 20.8%-38.9%) in Study MMY2002. After 
a median duration of follow-up of 20.7 months in Study MMY2002, the Kaplan-Meier based 
median OS was 20.1 months.
Among 156 subjects treated with Dara-IV 16 mg/kg as monotherapy in Studies GEN501, 
MMY2002, and MMY1002 (a single-arm, open-label Phase 1 study of pharmacokinetics and 
safety conducted in Japanese subjects), 6 subjects (4%) discontinued Dara-IV treatment due to a 
treatment emergent adverse event. Three subjects (2%) died due to treatment emergent adverse 
events. The most frequently reported treatment emergent adverse events were fatigue (40%), 
nausea (28%), anemia (28%), back pain (26%), cough (24%), neutropenia (23%), pyrexia (22%), 
upper respiratory tract infection (22%), and thrombocytopenia (21%). Serious adverse events 
were reported in 33% of subjects; the most frequently reported serious adverse events were 
pneumonia (6%) and pyrexia, hypercalcemia, or general physical health deterioration (3% each). 


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1.2.1.2.
Combination Therapy Studies
Two Phase 3 studies examined the safety and efficacy of Dara-IV in combination with other 
therapies in the treatment of relapsed multiple myeloma: 

In Study MMY3003, subjects with multiple myeloma received Dara-IV in combination with 
lenalidomide and dexamethasone (DRd). At the time of the first interim analysis, treatment 
with DRd resulted in a 63% reduction in the risk of disease progression or death compared 
to the combination of lenalidomide and dexamethasone (Rd). The median progression-free 
survival (PFS) was not reached in the daratumumab group; median PFS was 18.4 months in 
the Rd group. The ORRs were 93% for the DRd group and 76% for Rd group.

In Study MMY3004, subjects with multiple myeloma received Dara-IV in combination with 
bortezomib and dexamethasone (DVd). At the time of the first interim analysis, treatment 
with DVd showed a 61% reduction in the risk for disease progression or death compared to 
the combination of bortezomib and dexamethasone (Vd). The median PFS was not estimable
in the DVd group; median PFS was 7.2 months, in the Vd group. The ORRs were 83% for 
the DVd group and 63% for the Vd group. 
For further details and the most up-to-date information about combination therapy studies, please 
refer to the Investigator's Brochure (IB Daratumumab10).
1.3.
Daratumumab for Subcutaneous Injection
Dara-IV infusion requires a large volume (500 mL to 1000 mL) of infusate, resulting in a median 
infusion time for the first infusion of 7 hours. Subsequent infusions are approximately 3 to 
4 hours. To shorten the infusion time and decrease the risk of infusion-related reactions (IRRs), a 
technology based on a recombinant human hyaluronidase PH20 (rHuPH20) was developed to 
facilitate subcutaneous (SC) administration of protein therapeutics. rHuPH20 is the active 
ingredient of the commercial product Hylenex® recombinant (hyaluronidase human injection), 
which was approved for use in the US in December 2005. Daratumumab has been administered 
in combination with rHuPH20 in a Phase 1 study (see Section 1.3.2, Clinical Studies). In some 
regions, rHuPH20 is also approved in combination with protein therapeutics for SC 
administration, such as HyQvia (Immune globulin infusion 10% [human] with recombinant 
human hyaluronidase), as well as anticancer medications such as Herceptin® SC (trastuzumab) 
and MabThera® SC (rituximab). 
1.3.1.
Nonclinical Studies
rHuPH20 is a human recombinantly expressed version of hyaluronidase that acts locally and 
transiently within the SC space to increase the tissue dispersion and absorption of injected drugs 
and fluids. rHuPH20 de-polymerizes the gel-like hyaluronan, resulting in decreased resistance to 
fluid flow and a transient increase in the permeability of the local SC tissue.
In a single-dose rabbit local tolerance study, male New Zealand White rabbits (n=6/group) 
received 14 mL SC infusions of rHuPH20 (200 or 1000 U/mL) in an aqueous solution of 25 mM 
sodium acetate, 60 mM NaCl, 140 mM mannitol, 0.04% polysorbate 20 at pH 5.5, alone or in 
combination with daratumumab (20 mg/mL) at an infusion rate of 5 mL/min. There was no 
mortality. Clinical signs consisting of barely perceptible erythema, flaking, and purple 


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discolorations at the injection site were observed in all groups. Dosing with rHuPH20 (at 200 or 
1000 U/mL) in combination with daratumumab (20 mg/mL) had no effect on body weight, body 
weight gain, food consumption, dermal scoring, or body temperature compared to rHuPH20 
alone. There were no daratumumab related macroscopic or microscopic findings.
1.3.2.
Clinical Studies
Study MMY1004 is an ongoing, open-label, dose-escalation, Phase 1b study to assess the safety 
and pharmacokinetics of SC delivery of daratumumab. In Part 1 of this study, a mix-and-deliver 
SC presentation (Dara-MD) of the currently approved daratumumab IV formulation was used: 
rHuPH20 and daratumumab were mixed just prior to delivery. Up to 90 mL of Dara-MD was 
administered SC weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks 
thereafter. Preliminary data from this study show that SC administration is feasible and has a 
substantially shortened administration time compared with standard IV administration. Fifty-
three subjects who received Dara-MD (1200 mg [n=8];
1800 mg [n=45]) between 
November 2015 and August 2016 were evaluable for safety and efficacy. Treatment-emergent 
adverse events for Dara-MD in this study appeared to be similar to those reported in single-agent 
studies of Dara-IV (Lokhorst 2015; Lonial 2016).14,15 After a median treatment duration of 
2.6 months (range 0.7-12) for the 1200 mg cohort and 3.4 months (range 0.7-8.6) for the 
1800 mg cohort, the key safety findings are as follows:

The incidence of all-grade IRRs was 13% and 24% in the Dara-MD 1200 mg and 1800 mg 
cohorts, respectively. By comparison, IRRs were reported in approximately half of the 
subjects in single-agent studies of Dara-IV.

IRRs were mostly Grade 1 or 2. One subject in the Dara-MD 1200 mg cohort developed 
a Grade 3 IRR. 

All IRRs developed during or within 6 hours of the start of the first SC administration 
and did not result in treatment discontinuation. No IRRs were reported on subsequent 
SC administrations. 

Local injection site reactions: SC administration of Dara-MD in the abdominal SC tissue
was generally well tolerated with observations including induration and erythema, and 
which usually resolved within 60 minutes after the end of the infusion. Postinfusion 
erythema was reported in 34% of subjects (1200 mg: 63%; 1800 mg: 29%) and postinfusion 
induration at the injection site was observed in 26% of subjects (1200 mg; 50%; 1800 mg: 
22%). 

The most frequently reported treatment-emergent adverse events (20% of all subjects) with 
Dara-MD were anemia (1200 mg: 25%; 1800 mg: 31%), thrombocytopenia (1200 mg: 38%; 
1800 mg:18%), fatigue (1200 mg: 25%; 1800 mg: 20%) and pyrexia (1200 mg: 25%; 
1800 mg: 22%). These events were reported with similar incidences in single-agent studies 
of Dara-IV 16 mg/kg.

Grade 3 or 4 treatment-emergent adverse events were reported in 63% and 40% of subjects 
in the 1200 mg and 1800 mg cohorts, respectively. By comparison, Grade 3 or 4 
treatment-emergent adverse events were reported in 56% of subjects in single-agent studies 
of Dara-IV 16 mg/kg. 


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
Serious adverse events were reported in 50% and 22% of subjects in the 1200 mg and 
1800 mg cohorts, respectively. By comparison, serious adverse events were reported in 33% 
of subjects in single-agent studies of Dara-IV 16 mg/kg.

There were no treatment-related deaths. 
In the Dara-MD 1200 mg cohort, the ORR was 25% (95% CI: 3-65%), both PRs. In the 
Dara-MD 1800 mg cohorts, 17 responses were observed for an ORR of 38% (95% CI: 24-54%). 
One subject had sCR (2%), 3 subjects (7%) had VGPR, and 13 subjects (29%) had PR. The 
median time to first response was 4 weeks (range, 4-8). For further details and the most 
up-to-date information about Study MMY1004, refer to the Investigator's Brochure 
(IB Daratumumab10).
1.4.
Overall Rationale for the Study
The final SC daratumumab formulation intended for commercial use will be a co-formulated 
drug product for fixed-dose administration, containing rHuPH20 drug substance (2000 U/mL) 
and daratumumab drug substance (120 mg/mL) in a single vial (approximately 15 mL). This 
co-formulated drug product (Dara-CF) was selected for Part 2 of Study MMY1004 to confirm 
the safety and pharmacokinetics of the 1800 mg dose recommended for this Phase 3 study.
Hereafter, Dara-CF will be referred to as Dara-SC.
As described in Section 1.2.1.1, Single-agent Studies, Dara-IV, administered as monotherapy, 
induces deep and durable responses in subjects with heavily pretreated multiple myeloma. In 
clinical studies, a low number of subjects discontinued Dara-IV treatment due to a 
treatment-emergent adverse event, there was a low number of deaths due to treatment-emergent 
adverse events, and use of hematopoietic growth factors (ie, G-CSF) was relatively infrequent. 
Approximately half of the subjects receiving Dara-IV experience IRRs (mostly Grade 1 and 2). 
Most IRRs (>90%) occur during the first infusion. The median infusion time for Dara-IV 
administration is 7 hours for the first infusion and 3 to 4 hours for subsequent infusions.
Several other protein therapeutics are approved for SC administration in combination with 
rHuPH20. This study will investigate the efficacy and safety of SC administration of Dara-SC.
Study MMY1004 provided preliminary evidence of local tolerance for SC administration of 
Dara-MD, consisting of Dara-IV mixed with rHuPH20 at the study center before administration. 
Preliminary efficacy data suggest that, in this patient population, SC administration of Dara-MD 
may enable comparable or better response rates compared with Dara-IV. Furthermore, to date, 
the rate of IRRs with SC administration of Dara-MD has been substantially lower than the rate 
reported with Dara-IV. The SC formulation of daratumumab would offer several tangible 
benefits for both patients and health care providers:

Potential reduction in the incidence rate and severity of IRRs (compared with IV infusion), 
due to slower absorption of daratumumab into systemic circulation 

Shorter administration time (approximately 3 to 5 minutes compared with 4 to 7 hours for 
IV infusion)


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
Reduced administration volume (SC administration of approximately 15 mL instead of 
500 mL to 1000 mL IV infusion), which may be clinically meaningful for elderly patients 
with comorbid cardiac or renal insufficiency 
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESES
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives

To show that SC administration of daratumumab co-formulated with recombinant human 
hyaluronidase PH20 (Dara-SC) is non-inferior to IV administration of daratumumab 
(Dara-IV) in terms of the ORR

To show that Dara-SC is non-inferior to Dara-IV in terms of the maximum trough 
concentration (Ctrough)
Secondary Objectives

To assess the pharmacokinetics and immunogenicity of Dara-SC and Dara-IV

To evaluate the safety of Dara-SC and Dara-IV

To evaluate the clinical benefit of Dara-SC and Dara-IV

To evaluate the immunogenicity of rHuPH20 following Dara-SC administration

To evaluate patient-reported satisfaction with Dara-SC and Dara-IV
2.1.2.
Endpoints
Primary Endpoints
The co-primary endpoints of this study are:

ORR, defined as the proportion of subjects with a PR or better according to the International 
Myeloma Working Group (IMWG) response criteria

Maximum Ctrough, defined as the serum predose concentration of daratumumab on Cycle 3 
Day 1
Secondary Endpoints

Rate of IRRs

PFS, defined as the time from randomization to the date of disease progression or death due 
to any cause, whichever occurs first

Rate of VGPR or better, according to the IMWG response criteria 

Rate of CR or better, according to the IMWG response criteria

Time to next therapy (TNT), defined as the time from randomization to the start of the first 
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
OS, defined as the time from randomization to the date of death

Patient-reported satisfaction with therapy, defined as the mean of responses to 7 of 
9 questions in the modified Cancer Therapy Satisfaction Questionnaire (modified-CTSQ)

Duration of response, defined as date of onset of first response until date of disease 
progression or death

Time to response, defined as the time from randomization until onset of first response
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2.
Hypothesis
The ORR and maximum Ctrough for Dara-SC 1800 mg are not inferior to the ORR and maximum 
Ctrough, respectively, for Dara-IV 16 mg/kg in subjects with multiple myeloma who have received 
at least 3 prior lines of therapy including a PI and an IMiD, or whose disease is refractory to both 
a PI and an IMiD.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a Phase 3, randomized, open-label, active-controlled, multicenter study to demonstrate 
that the efficacy and pharmacokinetics of Dara-SC are not inferior to those for Dara-IV. The 
study population will consist of adults diagnosed with multiple myeloma who have received at 
least 3 prior lines of therapy including a PI and an IMiD, or whose disease is refractory to both a 
PI and an IMiD. Approximately 480 subjects will be assigned randomly to the Dara-SC group or 
the Dara-IV group in a 1:1 ratio. The randomization will be stratified by body weight at baseline 
(65 kg, 66 kg to 85 kg, >85 kg), number of prior lines of therapy (prior lines versus >4 prior 
lines), and type of myeloma (IgG versus non-IgG).
The study consists of 3 phases: a Screening Phase, a Treatment Phase, and a Follow-up Phase. A 
diagram of the study design is provided in Figure 1. The Screening Phase will be up to 28 days 
before randomization. The Treatment Phase will extend from randomization until 
discontinuation of study treatment. Each subject will be treated until the sponsor confirms that 
disease progression has occurred for that subject, the subject has unacceptable toxicity, or other 
reasons (refer to Section 10.1, Discontinuation of Study Treatment). The Follow-up Phase begins 
immediately following the End-of-Treatment Visit, and will continue until death, loss to follow 
up, withdrawal of consent for study participation, or end of the data collection period, whichever 
occurs first.
Treatment cycles are 28 days in length. The dosing schedule for both groups will be weekly for 
Cycles 1 and 2, every 2 weeks for Cycles 3 to 6, and every 4 weeks thereafter. Subjects who are 
assigned to the Dara-SC group will receive a fixed dose of Dara-SC 1800 mg (daratumumab 
1800 mg co-formulated with rHuPH20 2000 U/mL). Dara-SC will be delivered by SC injection 
in the abdominal SC tissue in left/right locations, alternating between individual doses. All 
subjects in the Dara-SC group will be observed for at least 6 hours after the end of the SC 
injection during Cycle 1 Day 1 and, if deemed necessary by the investigator, after consecutive 


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injections. Subjects who are assigned to the Dara-IV group will receive Dara-IV 16 mg/kg by IV 
infusion pump. 
All subjects initially randomized to the Dara-IV group received the Dara-IV formulation; 
however, following implementation of Protocol Amendment 4, subjects still receiving treatment 
with Dara-IV will have the option to switch to Dara-SC on Day 1 of any cycle, at the discretion 
of the investigator. Subjects with a known allergy/intolerance to sorbitol will not be eligible to 
switch to Dara-SC.
Figure 1:
Schematic Overview of Study Design
* As per Amendment 4, subjects still receiving Dara-IV have the option to switch to Dara-SC treatment at the discretion of the 
investigator
Assessment of disease response will be conducted in accordance with the IMWG response 
criteria using a computerized algorithm. Efficacy assessments will include: monoclonal 
paraprotein (M-protein) measurements (serum and urine), serum free light chain (FLC), 
examination of bone marrow aspirate, skeletal survey, documentation of extramedullary 
plasmacytomas, and serum calcium corrected for albumin. Safety evaluations will include 
adverse event monitoring, physical examinations, electrocardiogram (ECG) monitoring, SC 
injection site evaluations, clinical laboratory parameters (hematology and chemistry), vital sign 
measurements, and Eastern Cooperative Oncology Group (ECOG) performance status. The 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Version 4.03 will be used to grade toxicity throughout the study. Blood samples will be drawn 
for assessment of pharmacokinetic and biomarker parameters. If a fresh bone marrow aspirate is 
collected at Screening, a portion will be sent to a central laboratory for DNA/RNA sequencing. If 


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feasible, a bone marrow aspirate will be collected from subjects at disease progression to 
evaluate mechanisms of daratumumab resistance. All study evaluations will be conducted 
according to the Time and Events Schedule. 
An Independent Data Monitoring Committee (IDMC) will review safety data at regular intervals 
during the study. The data cutoff for the primary analysis will occur approximately 6 months 
after 480 subjects have been randomized. All available data at the time of this data cutoff will be
included in the Clinical Study Report. The IDMC will no longer review study data after primary 
analysis has been completed.
The data collection period will end, and the clinical database will be closed approximately 
24 months after the last subject was randomized or when median overall survival for both arms
has been reached, whichever occurs first. There will be no data collection in the eCRF after the 
data collection period has ended. Data collected through the end of the data collection period will 
be included in the final study analysis and reported in a Clinical Study Report. Data collected 
following the data collection period up to the study end will be reported as an addendum to the 
CSR.
The sponsor will ensure that subjects benefiting from treatment with either the IV or SC 
formulation of daratumumab are able to continue receiving the appropriate daratumumab 
treatment after the end of the data collection period until the applicable formulation is 
commercially available or available from another source, or until the study is complete.
The sponsor may decide to end the study at any time, as described in Section 17.9.2.
3.2.
Study Design Rationale
Blinding, Control, Study Phase/Periods, Treatment Groups
This is a study 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 refractory to both a PI and an IMiD. The 
approved route of administration of daratumumab in this population is IV infusion. This study is 
designed to determine if the ORR and maximum Ctrough for single-agent Dara-SC are non-inferior 
to the ORR and maximum Ctrough, respectively, for single-agent Dara-IV. Therefore, important 
efficacy assessments will be performed symmetrically in the 2 treatment groups. Furthermore, 
local tolerability data will be collected from the subject and the investigator, as well as patient 
reported outcomes data related to the different routes of administration.
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (eg, demographic and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity 
of statistical comparisons across treatment groups. To further minimize treatment imbalance 
across prognostic groups, subjects will be stratified based on body weight at baseline (65 kg, 
66 kg to 85 kg, >85 kg), number of prior lines of therapy (4 prior lines versus >4 prior lines), 
and type of myeloma (IgG versus non-IgG).


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Rationale for Co-primary Endpoints
ORR has been chosen as a co-primary endpoint for this non-inferiority study due to its direct 
measure of a treatment effect. It is a measure of drug anti-tumor activity and is less susceptible to 
the influence of disease assessment schedules or patients dropping out before disease 
progression. It correlates well with long-term outcomes such as PFS and OS and is a well-
established surrogate endpoint in the setting of refractory disease (Food and Drug 
Administration 2007).9 ORR was the basis of the recent approval of daratumumab monotherapy, 
carfilzomib monotherapy, and pomalidomide in combination with dexamethasone for patients 
with relapsed and refractory multiple myeloma. In particular, the first 2 approvals were based on 
single-arm studies. Moreover, its use in non-inferiority studies is supported by precedent, as 
ORR was a key efficacy endpoint in other non-inferiority clinical studies conducted to study SC 
formulations of VELCADE (approved in US in 2012), and Herceptin and MabThera, which were 
recently approved in the EU.
The 60% retention will result in minimal loss of benefit in terms of observed ORR. For example, 
if the observed ORR for Dara-IV is 30%, then an ORR of at least 25% needs to be observed for 
Dara-SC. The clinical relevance of the 60% retention of ORR was justified based on the 
benefit/risk of Dara-SC and a strong indication of similar efficacy from early efficacy and 
pharmacokinetics data. Subjects enrolled into MMY2002 had a median of 5 prior lines of 
therapy. Outcomes for this population of patients generally are measured in months. Due to prior 
therapies, these patients also tend to be more frail, with lower organ reserves, compared with 
subjects with newly diagnosed multiple myeloma. A shorter infusion time would reduce time 
spent in a healthcare setting and a lower incidence of IRRs could enable them to stay on therapy 
longer. In addition, in the daratumumab Study MMY1004 Part 1, the ORR was 38% for 
45 subjects receiving Dara-MD 1800 mg, and the maximum Ctrough was similar or higher 
compared to Dara-IV, strongly suggesting similar efficacy with Dara-SC. 
The maximum Ctrough for daratumumab at Cycle 3 Day 1 (at the end of 8 weeks of weekly 
dosing) was shown in population pharmacokinetic and exposure-response analyses to be related 
to ORR in multiple myeloma. A maximum Ctrough of 274 µg/mL was associated with 90% 
maximal effect on ORR and a concentration of 236 µg/mL was needed to achieve 99% 
model-predicted target (CD38) saturation. The pharmacokinetic goal of SC delivery is to 
maintain maximum Ctrough similar to or higher than that observed with IV delivery.
Rationale for Daratumumab Subcutaneous Dose Selection
In Part 1 of Study MMY1004, starting doses of Dara-MD 1200 mg and Dara-MD 1800 mg were 
selected on the basis of pharmacokinetics modeling to achieve maximum Ctrough at Cycle 3 Day 1 
(at the end of weekly dosing) similar to those achieved by Dara-IV 16 mg/kg and Dara-IV 
24 mg/kg, respectively, for a 75-kg person. Previously, the highest Dara-IV dose administered 
was 24 mg/kg. No dose-limiting toxicities were observed in the 3 subjects who received this high 
dose in Study GEN501. The fixed doses of Dara-MD assumed bioavailability would be 100% 
(ie, complete absorption). Based on emerging data from the first cohort in MMY1004, the dose 
was escalated to
a fixed
dose of Dara-MD 1800 mg. Analysis of the preliminary 


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pharmacokinetics data indicated the 1800 mg Dara-MD dose achieved Cycle 3 Day 1 Ctrough
values comparable to or higher than those for Dara-IV 16 mg/kg. 
Preliminary pharmacokinetic data for Dara-MD 1200 and 1800 mg doses in Study MMY1004
Part 1 showed a serum concentration-time curve that increased slowly and reached peak 
daratumumab concentrations by about 72 hours postdose. The Cycle 3 Day 1 Ctrough was 
543.90 µg/mL (coefficient of variation [CV]=44%) for Dara-MD 1200 mg (n=5) and 
755.27 µg/mL (CV=51%) for Dara-MD 1800 mg (n=41). The variability in Cycle 3 Day 1 Ctrough
appeared to be similar between the Dara-IV studies (GEN501 and MMY2002) and both 
Dara-MD dose cohorts with %CV in the range of 44%-58% across all studies. Based on 
modeling, the estimated bioavailability of Dara-MD is approximately 77%. Approximately 88% 
of subjects dosed with Dara-MD 1800 mg would be expected to achieve the effective maximum 
Ctrough of 274 µg/mL (the serum daratumumab concentration associated with 90% maximal effect 
on ORR in monotherapy studies), whereas only 73% of subjects dosed with Dara-MD 1200 mg 
would achieve the effective maximum Ctrough. With a Dara-IV 16 mg/kg dose, approximately 
80% of subjects achieve the effective maximum Ctrough. 
The body weight range in Part 1 of Study MMY1004 was 48 to 133 kg, which was similar to that 
in Dara-IV studies (MMY2002 and GEN501, 38.4 to 160.2 kg). The preliminary Ctrough data 
from Cycle 3 Day 1 for the Dara-MD 1800 mg dose were assessed across a range of simulated 
body weights and compared with the body-weight based Dara-IV dosing. Across the quartiles of 
weights for the simulated patients (n=1000), similar exposure was predicted for each dosing 
approach (either Dara-MD 1800 mg or Dara-IV 16 mg/kg) (Figure 2). Furthermore, the 
variability in the exposure for Dara-MD 1800 mg in all weight quartiles was predicted to be 
similar compared to that for Dara-IV 16 mg/kg. The fixed Dara-MD 1800 mg dose appeared to 
produce a median concentration that was close to the overall population median concentration, 
with a ratio of approximately 1 in each weight quartile (Figure 3). Based on these simulations 
and observations in the ongoing MMY1004 study, fixed dosing for SC administration is a 
feasible approach and will be used in this study. Dara-IV exhibits a wide therapeutic window and 
there is no apparent relationship between drug exposure in the therapeutic dose range and 
adverse events of interest, which also supports the feasibility of utilizing a fixed dose approach in 
SC administration.


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Figure 2:
Predicted Maximal Trough Concentrations at Cycle 3 Day 1 for Dara-MD 1800 mg 
(subcutaneous administration) and Dara-IV 16 mg/kg (intravenous administration)
Dara-MD 1800 mg
Dara-IV 16 mg/kg
Dashed line is the effective concentration of 274 µg/mL.
C3D1=Cycle 3 Day 1.
Figure 3:
Predicted Median-normalized Maximal Trough Concentrations at Cycle 3 Day 1 (ratio of 
trough concentrations and median trough concentration for overall population at each dose) for 
Dara-MD 1800 mg (subcutaneous administration) and Dara-IV 16 mg/kg (intravenous 
administration)
Dara-MD 1800 mg
Dara-IV 16 mg/kg
C3D1=Cycle 3 Day 1.
Ideal trough concentration is 1.0.


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In this study, the concentration of rHuPH20 in Dara-SC will be 2000 U/mL. Products approved 
for commercial use, such as Herceptin SC (trastuzumab) and MabThera SC (rituximab), also 
contain 2000 U/mL of rHuPH20. Two studies in minipigs support the use of this concentration of 
rHuPH20 in Dara-SC. In the first study, 20 mg/mL of human IgG in daratumumab formulation 
buffer was formulated with 200, 500, or 800 U/mL of rHuPH20 and infused SC into the 
abdomen of sedated animals at a rate of 2 or 4 mL/min using a syringe pump. The higher 
infusion rate (4 mL/min) resulted in less local swelling and erythema. Erythema, when present, 
was mild and subsided by the next day. Infusion pressures were similar for all concentrations of 
rHuPH20 at both infusion rates (~40 to 60 mmHg or 1 PSI). The second study evaluated 
100 mg/mL daratumumab formulated with 50, 500, 2000, or 5000 U/mL of rHuPH20. Sixteen
(16) mL of each formulation was infused SC into the abdomen of sedated animals at a rate of 
3 mL/minute. Infusion pressures showed a dose-dependent trend where pressures were reduced 
as the concentration of rHuPH20 increased. Formulations with ≥500 U/mL of rHuPH20 showed 
relatively small areas of local swelling that was mainly soft to the touch with mild to no 
erythema. These all resolved by the following day, with many resolving within an hour.
Rationale for Pharmacokinetics and Immunogenicity Assessments
Data obtained from this study will provide information about the pharmacokinetic profile of 
Dara-SC, as well as additional information about the pharmacokinetic profile of Dara-IV, in 
subjects with multiple myeloma. Therefore, samples will be obtained from all subjects for 
pharmacokinetic assessments. Data may also be used for a population pharmacokinetic analysis 
to estimate additional pharmacokinetic parameters and provide information about the 
determinants of inter-subject variability in this population.
Immunogenicity to daratumumab or rHuPH20 is possible. Therefore, the presence of antibodies 
to daratumumab (immunogenicity) will be determined from pharmacokinetic serum samples 
collected from all subjects. The presence of antibodies to rHuPH20 (immunogenicity) will be 
determined from plasma samples collected from subjects who receive Dara-SC, excluding
subjects who switch from Dara-IV to Dara-SC following Amendment 4.
rHuPH20 
immunogenicity samples should not be collected from subjects who switch from Dara-IV to 
Dara-SC administration.
Rationale for Biomarker Evaluations
Biomarker studies are designed to evaluate if there are any differences with Dara-SC and 
Dara-IV on daratumumab pharmacodynamic and mechanism of action biomarkers. These studies 
may also identify markers predictive of response or resistance to daratumumab. Biomarker 
samples will be collected to evaluate contributions to daratumumab response including but not 
limited to myeloma cell CD38 expression, resistance markers and adaptive responses via 
technologies such as DNA sequencing of T-cell receptor genes. Response rates in specific 
molecular subgroups may also be determined by DNA/RNA sequencing of myeloma cells for 
assessment of risk-associated genetic modifications such as del17p, amp1q21, and t(4;14), and
for identification of biomarkers of response or resistance to daratumumab. The DNA and RNA 
sequencing data may be used for the identification of myeloma specific neoantigens to determine 
if antigen-specific T-cell responses are generated. Also, in previous Dara-IV studies of subjects 


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with multiple myeloma, NK cell counts were reduced significantly following the first dose of 
Dara-IV and maintained at low levels on therapy while other immune cell populations were not 
susceptible to decreases. Therefore, the dynamics of immune cell populations may be examined 
to determine whether similar changes may play a role in daratumumab response and 
development of resistance. Additional phenotypic and functional profiling may be performed on 
blood and bone marrow aspirate samples. Proteomic analysis may also be used to evaluate 
potential biomarkers of response and resistance. 
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed during a 28 day period prior to randomization.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. Prior to randomization, the sponsor will review key eligibility criteria 
for all subjects. Eligibility information will be provided to the sponsor for review prior to
approval for randomization being granted by the sponsor. If the sponsor agrees that the eligibility 
criteria have been met, then the investigator will receive confirmation that the subject may be 
randomized into the study. If the sponsor considers that the eligibility criteria have not been met, 
then the sponsor will contact the investigator to discuss the subject. If there is a question about 
the inclusion or exclusion criteria below, the investigator must consult with the appropriate 
sponsor representative and resolve any issues before enrolling a subject in the study. Waivers are 
not allowed. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study: 
1.
At least 18 years of age.
2.
Criterion updated as per Amendment 1
2.1. Documented multiple myeloma as defined by the criteria below:

Multiple myeloma diagnosis according to the IMWG diagnostic criteria (refer to 
Attachment 1).

Measurable disease at Screening as defined by any of the following: 

Serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or

Light chain multiple myeloma without measurable disease in the serum or the urine: 
Serum immunoglobulin FLC ≥10 mg/dL and abnormal serum immunoglobulin 
kappa lambda FLC ratio.
3.
Evidence of a response (PR or better based on investigator’s determination of response by 
IMWG criteria) to at least 1 prior treatment regimen.
4.
Relapsed or refractory disease as defined below: 

Relapsed disease is defined as an initial response to previous treatment, followed by 
confirmed PD by IMWG criteria >60 days after cessation of treatment. 

Refractory disease is defined as <25% reduction in M-protein or confirmed PD by 
IMWG criteria during previous treatment or 60 days after cessation of treatment.


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5.
Received at least 3 prior lines of therapy (refer to Attachment 2) including a PI (≥2 cycles or 
2 months of treatment) and an IMiD (≥2 cycles or 2 months of treatment) in any order 
during the course of treatment (except for subjects who discontinued either of these 
treatments due to a severe allergic reaction within the first 2 cycles/months). A single line of 
therapy may consist of 1 or more agents, and may include induction, hematopoietic stem cell 
transplantation, and maintenance therapy. Radiotherapy, bisphosphonate, or a single short 
course of corticosteroids (no more than the equivalent of dexamethasone 40 mg/day for 
4 days) would not be considered prior lines of therapy.
or
Refractory to both a PI and an IMiD. For subjects who have received more than 1 type of PI, 
their disease must be refractory to the most recent one. Similarly, for those who have 
received more than 1 type of IMiD, their disease must be refractory to the most recent one.
6.
ECOG Performance Status score of 0, 1, or 2 (refer to Attachment 3).
7.
Pretreatment clinical laboratory values meeting the following criteria during the Screening 
Phase:
a.
hemoglobin 7.5 g/dL (mmol/L) (without prior red blood cells [RBC] transfusion 
within 7 days before the laboratory test; recombinant human erythropoietin use is 
permitted);
b.
absolute neutrophil count 1.0 × 109/L (prior growth factor support is permitted);
c.
platelet count 50 × 109/L (transfusions are not permitted within 7 days of testing to 
achieve this minimum platelet count);
d.
aspartate aminotransferase (AST) 2.5 × upper limit of normal (ULN);
e.
alanine aminotransferase (ALT) 2.5 × ULN;
f.
total bilirubin 2.0 × ULN; except in subjects with congenital bilirubinemia, such as 
Gilbert syndrome (in which case direct bilirubin 2.0 × ULN is required);
g.
estimated creatinine clearance mL/min per 1.73m2 (refer to Attachment 4); 
h.
albumin-corrected serum calcium 14 mg/dL (3.5 mmol/L) or free ionized calcium 
6.5 mg/dL (1.6 mmol/L) (refer to Attachment 5).
8.
Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously. 
This includes one highly effective form of contraception (tubal ligation, intrauterine device, 
hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or 
partner's vasectomy) and one additional effective contraceptive method (male latex or 
synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks prior to 
dosing. Reliable contraception is indicated even where there has been a history of infertility, 
unless due to hysterectomy.
9.
Women of childbearing potential must have a negative urine or serum pregnancy test at 
screening within 14 days prior to randomization.
10. 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 


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the study and are willing to participate in the study. Subjects 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.
Received daratumumab or other anti-CD38 therapies previously.
2.
Received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the 
treatment, whichever is longer, before the date of randomization. The only exception is 
emergency use of a short course of corticosteroids (equivalent of dexamethasone 40 mg/day 
for a maximum of 4 days [refer to Attachment 6]) before treatment. A list of anti-myeloma 
treatments with the corresponding pharmacokinetic half-lives is provided in the Site 
Investigational Product Procedures Manual (SIPPM).
3.
Received autologous stem cell transplant within 12 weeks before the date of randomization, 
or the subject has previously received allogeneic stem cell transplant (regardless of timing).
4.
Plans to undergo a stem cell transplant prior to progression of disease on this study (these 
subjects should not be enrolled to reduce disease burden prior to transplant).
5.
Criterion updated as per Amendment 1
5.1
Criterion updated as per Amendment 2
5.2
History of malignancy (other than multiple myeloma) unless all treatment of that 
malignancy was completed at least 2 years before consent and the patient has no evidence 
of disease. Further exceptions are squamous and basal cell carcinomas of the skin and 
carcinoma in situ of the cervix, or breast, or other non-invasive lesion, that in the opinion 
of the investigator, with concurrence with the sponsor's medical monitor, is considered 
cured with minimal risk of recurrence within 3 years.
6.
Clinical signs of meningeal involvement of multiple myeloma.
7.
Either of the following:
a.
Known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume 
in 1 second (FEV1) is <50% of predicted normal. Note that FEV1 testing also is required 
for subjects suspected of having COPD and subjects must be excluded if FEV1 is <50% 
of predicted normal.
b. Known moderate or severe persistent asthma, or a history of asthma within the last 
2 years, or currently has uncontrolled asthma of any classification (refer to 
Attachment 7). (Subjects who currently have controlled intermittent asthma or controlled 
mild persistent asthma are allowed to participate in the study.)
8.
Criterion updated as per Amendment 1
8.1
Criterion updated as per Amendment 2
8.2
Any of the following:
a.
Known to be seropositive for human immunodeficiency virus (HIV)


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b. Known to be seropositive for hepatitis B (defined by a positive test for hepatitis B 
surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are positive 
for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B 
surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction 
(PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR 
positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of 
HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known 
history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
c.
Known to be seropositive for hepatitis C (except in the setting of a sustained virologic 
response [SVR], defined as aviremia at least 12 weeks after completion of antiviral 
therapy). 
9.
Concurrent medical or psychiatric condition or disease (eg, active systemic infection, 
uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere 
with study procedures or results, or that in the opinion of the investigator would constitute a 
hazard for participating in this study.
10. Clinically significant cardiac disease, including:

Myocardial infarction within 6 months before date of randomization, or unstable or 
uncontrolled disease/condition related to or affecting cardiac function (eg, unstable 
angina, congestive heart failure, New York Heart Association Class III-IV [refer to 
Attachment 8]).

Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 4.03) or 
clinically significant ECG abnormalities.

Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia's 
formula >470 msec.
11. Known allergies, hypersensitivity, or intolerance to any of the study drugs, hyaluronidase, 
mAbs, human proteins, or their excipients (refer to daratumumab IB10), or known sensitivity 
to mammalian-derived products.
12. Plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or 
Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, 
endocrinopathy, M-protein, and skin changes) or amyloidosis.
13. Known or suspected of not being able to comply with the study protocol (eg, because of 
alcoholism, drug dependency, or psychological disorder) or the subject has any condition for 
which, in the opinion of the investigator, participation would not be in the best interest of the 
subject (eg, compromise their well-being) or that could prevent, limit, or confound the 
protocol-specified assessments.
14. Pregnant, breast-feeding, or planning to become pregnant while enrolled in this study or 
within 3 months after the last dose of study drug.
15. Plans to father a child while enrolled in this study or within 3 months after the last dose of 
study drug.
16. Received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 4 weeks before the planned first dose of study drug 
(except for investigational anti-myeloma treatments, which cannot be taken within 2 weeks 
before Cycle 1 Day 1).


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17. Major surgery within 2 weeks before randomization, or has not fully recovered from an 
earlier surgery, or has major surgery planned during the time the subject is expected to 
participate in the study or within 2 weeks after the last dose of study drug administration. 
Kyphoplasty or vertebroplasty are not considered major surgery. Note: subjects with 
planned surgical procedures to be conducted under local anesthesia may participate. If there 
is a question whether a procedure is considered a major surgery, the investigator must 
consult with the appropriate sponsor representative and resolve any issues before enrolling a 
subject in the study. 
18. Plasmapheresis within 28 days before randomization.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study drug is given such 
that he or she no longer meets all eligibility criteria, then the subject should be excluded from 
participation in the study. Section 17.4, Source Documentation, describes the required 
documentation to support meeting the enrollment criteria. Subjects who fail to meet the inclusion 
criteria or who fulfill any of the exclusion criteria (ie, screen failures) may be rescreened if their 
condition changes. Rescreening must be discussed with and approved by the sponsor on a 
case-by-case basis. Subjects who are determined to be eligible for the study after rescreening 
must sign a new ICF and then will 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, Prohibited Therapies.
1. For women of childbearing potential, adequate contraception as specified in Section 4.1, 
Inclusion Criteria must continue during the Treatment Phase, during any dose interruptions, 
and for 3 months after the last dose of daratumumab. In addition, women must not donate 
ova during the study and for 3 months after the last dose of daratumumab.
2. A man who is sexually active with a woman of childbearing potential must always use a latex 
or synthetic condom during the study and for 3 months after discontinuing daratumumab. All 
men must not donate sperm during the study and for 3 months after the last dose of 
daratumumab.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Central randomization will be implemented in this study. Subjects will be assigned randomly to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by body weight at baseline (≤65 kg, 66 kg 
to 85 kg, >85 kg), number of prior lines of therapy (≤4 prior lines versus >4 prior lines), and type 
of myeloma (IgG versus non-IgG). The interactive web response system (IWRS) will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kit 


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for the subject. The requestor must use his or her own user identification and personal 
identification number when contacting the IWRS, and will then give the relevant subject details 
to uniquely identify the subject.
6.
DOSAGE AND ADMINISTRATION
In this protocol, “study drug” refers to Dara-SC or Dara-IV. The SIPPM and Investigational 
Product Preparation Instructions (IPPI) contain detailed descriptions for preparation and 
administration of daratumumab and will be supplied to each pharmacy and site.
6.1.
Preparation
6.1.1.
Subcutaneous Preparation
In the Dara-SC group, Dara-SC will be provided as a fixed-dosed, combination drug product 
containing rHuPH20 drug substance (2000 U/mL) and daratumumab drug substance 
(120 mg/mL) in a single vial. 
6.1.2.
Intravenous Preparation
In the Dara-IV group, infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL 
(second and subsequent doses) dilution of Dara-IV in sterile, pyrogen-free 0.9% NaCl. 
6.2.
Treatment Schedule and Administration
Each treatment cycle is 28 days. Study drug will be administered once weekly in Cycles 1 and 2, 
every 2 weeks in Cycles 3 to 6, and then every 4 weeks thereafter. Dosing days may be adjusted 
to accommodate the schedule of the site or the subject, as shown in Table 3. Tight visit windows 
(±1 day) are required for Day 1 in the first 3 treatment cycles because of the co-primary endpoint 
assessments at those visits. Changes to within-cycle dosing should not affect Day 1 of the next 
cycle. Subjects will continue to receive study treatment until disease progression, unacceptable 
toxicity, or other reasons as listed in Section 10.1, Discontinuation of Study Treatment.
Table 3:
Study Drug (Dara-SC or Dara-IV) Administration Schedule
Cycle
Schedule
Day 1
Day 8
Day 15
Day 22
Cycles 1-2
Weekly
Day 1
Day 8 (±1d)
Day 15 (±1d)
Day 22 (±1d)
Cycle 3
Every 2 weeks
Day 1 (±1d)
–
Day 15 (±3d)
–
Cycles 4-6
Every 2 weeks
Day 1 (±3d)
–
Day 15 (±3d)
–
Cycles 7+
Every 4 weeks
Day 1 (±3d)
–
–
–
Every effort should be made to keep subjects on the planned dosing schedule. Refer to 
Section 6.5, Dose Delays and Modification for information on the management of cycle delays.
All doses will be administered at outpatient visits. Subjects will receive predose medications and 
postdose medications as detailed in Section 6.3, Predose and Postdose Medications.
As noted in the Time and Events Schedule, all subjects should have vital signs monitored at each 
dose. If a subject experiences any significant medical event, then the investigator should assess 
whether the subject should stay overnight for observation. If the subject has not experienced a 


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significant medical event but is hospitalized overnight only for observation, then the 
hospitalization should not be reported as a serious adverse event.
6.2.1.
Subcutaneous Dosing
In the Dara-SC group or for subjects who switch from Dara-IV to Dara-SC dosing following 
Protocol Amendment 4, Dara-SC will be administered by SC injection at a fixed dose of 
1800 mg. Doses will be administered by manual push over approximately 3-5 minutes in the 
abdominal SC tissue in left/right locations, alternating between individual doses. The volume of 
the SC solution will be 15 mL for the 1800 mg dose. Refer to the IPPI for additional guidance on 
SC administration of Dara-SC. All subjects in the Dara-SC group will be observed for at least 
6 hours after the end of the SC injection during Cycle 1 Day 1 and, if deemed necessary by the 
investigator, after consecutive injections.
Following Protocol Amendment 4, subjects who were randomized to receive Dara-IV and are 
currently receiving treatment will have the option to switch to Dara-SC on Day 1 of any cycle, at 
the discretion of the investigator. Subjects with a known allergy/intolerance to sorbitol will not 
be eligible to switch to Dara-SC. It is recommended that subjects who switch to SC dosing are 
observed for a period of time deemed appropriate by the investigator following the first Dara-SC 
dose and, if necessary, after subsequent injections. Reasons for continued observation on 
subsequent daratumumab administrations may include but are not limited to the following: 
subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with COPD who have an FEV1 <80% at screening or developed FEV1 <80% during the 
study without any medical history), subjects who experienced one or more IRRs with prior 
administrations of study drug, subject with a decreased condition on day of dosing compared to 
prior dosing day.
6.2.2.
Intravenous Administration
In the Dara-IV group, Dara-IV 16 mg/kg will be administered by IV infusion. Each subject's 
dose will be calculated based on the subject's weight rounded to the nearest kilogram, but does 
not need to be recalculated for weight changes that are <10% from baseline. For guidance on the 
dilution volumes, infusion rates, and increment of infusion rates for the first, second, and 
subsequent doses, and accelerated infusion rates (following Protocol Amendment 4) in the 
absence of an IRR >Grade 1, please refer to the SIPPM.
For subjects who initially received Dara-IV and then switch to Dara-SC following Protocol 
Amendment 4, please refer to Section 6.2.1 for Dara-SC dosing.


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6.3.
Predose and Postdose Medications
6.3.1.
Predose Medications
In an effort to prevent IRRs, all subjects will start the following medications approximately 1 to 
3 hours prior to each study drug administration (1 hour prior to study drug administration is 
preferred):

An antipyretic: paracetamol (acetaminophen) 650-1000 mg IV or orally (PO)

An antihistamine: diphenhydramine 25-50 mg IV or PO, or equivalent. Avoid the use of IV 
promethazine. (See Attachment 9 for a list of antihistamines that may be used)

A corticosteroid: methylprednisolone 100 mg IV or PO or equivalent for the first 2 doses 
and 60 mg for all subsequent doses (in the absence of IRR adverse events in the first 
2 doses). Substitutions for methylprednisolone are allowed (refer to Attachment 6).
Predose administration of a leukotriene inhibitor (montelukast 10 mg PO, or equivalent) is 
optional on Cycle 1 Day 1. If necessary, all PO predose medications may be administered 
outside of the clinic on the day of study drug administration, provided they are started within 1 to 
3 hours before study drug administration. 
6.3.2.
Postdose Medications 
In an effort to prevent delayed IRRs, all subjects will receive a long- or intermediate-acting 
corticosteroid (20 mg methylprednisolone PO or IV or equivalent [refer to Attachment 6], in 
accordance with local standards) on the 2 days following each study drug administration 
(beginning the day after study drug administration). In the absence of IRR adverse events after 
the first 3 doses, postdose corticosteroids should be administered per investigator discretion. For 
subjects previously treated with Dara-IV who switch to Dara-SC, postdose medications may be 
offered for the first and subsequent doses of Dara-SC, per investigator discretion.
For subjects with a higher risk of respiratory complications (eg, subjects with COPD who have 
an FEV1 <80% or subjects with asthma), the following postdose medications should be 
considered:

antihistamine (diphenhydramine or equivalent) on the first and second days after each dose;

short-acting β2 adrenergic receptor agonist such as salbutamol aerosol; and

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 
study drug administration. If these at-risk 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 each study drug administration. 
If the subject has not experienced a significant medical event but is hospitalized overnight only 
for observation, then the hospitalization should not be reported as a serious adverse event. 
Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that are deemed 


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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 IRRs, then these 
postdose medications may be waived after 4 doses at the investigator's discretion. 
6.4.
Management of Injection-site and Infusion-related Reactions
6.4.1.
Local Injection-site Reactions
In Study MMY1004 Part 1, SC administration of Dara-MD in abdominal SC tissue was 
associated with local injection-site reactions such as induration and erythema in some subjects.
The reactions usually resolved within 60 minutes. Injection-site reactions should be managed per 
institutional standards.
6.4.2.
Infusion-related Reactions
Subjects should be observed carefully during study drug administrations. Trained study staff at 
the clinic should be prepared to intervene in case of any IRRs, and resources necessary for 
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical 
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available 
at the bedside.
If an IRR develops, then the infusion or injection should be temporarily interrupted or slowed 
down. Subjects who experience adverse events during the infusion must be treated for their 
symptoms. Subjects should be treated with acetaminophen, antihistamine, or corticosteroids as 
needed. Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects 
may require antihistamines, oxygen, corticosteroids, or bronchodilators. For hypotension, 
subjects may require vasopressors. In the event of a life-threatening IRR (which may include 
pulmonary or cardiac events) or anaphylactic reaction, daratumumab should be discontinued and 
no additional daratumumab should be administered to the subject. Aggressive symptomatic 
treatment should be applied. In case of interruption of the administration of the study drug due to 
an adverse event related to the study drug, the investigator/study coordinator should review the 
information of the dispensed study drug on the IPPI and ensure the correct drug product is being 
used before restarting the administration.
If an infusion/injection is paused or the infusion rate is decreased, then a longer-than-anticipated
infusion/injection time may occur. Overnight stays at the hospital because of slow 
infusion/injection times should not be reported as serious adverse events. However, if the 
underlying cause of the delayed infusion/injection time is an adverse event or serious adverse 
event, then that should be reported as such.
Infusion-Related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR adverse event to be related to administration of study 
drug, then the Dara-IV infusion or Dara-SC injection should be paused. Once IRR symptoms 
resolve and the subject's condition is stable, the Dara-IV infusion or Dara-SC injection may be 
restarted at the investigator's discretion. Upon restart of Dara-IV infusion, the infusion rate 
should be half of that employed before the interruption. If the subject does not experience any 


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further IRR symptoms, infusion rate escalation may resume at increments and intervals as 
clinically appropriate up to the maximum rate of 200 mL/hour (see the SIPPM).
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the subject must be withdrawn from daratumumab treatment. 
Infusion-Related Reactions of Grade 3 or Higher
For IRR adverse events that are Grade 4, the Dara-IV infusion or Dara-SC injection must be 
stopped and the subject withdrawn from daratumumab treatment. 
For IRR adverse events that are Grade 3, the Dara-IV infusion or Dara-SC injection must be 
stopped and the subject must be observed carefully. Once reaction symptoms resolve, if 
continuing treatment is deemed appropriate by the investigator, restart the infusion at no more 
than half the rate at which the reaction occurred. If the subject does not experience additional 
symptoms, resume infusion rate escalation at increments and intervals as outlined in the SIPPM.
If the intensity of the adverse event returns to Grade 3 after restart of the Dara-IV infusion or 
Dara-SC injection, then the procedure described in this section should be repeated, or the subject 
may be withdrawn from treatment. Should the intensity of the adverse event increase to Grade 3 
for a third time, then the subject must be withdrawn from daratumumab treatment.
6.5.
Dose Delays and Modification
Dose modification of 16 mg/kg Dara-IV or 1800 mg Dara-SC (increase or decrease) is not 
permitted. Dose delay is the primary method for managing daratumumab-related toxicities. On 
the first day of each new treatment cycle and before each dose of study drug, the subject will be 
evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI-CTCAE, Version 4.03. Cycle 
delays will be based on the toxicity experienced during the previous cycle of therapy or newly 
encountered on Day 1 of a cycle.
The study treatment must be held if any of the following criteria are met, to allow for recovery 
from toxicity, regardless of relationship to study drug: 

Grade 4 hematologic toxicity, except for Grade 4 lymphopenia

Grade 3 or higher thrombocytopenia with bleeding

Febrile neutropenia

Neutropenia with infection, of any grade

Grade 3 or higher non-hematologic toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days


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
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

Grade 3 pain associated with symptoms of multiple myeloma (bone/joint pain)
Study treatment should be resumed when the toxicity has resolved to Grade 2. If study drug 
administration does not commence within the prespecified window of the scheduled 
administration date (Table 4), then the dose will be considered a missed dose. Administration 
may resume at the next planned dosing date. A missed dose will not be made up.
Table 4:
Daratumumab Administration Schedule
Cycles
Frequency
Dose Held
Dosing Restart
1 and 2
Weekly (q1wk)
>3 days
Next planned weekly dosing date
3 to 6
Every 2 weeks (q2wks)
>7 days
Next planned every 2 weeks dosing date
7+
Every 4 weeks (q4wks)
>14 days
Next planned every 4 weeks dosing date
Any dose hold of more than 28 days due to toxicity will result in permanent discontinuation of 
daratumumab. Dose holds of more than 28 days for other reasons should be discussed with the 
sponsor. If a dose delay occurs, then pharmacokinetic and pharmacodynamic assessments should 
be performed on (or relative to, in the case of C1D4 and C3D4 PK collections in the Dara-SC 
group) the actual day of study drug administration, not on the original scheduled administration 
day.
Delay of Day 1 drug dosing in any given cycle should not result in a skipped dose but should 
lead to a delay of the entire cycle instead. A minimum of 4 days between daratumumab doses 
must be observed.
A study drug dose held for more than 3 days 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 missing ≥3 consecutive planned 
doses of study drug for reasons other than toxicity should be withdrawn from treatment, 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. Investigators should consider the applicable infusion reaction guidance 
provided in Section 6.4.2 when restarting treatment after a long delay.
7.
TREATMENT COMPLIANCE
Study drug (Dara-IV or Dara-SC) will be administered by qualified site staff, and the details of 
each administration will be recorded in the electronic case report form (eCRF). Additional details 
are provided in the IPPI.


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8.
PRESTUDY AND CONCOMITANT THERAPY
All prestudy antineoplastic and multiple myeloma therapies must be recorded at screening. 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.3,
Prohibited Therapies. The sponsor must be notified in advance (or as soon as possible thereafter) 
of any instances in which prohibited therapies are administered.
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 during the data collection period or until the start of subsequent 
anticancer 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 anticancer therapy 
(including radiation). Concomitant medications to manage adverse events and serious adverse 
events will be recorded as per Section 12.3, Procedures.
8.1.
Recommended Therapies
8.1.1.
Bisphosphonate Therapy
Bisphosphonate therapy is strongly recommended for all subjects with evidence of lytic 
destruction of bone or with osteopenia. Bisphosphonate therapy is recommended to be continued 
per treatment guidelines (NCCN 201317; Moreau 201316). Commercially available IV 
bisphosphonates (pamidronate and zoledronic acid) are preferred when available, and should be 
used according to the manufacturer's recommendations, as described in the prescribing 
information, for subjects with osteolytic or osteopenic myelomatous bone disease. Oral 
bisphosphonates may be used as alternatives if IV bisphosphonates are not available at the study 
site. Investigators should use the same route of bisphosphonate therapy for all subjects at their 
sites.
8.1.2.
Therapy for Tumor Lysis Syndrome
Subjects should be monitored for symptoms of tumor lysis syndrome. Management of tumor 
lysis syndrome, including hydration for abnormal laboratory test results such as hyperkalemia, 
hyperuricemia, and hypocalcemia, is highly recommended. High-risk subjects (ie, those with a 
high tumor burden) should be treated prophylactically in accordance with local standards 
(eg, rehydration, diuretics, allopurinol 300 mg daily, and medication to increase urate excretion).
8.1.3.
Therapy for Pneumocystis carinii/jirovecii
Pneumocystis carinii/jirovecii pneumonia prophylaxis should be considered, as per institutional 
guidelines.


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8.1.4.
Prophylaxis for Herpes Zoster Reactivation
The initiation of antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after 
starting study treatment and continuing for 3 months following study treatment is recommended. 
Acceptable antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times a day, or
800 mg given orally 2 times a day or per institutional standards), famcyclovir (eg, 125 mg given 
orally, twice a day or per institutional standards), or valacyclovir (eg, 500 mg given orally, twice 
a day or per institutional standards), initiated within 1 week after the start of study drug.
8.1.5.
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), sucralfate, or H2 blockers (ranitidine or equivalent).
8.1.6.
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care. Per protocol, HBV DNA 
testing by PCR is mandatory for subjects at risk for HBV reactivation, see Section 9.7.
For subjects with evidence of positive HBV serology, monitor for clinical and laboratory signs of 
HBV reactivation during, and for at least 6 months following the end of study treatment. Manage 
subjects according to current clinical guidelines. Consider consulting a hepatitis disease expert as 
clinically indicated.
For subjects who develop reactivation of HBV while on study treatment, suspend study treatment 
and institute appropriate treatment for HBV or follow country-specific clinical guidelines.
Resumption of study treatment in subjects whose HBV reactivation is adequately controlled 
should be discussed with physicians with expertise in managing HBV.
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:

Antivirals

Colony stimulating factors, erythropoietin, and transfusion of platelets and red cells is 
allowed, except as prophylaxis during Cycle 1

Laxatives or stool softeners

Adequate hydration is recommended for prevention of myeloma-related kidney disease.
Other symptoms may be managed according to institutional guidelines provided prohibited 
therapies are not administered (see Section 8.3, Prohibited Therapies).


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8.3.
Prohibited Therapies
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered. Concomitant administration of any other 
antineoplastic therapy for the intention of treating multiple myeloma is prohibited, including 
medications that target CD38, as well as medications used for other indications that have 
anti-myeloma properties (eg, interferon and clarithromycin). Continuation of study treatment 
(during or after emergency orthopedic surgery or radiotherapy because of subject benefit) may 
only occur in the absence of disease progression and after consultation with and approval by the
sponsor. 
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 for whom delay of systemic therapy is not appropriate. 
Radiotherapy must occur within the first 2 cycles of treatment and only if disease progression 
has not occurred. Before radiotherapy, the sponsor will review the evidence and confirm that 
disease progression has not occurred.
Concomitant administration of investigational agents and of commercially available agents with 
activity against or under investigation for multiple myeloma are prohibited. Systemic 
corticosteroids (>10 mg prednisone per day or equivalent) (other than those given for IRRs as 
described in Section 6.3, Predose and Postdose Medications) should be avoided. Nonsteroidal 
anti-inflammatory agents should be avoided to prevent myeloma-related kidney disease. 
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules (Table 1 and Table 2) summarize the frequency and timing of 
measurements applicable to this study. Every effort should be made to keep subjects on the 
planned study schedule including subjects who switch from Dara-IV to Dara-SC following 
Protocol Amendment 4. At each visit, study assessments should be completed before study 
treatment administration. The modified-CTSQ should be conducted and completed before any 
tests, procedures, or other consultations for that visit, to prevent influencing subject perceptions.
Disease evaluations must be performed every 28 days (±7days) starting from Cycle 1 Day 1. Any 
missed visits, tests not performed, or examinations that are not conducted must be reported as 
such on the eCRF. 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 maximum blood volume for a subject who completes 8 cycles and the post-treatment 
assessments is approximately 490 mL. The total blood volume to be collected is estimated at 
approximately 34 mL for Screening, 100 mL for Cycles 1 and 2, 161 mL for Cycles 3-6, 21 mL 
at each subsequent cycle, 55-85 mL for pharmacokinetics (depending on treatment group), 5 mL 


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when CR is suspected or maintained, and 50 mL at the End-of-Treatment visit. 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. In the Follow-up Phase, subjects who discontinue study 
drug prior to PD will continue to have approximately 20 mL blood drawn every 2 months for 
serum disease evaluations.
Subjects benefiting from daratumumab after the data collection period has ended may continue 
receiving study drug (see Attachment 13).
9.1.2.
Screening Phase
The Screening Phase begins when the ICF is signed. During the Screening Phase, eligibility 
criteria will be reviewed and a complete clinical evaluation will be performed as specified in the 
Time and Events Schedule. Screening procedures will be performed within 28 days before
randomization, with the exceptions of disease evaluations, laboratory tests, and pregnancy tests. 
Serum and urine baseline disease evaluations are to be performed by the central laboratory 
within 14 days before randomization. It is not mandatory to collect these samples again at the 
Cycle 1, Day 1 visit. Results from skeletal survey and radiologic plasmacytoma assessments 
performed as routine follow up for subject's disease within 42 days before randomization and 
bone marrow aspirate/biopsy within a maximum of 42 days before randomization may be used 
without these tests being repeated. If the 24h collection of urine M-protein quantitation by 
electrophoresis (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. During Screening, a pregnancy test must be performed 
within 14 days prior to dosing. If approved by the sponsor, subjects who are screen failures may 
be rescreened if their condition changes (see Section 4.2, Exclusion Criteria, for details).
Prior to randomization, the sponsor will review key eligibility criteria for all subjects. Eligibility 
information will be provided to the sponsor for review prior to approval for randomization being 
granted by the sponsor. If the sponsor agrees that the eligibility criteria have been met, then the 
investigator will receive confirmation that the subject may be randomized into the study. If the 
sponsor considers that the eligibility criteria have not been met, then the sponsor will contact the 
investigator to discuss the subject.
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. 
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 confirmed, then the subject will discontinue study 
treatment, complete the End-of-Treatment Visit, and enter the Follow-up Phase.


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End-of-Treatment Visit
Unless a subject withdraws consent for study participation or is lost to follow up, an 
End-of-Treatment Visit is to occur 4 weeks after the last dose of study treatment for collection of 
adverse events for 30 days postdose, or as soon as possible before the start of subsequent 
therapy. 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 and 
concomitant medications used to treat adverse events as specified in Section 12.3.1, All Adverse 
Events. If the End-of-Treatment visit occurs before 30 days, then the subject should be contacted 
after 30 days so that all adverse events that occurred within the 30-day period are recorded. 
Additional information on reporting of adverse events is presented in Section 12, Adverse Event 
Reporting.
9.1.4.
Follow-Up Phase 
Each subject is to have a follow-up visit 8 weeks after the last dose of study treatment. Beyond
30 days after the last dose, serious adverse events considered related to study treatment will 
continue to be collected. For a subject who discontinues study treatment before disease 
progression, disease evaluations should continue to be performed as specified in the Time and 
Events Schedule. After disease progression is documented, survival status, subsequent anticancer 
treatment, response to subsequent anticancer treatment, and date of progression will be recorded. 
Information on all new second primary malignancies will also be collected until the end of the 
data collection period. If the information is obtained via telephone contact, then written 
documentation of the communication must be available for review in the source documents. If 
the subject has died, then the date and cause of death will be collected and documented on the 
eCRF.
Follow-up will continue until the end of the data collection period, approximately 24 months 
after the last subject was randomized or when median overall survival for both arms has been 
reached, whichever occurs first.
Continuation of Follow-up Phase study procedures is not required once the end of the data 
collection period is reached, and the End of Trial page of the eCRF should completed at that time 
for subjects ongoing in the Follow-up Phase.
9.1.5.
Post Data Collection Period to End of Study
The sponsor will ensure that subjects benefiting from treatment with either the IV or SC 
formulation of daratumumab will be able to continue receiving treatment after the end of the data 
collection period until the applicable formulation is commercially available or available from 
another source, or until the study is complete (Section 17.9.1). Attachment 13 describes study 
procedures to be followed for subjects who continue treatment with study drug after the end of 
the data collection period.


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9.2.
Efficacy Evaluations
9.2.1.
Response Categories
Disease evaluations must be performed every 28 days (±7days), regardless of any changes to the 
dosing regimen, until disease progression. 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 20067; Kumar 201611;
Rajkumar 201122) presented in Table 5. For quantitative immunoglobulin (QIg), M-protein, and 
immunofixation measurements in serum and 24 hour urine, the investigator will use results 
provided by the central laboratory. For subjects with light chain multiple myeloma, only serum 
FLC assay will be performed routinely. Otherwise, serum FLC assay test results will be analyzed 
by the central laboratory only for the assessment of sCR. For subjects with suspected 
daratumumab interference on serum M-protein quantitation by electrophoresis (SPEP) and 
immunofixation, a reflex assay will be performed (Attachment 10). Subjects with confirmed 
daratumumab interference who meet all other clinical criteria for CR or sCR will be considered 
CR/sCR.
Table 5:
International Uniform Response Criteria Consensus Recommendations
Response 
Response Criteria
Stringent complete
Response (sCR)

CR as defined below, plus

Normal FLC ratio, and

Absence of clonal PCs by immunohistochemistry, immunofluorescencea or 2- to 4-color flow 
cytometry
Complete response (CR)*

Negative immunofixation on the serum and urine, and

Disappearance of any soft tissue plasmacytomas, and

<5% PCs in bone marrow
Very good partial
Response (VGPR)*

Serum and urine M-component detectable by immunofixation but not on electrophoresis, or

≥90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours
Partial response (PR)

≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to 
<200 mg/24 hours

If the serum and urine M-protein are not measurable, a decrease of ≥50% in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria

If serum and urine M-protein are not measurable, and serum free light assay is also not 
measurable, ≥50% reduction in bone marrow PCs is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was ≥30%

In addition to the above criteria, if present at baseline, a ≥50% reduction in the size of soft 
tissue plasmacytomas is also required.
Minimal response (MR)

25% but 49% reduction of serum M-protein, and

Reduction in 24-h urine M-protein by 50–89%

In addition to the above criteria, if present at baseline, a 25% to 49% reduction in the size of 
soft tissue plasmacytomas also is required
Stable disease (SD)

Not meeting criteria for CR, VGPR, PR, MR, or PD
Progressive disease (PD)†

Increase of 25% from lowest response value in any one of the following:

Serum M-component (absolute increase must be ≥0.5 g/dL), 

Urine M-component (absolute increase must be ≥200 mg/24 hours), 

Only in subjects without measurable serum and urine M-protein levels: the difference between 
involved and uninvolved FLC levels (absolute increase must be >10 mg/dL)

Only in subjects without measurable serum and urine M-protein levels and without measurable 
disease by FLC levels, bone marrow PC percentage (absolute percentage must be ≥10%)

Bone marrow plasma cell percentage: the absolute percentage must be >10%

Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in 
the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed 
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Table 5:
International Uniform Response Criteria Consensus Recommendations
Response 
Response Criteria
CR=complete response; FLC=free light chain; IMWG=International Myeloma Working Group; M-protein=monoclonal 
paraprotein; MR=minimal response; PC=plasma cell; PD=progressive disease; PR=partial response; sCR=stringent complete 
response; SD=stable disease; VGPR=very good partial response
All response categories (CR, sCR, VGPR, PR, and PD) require 2 consecutive assessments made at any time before the institution
of any new therapy; CR, sCR, VGPR, PR, and SD categories also require no known evidence of progressive or new bone lesions 
if radiographic studies were performed. VGPR and CR categories require serum and urine studies regardless of whether disease 
at baseline was measurable on serum, urine, both, or neither.
Radiographic studies are not required to satisfy these response requirements. Bone marrow assessments need not be confirmed. 
For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M-component is 
≥5 g/dL.
* Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC 
levels: CR in such subjects indicates a normal FLC ratio 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 IMWG criteria (Durie 20067; Kumar 201611;
Rajkumar 201122). In 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.
M-protein levels need to meet the definition of disease progression (see Table 5) for subjects to 
have disease progression. Disease evaluations will continue beyond relapse from CR until 
disease progression is confirmed.
Disease progression must be consistently documented across clinical study sites using the criteria 
in Table 5. It is important that instances of disease progression be reported to the sponsor as soon 
as possible. Diagnosis and documentation of disease progression will be reported to the sponsor
within 24 hours of suspected disease progression. The medical monitor will review the 
information to confirm that the IMWG criteria for disease progression have been met. If the 
medical monitor agrees that disease progression has occurred, then a confirmation will be 
returned to the investigator, and the subject will be withdrawn from study treatment. If the 
medical monitor considers that the IMWG criteria for disease progression have not been met, 
then the medical monitor will contact the investigator to discuss the subject.


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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 IMWG criteria.
For subjects who discontinue study treatment before disease progression, disease evaluations 
should continue to be performed as described in the Time and Events Schedule, until confirmed 
disease progression, death, start of a new treatment for multiple myeloma, withdrawal of consent 
for study participation, or the end of the data collection period, whichever occurs first. Blood and 
urine for disease evaluations scheduled for treatment days should be collected before study 
treatment is administered.
Refer to Attachment 13 details on efficacy evaluations after the end of the data collection period.
9.2.2.
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples will be collected as specified in the Time and Events Schedule 
until the development of confirmed disease progression. 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:

Serum QIgs: All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD at Screening. 
During the study, subjects with IgD or IgE disease will be evaluated for IgG, IgA, IgM, IgE, 
and IgD and subjects with IgG, IgA, or IgM disease will be evaluated for IgG, IgA, and 
IgM.

Serum M-Protein quantification by electrophoresis (SPEP)

Serum immunofixation at Screening and thereafter when a CR is suspected. If daratumumab 
interference is suspected based on SPEP and immunofixation (IFE) results, additional reflex 
IFE testing may be performed.

Serum FLC assay

24-hour UPEP

Urine immunofixation at Screening and thereafter when a CR is suspected
Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 
1 repeat investigation. Disease evaluations will continue beyond relapse from CR until disease 
progression is confirmed. 
Subjects with a urine M-protein on UPEP >100 mg/24h at Screening will provide samples for 
UPEP assessment on the same schedule as SPEP throughout the study according to the Time & 
Events Schedule. Subjects can stop collecting samples for UPEP assessments after C1D1 only if 
1) they have urine M-protein <100 mg/24h at Screening, or 2) they have measurable urine 
M-protein >100 mg/24h at Screening but then urine M-protein <100 mg/24h at 2 consecutive 
post-baseline measurements. A urine sample for UPEP assessment should be obtained to 
document VGPR, CR, and sCR and at suspected disease progression for all subjects with 


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measurable disease by SPEP or UPEP (non-FLC), regardless of UPEP collection exemptions as 
described above.
Serum and urine immunofixation test and serum FLC 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). For subjects with suspected daratumumab 
interference on serum immunofixation, another reflex assay using the anti-idiotype mAb will be 
used to confirm daratumumab migration on immunofixation. Subjects that meet all other IMWG 
criteria for CR, and whose positive immunofixation is confirmed to be daratumumab, will be 
considered complete responders. However, for subjects with light chain multiple myeloma, 
serum FLC assay will be performed routinely. Serum immunofixation assay samples will be split 
into 2 aliquots, with 1 reserved for potential follow-on testing if daratumumab interference with 
immunofixation is suspected. As daratumumab is a monoclonal IgG antibody, additional serum 
samples may be utilized to monitor for potential daratumumab interference with immunofixation.
Note: All attempts should be made to determine eligibility of the subject based on the central 
laboratory results of screening blood and urine M-protein measurements. In exceptional 
circumstances, the local laboratory results of blood and urine M-protein measurements may be 
used to determine eligibility, but only if the results are clearly (eg, 25% or more) above the 
thresholds for measurability. In such cases, central laboratory results are still required to be 
obtained in order to establish baseline values and confirm the results from the local laboratory.
9.2.3.
Serum Calcium Corrected for Albumin
Blood samples for calculating serum calcium corrected for albumin will be collected as specified 
in the Time and Events Schedule and analyzed centrally until the development of confirmed 
disease progression. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 
2.8 mmol/L) can indicate disease progression or relapse if it is not attributable to any other cause 
(see disease response criteria in Table 5). Calcium binds to albumin and only the unbound (free) 
calcium is biologically active; therefore, the serum calcium level must be adjusted for abnormal 
albumin levels (“corrected serum calcium”). The formula for adjustment is presented in 
Attachment 5.
When blood is analyzed at a local laboratory, measurement of free ionized calcium is an 
acceptable alternative to corrected serum calcium to determine hypercalcemia. Free ionized 
calcium levels greater than the ULN (local laboratory reference ranges) are considered to be 
hypercalcemic for this study.
9.2.4.
β2-microglobulin and Albumin
Blood samples for β2-microglobulin and albumin are to be collected at Screening and will be 
analyzed by the central laboratory and used for the assessment of International Staging System 
staging at study entry. The central laboratory will also measure albumin at any time during the 
study that a serum calcium sample is taken.


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9.2.5.
Bone Marrow Examination
Bone marrow assessments to be performed locally and centrally are summarized in Table 6.
Table 6:
Bone Marrow Testing
Local Testing
Central Testing
Screening
Bone marrow 
aspirate/biopsy
Disease characterization (morphology and either 
immunohistochemistry, immunofluorescence, or flow 
cytometry). Cytogenetics by FISH (preferred) or 
karyotyping.
If a fresh bone marrow aspirate is 
collected at Screening, a portion will be 
sent to a central laboratory for
biomarker evaluation.
CR, sCR
Bone marrow 
aspirate or biopsy 
(or both)
For response confirmation, additional bone marrow 
aspirates or biopsies (or both) will be performed locally 
(Disease characterization [morphology and either 
immunohistochemistry, immunofluorescence, or flow 
cytometry]) to confirm sCR or CR. 
For sCR: immunohistochemistry, immunofluorescence 
(requires kappa/lambda ratio from analysis of 100 cells) or 
2- to 4-color flow cytometry.
Disease Progression
Bone marrow 
aspirate or biopsy 
(or both)
Not applicable
If feasible, a bone marrow aspirate may 
be collected from subjects at disease 
progression to evaluate mechanisms of 
daratumumab resistance.
CR=complete response; FISH=fluorescence in situ hybridization; sCR=stringent complete response
9.2.6.
Assessment of Lytic Bone Disease
A complete skeletal survey (including skull, entire vertebral column, pelvis, chest, humeri, 
femora, and any other bones for which the investigator suspects involvement by disease or the 
local standard of care imaging, [eg, low-dose CT]) is to be performed and evaluated at the study 
site during the Screening Phase. 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, x-rays should be performed to document response or progression 
whenever clinically indicated based on symptoms. Magnetic resonance imaging (MRI) or 
low-dose CT are acceptable methods for evaluation of bone disease and may be included at the 
discretion of the investigator (see the disease response criteria in Table 5). 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. In these cases, disease progression may be documented 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 x-rays are 
necessary. In instances where changes may be more subtle, a repeat x-ray may be needed in 1 to 
3 weeks.
9.2.7.
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 


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contraindication to the use of IV contrast. Positron emission tomography scan or ultrasound tests 
are not acceptable to document the size of extramedullary plasmacytomas.
For subjects with a history of plasmacytomas, extramedullary plasmacytomas should be assessed
at Screening by clinical examination or radiologic imaging. They should also be assessed to 
confirm response, disease progression, or as clinically indicated. 
To qualify for PR or better, 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 5). To qualify for CR or 
better, all extramedullary plasmacytomas must have resolved. To qualify for disease progression, 
either the sum of products of the perpendicular diameters of the existing extramedullary 
plasmacytomas must have increased by at least 50% or a new plasmacytoma must have 
developed. In the cases where not all existing extramedullary plasmacytomas are reported, but 
the sum of products of the perpendicular diameters of the reported plasmacytomas have 
increased by at least 50%, this will also qualify as disease progression.
9.3.
Pharmacokinetics and Immunogenicity
9.3.1.
Evaluations 
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the 
generation of anti-daratumumab antibodies (immunogenicity) will be drawn from all subjects 
according to the Time and Events Schedule. At specified time points, venous blood samples 
(5 mL per sample) will be collected and the serum will be divided into 3 aliquots (1 aliquot for 
pharmacokinetic analysis, 1 aliquot for immunogenicity assessment [when appropriate], and 
1 aliquot as a back-up). 
Samples will also be collected from all subjects receiving Dara-SC (with the exception of 
subjects who switch from Dara-IV to Dara-SC following Protocol Amendment 4) to evaluate the 
immunogenicity of rHuPH20 according to the Time and Events Schedule. At specified time 
points, venous blood samples (5 mL per sample) will be collected and the plasma will be divided 
into 5 aliquots to accommodate immunogenicity screening, confirmatory, and titer assays and 
neutralizing antibody analysis (when appropriate) as well as volume for backup. No rHuPH20 
immunogenicity samples should be collected from subjects who switch from Dara-IV to 
Dara-SC following Protocol Amendment 4.
The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual 
for sample collection requirements. Collected samples must be stored under the specified and 
controlled conditions for the temperatures indicated in the laboratory manual. Samples collected 
for determining serum concentrations of daratumumab in this study may be retained to address 
questions about drug characteristics that may arise at a later time point.
9.3.2.
Analytical Procedures
Samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab or rHuPH20 using validated immunoassay methods by or under the 


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supervision of the sponsor. For the daratumumab immunogenicity assessments, serum samples 
will be screened for antibodies binding to daratumumab and serum titer will also be determined 
from confirmed positive samples. Other immunogenicity analyses (eg, assessment of neutralizing 
capabilities) may be performed to further characterize the immune responses that are generated.
For the rHuPH20 immunogenicity assessments, plasma samples will be screened for antibodies 
binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary. 
Neutralizing antibody assessments may also be performed to further characterize immune 
responses that are generated.
9.3.3.
Pharmacokinetic Parameters
The pharmacokinetic parameters are defined as:
Maximum Ctrough
Serum predose concentration of daratumumab on Cycle 3 Day 1
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
Other pharmacokinetic parameters may be calculated. The Maximum Ctrough, Cmin, and Cmax will 
be determined based on the assigned collection timepoints. If there are sufficient data, population 
pharmacokinetic analysis of serum concentration-time data of daratumumab may be performed 
and may include data from other clinical studies. If performed, details will be provided in a 
population pharmacokinetic analysis plan and results of the analysis will be presented in a 
separate report. 
9.3.4.
Immunogenicity Assessments
Serum from venous blood samples collected from all subjects will be assessed for the generation 
of anti-daratumumab antibodies (immunogenicity) according to the Time and Events Schedule. 
Daratumumab concentration will be evaluated at all immunogenicity time points to ensure 
appropriate interpretation of immunogenicity data. When both daratumumab serum 
concentration and immunogenicity analyses are specified, they will be performed on aliquots 
from the same blood draw and no additional sampling is required. Plasma samples will be 
collected from all subjects receiving Dara-SC (with the exception of subjects who switch from 
Dara-IV to Dara-SC following Protocol Amendment 4) and assessed for antibodies to rHuPH20. 
Procedures for sample collection, preparation, identification, storage, and shipment will be 
provided in the laboratory manual or equivalent document.
When an IRR occurs associated with the second administration or beyond, 1 blood sample 
should be obtained, if possible, from subjects in the Dara-IV group for determination of 
antibodies to daratumumab; in the Dara-SC group, 2 blood samples should be obtained, if 
possible, for determination of both antibodies to daratumumab and antibodies to rHuPH20. For 
subjects who switch from Dara-IV to Dara-SC, only 1 sample should be collected when an IRR 
occurs (to determination antibodies to daratumumab only, as antibodies to rHuPH20 will not be 
assessed in subjects who switch from IV to SC). No unscheduled samples need to be collected 
for IRRs associated with the first administration of daratumumab. Daratumumab serum 
concentration will also be determined from the daratumumab infusion reaction sample for the 


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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. Procedures for sample collection, 
preparation, identification, storage, and shipment will be provided in the Laboratory Manual or 
equivalent document. Samples collected for the analysis of daratumumab immunogenicity/serum 
concentration or rHuPH20 immunogenicity may 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.
Subjects who discontinue treatment or withdraw from the study before confirmation of PD 
should have samples collected at the time of early discontinuation. Subjects who discontinue 
treatment will also be asked to return for immunogenicity evaluation during the Follow-up 
Phase. These samples will be tested by the sponsor or sponsor's designee.
9.4.
Biomarkers 
Samples for biomarker evaluations will be collected as specified in the Time and Events 
Schedule. Baseline bone marrow aspirate samples are required, if feasible, and may be subjected 
to DNA and RNA sequencing in order to identify multiple myeloma antigens to evaluate the 
generation of antigen specific immune responses, to classify subjects into high-risk molecular 
subgroups and to evaluate biomarkers of response and resistance to daratumumab. 
In addition to planned bone marrow aspirate assessment, whole blood samples will be collected 
from subjects as outlined in the Time and Events Schedule for processing to plasma and 
peripheral blood mononuclear cells (PBMCs). These samples will be drawn from all subjects to 
evaluate pharmacodynamic biomarkers and to evaluate the role of the immunomodulatory 
mechanism of action of daratumumab in response and development of resistance. Testing may 
include evaluation of specific subsets of immune cells such as cytotoxic T cells, regulatory 
T cells, myeloid-derived suppressor cells, B cells, and NK cells. Cells may also be used for 
additional phenotypic and functional profiling. Previous clinical studies indicate CD8+ T cell 
expansion, which could be an additional mechanism for daratumumab activity. If CD8+ T cell 
expansion is noted in this study, then T-cell receptor sequences may be analyzed on PBMC DNA 
to assess clonal expansion of cytotoxic T cells. 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 and to evaluate potential 
biomarkers of response and resistance.
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays. 
Biomarker analysis may be deferred or not performed, if during or at the end of the study, it 
becomes clear that the analysis will not have sufficient scientific value for biomarker evaluation, 
or if there are not enough samples or responders to allow for adequate biomarker evaluation. In 
the event the study is terminated early or shows poor clinical efficacy, completion of biomarker 
assessments is based on justification and intended utility of the data.


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9.5.
Patient-reported Outcomes
The modified-CTSQ is included in the clinical study as a measure to assess patient satisfaction 
with daratumumab treatment, support market access and the payer request for patient-reported 
outcomes (PRO) data, and assess superiority of Dara-SC. The modified-CTSQ is a secondary 
endpoint, not part of the statistical hierarchy. Non-inferiority will not be analyzed for this 
endpoint. Details on the statistical analyses will be included in the Statistical Analysis Plan. 
The Cancer Therapy Satisfaction Questionnaire (CTSQ) is a 16-item PRO measure that assesses 
satisfaction with and preference for chemotherapy, hormonal and biological therapies based on 
efficacy, tolerability, and convenience. The CTSQ was developed to compare IV administration 
with oral medication (Abetz 20051; Trask 200823). Minimally important differences for the 
Satisfaction with Therapy domain were estimated using distribution based methods and based on 
known-group differences (Trask 200823). Using known groups of perceived change in cancer the 
average difference between groups was 3.7 points and using distribution-based methods the 
minimally important difference was 6.88 for 0.5 standard deviation and 5.84 for 1 standard error 
or measure using internal consistency reliability (Trask 200823). 
The modified-CTSQ was adapted, with approval from the instrument developer, to contain 
9 items specific to satisfaction with therapy and for comparison of IV with SC administration 
(Attachment 11). A domain score for Satisfaction with Therapy is calculated based on 7-items. 
Each item asks about the most recent cancer therapy using a 5-point verbal rating scale. The 
modified-CTSQ takes less than 10 minutes to complete and will be completed by the subject 
using paper administration. 
The modified-CTSQ assesses previous administration of daratumumab, not the current visit
administration. To achieve unbiased assessments, the modified-CTSQ should be administered 
before the subject’s clinical examination, the subject receives any tests or test results, and the 
subject’s health, health data, or emotions are discussed. The modified-CTSQ will be completed 
per the Time and Events Schedule until the end of the data collection period.
9.6.
Medical Resource Utilization
Medical resource utilization data will be collected to determine the medical cost impact of the 
two administration routes that may be used to support the value story and cost-effectiveness 
modeling for market access. Medical resource utilization data associated with medical 
encounters due to IRRs or injection site reactions, primarily hospitalizations, outpatient visits and
emergency room visits, will be collected in the eCRF by the investigator and study-site personnel 
for all subjects throughout the study. Protocol-mandated procedures, tests, and encounters are 
excluded. The data collected will include:

Duration of hospitalization (total length of stay, including duration by each hospital unit)

Number and character of diagnostic and therapeutic tests and procedures 

Outpatient medical encounters (including physician, nurse practitioner or emergency room 
visits, tests and procedures)


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9.7.
Safety Evaluations
Details regarding the IDMC are provided in Section 11.12, Safety Data Monitoring. Safety will 
be measured by adverse events, physical examination findings, ECG, SC injection site 
evaluations, laboratory test results, vital sign measurements, and assessment of ECOG 
performance status score. All toxicities will be graded according to the NCI-CTCAE 
Version 4.03. 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 previous experience with daratumumab, IRRs, allergic reactions, hemolysis, and 
thrombocytopenia will be closely monitored. As daratumumab is a biologic agent, 
immunogenicity will also be monitored. Any of the safety monitoring assessments may be 
performed more frequently, and adverse events should be evaluated by the investigator according 
to the standard practice, if clinically indicated. Any clinically relevant changes occurring during 
the study must be recorded on the Adverse Event section of the eCRF.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject's legally acceptable representative) from the time a signed and dated informed 
consent is obtained until at least 30 days after the last dose of study treatment during the data 
collection period, unless the subject withdraws consent for study participation or starts 
subsequent anticancer therapy. Adverse events will be followed by the investigator as specified 
in Section 12, Adverse Event Reporting. After the data collection period has ended, only serious 
adverse events will be collected, as described in Attachment 13.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the adverse event section of the eCRF. The laboratory reports must 
be filed with the source documents.
The following tests will be performed by the local laboratory, unless otherwise specified:

Hematology Panel 
-hemoglobin
-white blood cell count, absolute neutrophil count, and absolute lymphocyte count
-platelet count


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
Serum Chemistry Panel 
-AST
-alkaline phosphatase
-ALT
-uric acid
-total bilirubina
-blood urea nitrogen or urea
-glucose
-calcium and albumin-adjusted calciumb
-creatinine
-lactic acid dehydrogenase
-sodium
-potassium
a
If Gilbert's disease, assessment of direct bilirubin.
b
These parameters will be part of the efficacy evaluations as specified in Section 9.2.3, Serum Calcium 
Corrected for Albumin, and will be analyzed at a central laboratory. 
Serum or Urine Pregnancy Testing
Serum or urine pregnancy testing will be performed for women of childbearing potential as 
specified in the Time and Events Schedule. 
Indirect Antiglobulin Test (IAT) 
Blood Type, Rh, and Indirect Antiglobulin Test (IAT) should be done before the first dose of 
daratumumab. Subject RBC phenotyping (standard or extended) is an alternative option to the 
IAT test, if locally required. Either method must be completed prior to first study drug 
administration.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to 
identify a patient's antibodies to minor antigens so that suitable donor blood can be given for 
transfusion. Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very 
low levels on erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a 
positive IAT (Indirect Coombs Test). This positive result masks the detection of antibodies to 
minor antigens and may prevent or delay blood banks from issuing donor blood for transfusion. 
This effect occurs during daratumumab treatment and for up to 6 months after treatment ends. 
Subjects will receive a patient identification wallet card for the study that includes the blood 
profile (ABO, Rh, and IAT or phenotyping) determined before the first study drug 
administration, along with information on the IAT interference for healthcare providers/blood 
banks. Subjects are to carry this card throughout the treatment period and for at least 6 months 
after treatment ends. Blood banks can eliminate the daratumumab interference with IAT by 
treating reagent RBCs with dithiothreitol (DTT) (Chapuy 20155; Chapuy 20164).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a.
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
b. Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice.


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Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. For additional details, refer to the 
daratumumab Investigator's Brochure (IB daratumumab10).
HBV DNA Tests
Subjects who are positive for anti-HBc or anti-HBs will undergo testing for hepatitis B DNA by 
PCR every 4 weeks (each cycle). Subjects who are positive for anti-HBs antibodies due to prior 
immunization are not required to be monitored by HBV DNA by PCR. During and following 
study treatment, subjects who have history of HBV infection will be closely monitored for 
clinical and laboratory signs of reactivation of HBV as specified in the Time and Events 
Schedule. Subjects with serologic findings suggestive of prior HBV vaccination (anti-HBs 
positivity as the only serologic marker) AND a known history of prior HBV vaccination do not 
need to be tested for HBV by PCR and do not need to be followed by repeat HBV PCR. Where 
required by local law, the result of HBV testing may be reported to the local health authorities.
Subjects benefiting from daratumumab after the data collection period has ended may continue 
receiving study drug, and HBV DNA testing will be performed as detailed in Attachment 13.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during screening.
Electrocardiogram (ECG)
A 12-lead ECG will be performed as described 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 blood pressure 
measurement is scheduled for the same time point as ECG recording, then the procedures should 
be performed in the following order: ECG(s), blood pressure, blood draw.
Vital Signs
Vital signs (pulse, temperature, blood pressure) will be performed as specified in the Time and 
Events Schedule. It is recommended that blood pressure and pulse measurements be preceded by 
at least 5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).
Physical Examination and ECOG Performance Status
A complete physical examination (including neurological examination) should be performed 
during the Screening Phase. Thereafter, only a symptom-directed physical examination is 
required. Height will be measured at screening only; weight will be measured on Day 1 of each 
treatment cycle. Abnormalities will be recorded in the appropriate section of the eCRF. ECOG 
performance status will be used to evaluate the effect of the disease status on the activities of 
daily living. 


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9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form. Refer to the Time and Events Schedule for the timing and frequency of all sample 
collections. Instructions for the collection, handling, storage, and shipment of samples are found 
in the laboratory manual that will be provided. Collection, handling, storage, and shipment of 
samples must be under the specified, and where applicable, controlled temperature conditions as 
indicated in the laboratory manual.
After the end of the data collection period, sample collection and handling will occur as detailed 
in Attachment 13.
10.
SUBJECT DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL 
FROM THE STUDY
10.1.
Discontinuation of Study Treatment
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued, this will not result in automatic withdrawal 
of the subject from the study. The End-of-Treatment Visits and Follow-up visit assessments 
should continue as specified in the Time and Events Schedule.
A subject's study treatment must be discontinued if:

The investigator believes that for safety or tolerability reasons (eg, adverse event) it is in the 
best interest of the subject to discontinue study treatment.

The subject becomes pregnant unless the subject (or the subject's legally acceptable 
representative), investigator, and sponsor agree the benefits outweigh the risks to the fetus 
and continuation of study treatment is in the best interests of the subject 

The subject (or the subject's legally acceptable representative) withdraws consent for 
administration of study drug

The subject experiences unacceptable toxicity, including IRRs described in Section 6.4, 
Management of Injection-site and Infusion-related Reactions

The subject’s dose is held for more than 28 days, or if 3 consecutive planned doses of 
daratumumab are missed for reasons other than toxicity unless, upon consultation with the 
sponsor and the review of safety and efficacy, continuation is agreed upon

The subject experiences disease progression (please see below); relapse from CR is not 
considered as disease progression

The subject experiences a second primary malignancy that cannot be treated by surgery 
alone (however, a subject who develops a malignancy that can be cured surgically may 
continue to receive the assigned study treatment and should continue to be followed for 
subsequent progression of multiple myeloma)
The primary reason for discontinuation of study treatment will be recorded in the eCRF.


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Study treatment will continue until confirmation of PD. Before subjects are discontinued from 
study treatment because of suspected PD:
1.
The investigator (or designee) will provide documentation of disease progression 
(for example, by completing a disease progression form or by contacting the IWRS) as soon 
as possible and within 48 hours of confirmation of disease progression. 
2.
The sponsor's medical monitor will review the provided documentation and confirm PD has 
occurred per IMWG criteria (see Section 9.2.1, Response Categories) and that study 
treatment should be discontinued. 
3.
After confirmation of PD by the sponsor, the subject will discontinue study treatment and 
enter the Follow-up Phase.
If a subject's study treatment must be discontinued, this will not result in automatic withdrawal 
of the subject from the study; instead, the subject will enter the Follow-up Phase. The 
End-of-Treatment Visit and Follow-up Visit assessments should continue as specified in the 
Time and Events Schedule.
10.2.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death

Sponsor terminates the study
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 before completing the study, the reason for withdrawal is documented 
in the eCRF and in the source document. Study drug assigned to the withdrawn subject may not 
be assigned to another subject. If subjects withdraw from the study, additional subjects will not 
be enrolled. If a subject discontinues study drug and withdraws from the study before the end of 
the Treatment Phase, End-of-Treatment assessments should be obtained. If the withdrawal from 
the study is withdrawal of consent then no additional assessments are allowed.
10.3.
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,
Long-term Retention of Samples for Additional Future Research). In such a case, samples will be 
destroyed after they are no longer needed for the clinical study. Details of the sample retention 
for research are presented in the main ICF. 


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11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
11.1.
Subject Information
The main analysis populations are:

Intent-to-treat population, defined as all randomized subjects

Safety population, defined as randomized subjects who receive at least 1 dose of study agent

Per-protocol population, defined as all treated subjects who have measurable disease at 
baseline and have no major protocol deviations with respect to eligibility

Pharmacokinetic evaluable population, defined as subjects who received all 8 weekly doses 
of Dara-IV or Dara-SC in Cycle 1 and Cycle 2 according to the Time and Events Schedule 
and provide a predose pharmacokinetic sample on Cycle 3 Day 1
The intent-to-treat population will be used to summarize the study population and efficacy. The 
safety population will be used to summarize the safety data. The per-protocol population will be 
used for critical sensitivity analyses of ORR in the context of the non-inferiority design. The 
pharmacokinetic evaluable population will be used to summarize the maximum Ctrough.
Descriptive statistics will be used to summarize data. For continuous parameters, number of 
observations, mean, standard deviation, median, and range will be used. For discrete parameters, 
frequency will be summarized. For time-to-event parameters, Kaplan-Meier estimates will be 
produced. When sample sizes are small, sample listings may be provided instead.
11.2.
Sample Size Determination
In a previous clinical study (MMY2002), of 106 subjects with relapsed or refractory multiple 
myeloma who had received at least 3 prior therapies and who were treated with Dara-IV 
16 mg/kg, an ORR of 29.2% (95% CI: 20.8%, 38.9%) was observed. Non-inferiority of Dara-SC
to Dara-IV in the current study is defined using a 60% retention of the lower bound (20.8%) of 
the 95% CI from Study MMY2002. With a planned 1:1 randomization, 480 subjects (n=240 in 
the Dara-SC group and n=240 in the Dara-IV group) will be needed to demonstrate 
non-inferiority with a power of 80% and a one-sided alpha=0.025, assuming that the true ORR is 
the same for both groups. The sample size calculation is based on the methodology for the 
non-inferiority test for non-unity null, as described by Farrington and Manning (1990).8
The study is also designed to establish non-inferiority of the co-primary pharmacokinetics 
endpoint, maximum Ctrough, between Dara-SC and Dara-IV. Dara-SC will be considered 
non-inferior to Dara-IV if the lower bound of the 90% CI for the ratio of the geometric means of 
Ctrough on Cycle 3 Day 1 is at least 80% (non-inferiority margin of 20%). A one-sided test is 
selected based on previous analyses that demonstrated a strong relationship between maximum 
Ctrough and efficacy. However, there is no apparent relationship between drug exposure in the 
therapeutic dose range and adverse events of interest. With the planned 1:1 randomization, 


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480 subjects a one-sided alpha=0.05, the power will be >95%. This assumes a true ratio of the 
maximum Ctrough of 1, a non-inferiority margin of at least 80% of the geometric mean ratio, and a 
coefficient of variation of 0.6.
11.3.
Co-primary Endpoints
1.
ORR: The number and proportion of subjects who achieve PR or better will be calculated for 
each group. The primary analysis will use the non-inferiority test for non-unity null 
according to Farrington and Manning (1990).8 The relative risk and its two-sided 95% CI 
will be provided. If the lower bound of the 95% CI is 60%, the non-inferiority of Dara-SC
relative to Dara-IV will be concluded. If non-inferiority in ORR is established and the lower 
limit of the 95% CI of the relative risk is ≥100%, the superiority of Dara-SC relative to 
Dara-IV will be concluded. The primary analysis will occur approximately 6 months after
480 subjects have been randomized. 
2.
Maximum Ctrough (Predose on Cycle 3 Day 1): see Section 11.5, Pharmacokinetic Analyses.
Once the null non-inferiority hypothesis is rejected for both the ORR and maximum Ctrough, 
non-inferiority of Dara-SC to Dara-IV will be established and a hierarchical procedure for 
superiority testing will be implemented to control familywise Type I error rate at a two-sided 
significance level of 0.05 for secondary endpoints including incidence of IRR, PFS, rate of 
VGPR or better, and overall survival. The detailed procedure will be specified in the statistical 
analysis plan.
11.4.
Secondary Endpoints
1.
IRR: The proportion of subjects who have an IRR and the 95% CI will be calculated for 
each treatment group. The IRR rate will be compared between the 2 groups using the 
stratified Cochran-Mantel-Haenszel test. The Mantel-Haenszel odds ratio will be provided 
along with its 2-sided 95% CI.
2.
PFS: The median PFS and 95% CI in each treatment group will be estimated using the 
Kaplan-Meier method. The PFS distributions between the 2 treatment groups will be 
compared using the stratified log-rank test. The treatment effect (hazard ratio) and its 
two-sided 95% CI will be estimated using a stratified Cox regression model with treatment 
as the sole explanatory variable. 
3.
VGPR or better: The proportion of subjects who have a VGPR or better and the 95% CI will 
be calculated for each treatment group. The rate of VGPR or better will be compared 
between the 2 treatment groups using the stratified Cochran-Mantel-Haenszel test. The 
Mantel-Haenszel odds ratio will be provided along with its 2-sided 95% CI. 
4.
CR or better: The proportion of subjects who have a CR or better and the 95% CI will be 
calculated for each treatment group. The rate of CR or better will be compared between the 
2 treatment groups using the stratified Cochran-Mantel-Haenszel test. The Mantel-Haenszel 
odds ratio will be provided along with its two-sided 95% CI.
5.
TNT: The median TNT and 95% CI in each treatment group will be estimated using the 
Kaplan-Meier method. The TNT distributions will be compared between the 2 treatment 
groups using the stratified log-rank test. The treatment effect (hazard ratio) and its two-sided 


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95% CI will be estimated using a stratified Cox regression model with treatment as the sole 
explanatory variable.
6.
OS: The median OS and 95% CI in each treatment group will be estimated using the 
Kaplan-Meier method. The OS distributions will be compared between the 2 treatment 
groups using the stratified log-rank test. The treatment effect (hazard ratio) and its 2-sided 
95% CI will be estimated using a stratified Cox regression model with treatment as the sole 
explanatory variable.
7.
Duration of response: A descriptive summary for duration of response will be provided. No 
statistical comparison will be made.
8.
Time to response: A descriptive summary for time to response will be provided. No 
statistical comparison will be made.
11.5.
Pharmacokinetic Analyses 
For the co-primary endpoint of maximum Ctrough, the ratio of the geometric means and the 
corresponding 90% CI utilizing logarithmic transformation of maximum Ctrough values will be 
provided. The 2 formulations of daratumumab will be considered similar if the lower bound of 
the 90% CI for the ratio of the geometric means of maximum Ctrough is at least 80% 
(non-inferiority margin of 20%). Summary statistics such as the geometric mean, coefficient of 
variation, median, and range will be provided by treatment group.
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. Concentrations below the lowest quantifiable concentration 
will be treated as zero in the summary statistics. All subjects and samples excluded from the 
analysis will be clearly documented in the Clinical Study Report.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each 
sampling time point and other pharmacokinetic parameters of daratumumab: Cmin, and Cmax. 
Additional pharmacokinetic parameters, when available, will also be summarized.
If sufficient data are available, then population pharmacokinetic analysis of
serum 
concentration-time data of daratumumab may be performed using nonlinear mixed effects 
modeling and may include data from other studies. If the population pharmacokinetic analysis is 
conducted, details will be given in a population pharmacokinetic analysis plan and the results of 
the analysis will be presented in a separate report.
11.6.
Immunogenicity Analyses 
The incidence of anti-daratumumab antibodies will be summarized for all subjects who receive 
at least 1 dose of Dara-SC or Dara-IV and have appropriate samples for detection of antibodies 
to daratumumab (ie, subjects with at least 1 sample obtained after their first dose of
daratumumab). The incidence of antibodies to rHuPH20 will be summarized for all subjects who 
receive a dose of Dara-SC and have appropriate samples for detection of antibodies to rHuPH20.
A listing of subjects who are positive for antibodies to daratumumab or rHuPH20 will be 
provided.


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11.7.
Biomarker Analyses 
Biomarker studies are designed to evaluate if there are any differences with Dara-SC and 
Dara-IV on biomarkers for daratumumab pharmacodynamics and mechanism of action. These 
studies also may identify markers predictive of response or resistance to daratumumab. Analyses 
will be stratified by clinical covariates or molecular subgroups using the appropriate statistical 
methods (eg, parametric or non-parametric, univariate or multivariate, analysis of variance, or 
survival analysis, depending on the endpoint). Correlation of baseline expression levels or 
changes in expression levels with response to time-to-event endpoints will identify responsive 
(or resistant) subgroups in addition to genes and pathways attenuated following treatment with 
daratumumab.
Any pharmacodynamic measures will be listed, tabulated, and where appropriate, plotted. 
Subjects may be grouped by cohort, dose schedule, or clinical response. Results of biomarker 
and pharmacodynamic analyses may be presented in a separate report. Planned analyses are 
based on the availability of clinically valid assays and may be deferred if emerging study data 
show no likelihood of providing useful scientific information.
11.8.
Pharmacokinetic/Pharmacodynamic Analyses 
If sufficient data are available, then other pharmacokinetic/pharmacodynamic modeling may be 
performed, including exploring the relationship between serum concentrations of daratumumab 
and endpoints of clinical efficacy and safety. If performed, details and results of the analysis will 
be presented in a separate report.
11.9.
Patient-reported Outcomes
The modified-CTSQ item scores and Satisfaction with Therapy domain score will be 
summarized for each time point, by treatment arm and descriptively reported. Mean Satisfaction 
with Therapy domain score will be compared between treatment arms at each time point.
11.10. Medical Resource Utilization Analyses 
Medical resource utilization will be descriptively summarized by treatment group. Additional 
analyses may be conducted; details and results of any additional analyses will be presented in a 
separate report.
11.11. 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). Treatment-emergent adverse 
events are adverse events with onset during the Treatment Phase or that are a consequence of a 
pre-existing condition that has worsened since baseline. All reported adverse events will be
included in the analysis. For each adverse event, the percentage of subjects who experience at 
least 1 occurrence of the given event will be summarized by treatment group. In addition, 
comparisons between treatment groups will be provided if appropriate.


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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 for each treatment group 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). 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 adverse event grade experienced by the subject during the study will be 
provided as shift tables.
Electrocardiogram (ECG)
Electrocardiogram data will be summarized based on categories of normal, abnormal either 
clinically significant or not clinically significant and listed.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point. The percentage of subjects with values beyond clinically important limits will be 
summarized.
Physical Examination
Physical examination findings will be summarized at baseline. Descriptive statistics will be 
calculated. Frequency tabulations of the abnormalities will be made.
11.12. Safety Data Monitoring
An IDMC, consisting of 2 clinicians and 1 statistician, will be established to review safety data 
periodically. 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.


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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 Council for Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events 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. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse or malignancy. These should 
usually be considered serious.


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If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study drug and the event (eg, death from anaphylaxis), the event must 
be reported as a suspected unexpected serious adverse reaction (SUSAR) even if it is a 
component of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. The expectedness of an adverse event will be 
determined by whether or not it is listed in the daratumumab Investigator's Brochure 
(IB daratumumab10). Anticipated events will be recorded and reported as described in 
Attachment 12.
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2, Attribution Definitions.
12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
The severity assessment for an adverse event or serious adverse event should be completed using 
NCI-CTCAE Version 4.03. Any adverse event or serious adverse event not listed in that


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document will be graded according to investigator clinical judgment by using the standard 
grading outlined in the NCI-CTCAE Version 4.03. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study drug

Unexpected therapeutic or clinical benefit from use of a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion)

Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious 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 final dose of 
study drug during the data collection period. The only exception is for subjects who have 
withdrawn informed consent for study participation or for subjects who have received additional 
treatment with therapeutic intent for multiple myeloma within 30 days after the final dose of 
Dara-IV or Dara-SC. For subjects who have received additional treatment with therapeutic intent 
for multiple myeloma during the adverse event reporting period, only adverse events that are 
considered to be possibly, probably, or definitely related to study drug must be reported (unless 
the subject has been withdrawn from the study).
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, and those that are considered related to study drug within the 
Follow-up Phase, must be reported using the Serious Adverse Event Form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.


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Death should not be recorded as an adverse event or serious adverse event, but as the outcome of 
an adverse event. The 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 12. Note: Some countries require 
reporting of all adverse events to the health authorities, while others will not identify anticipated 
events for the health authorities.
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). For 
anticipated events reported as individual serious adverse events the sponsor will make a 
determination of relatedness in addition to and independent of the investigator's assessment. The 
sponsor will periodically evaluate the accumulating data and, when there is sufficient evidence 
and the sponsor has determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the investigators (and the 
head of the investigational institute where required). The sponsor assumes responsibility for 
appropriate reporting of anticipated events to the regulatory authorities according to 
requirements of the countries in which the studies are conducted. The investigator (or sponsor 
where 
required) 
must 
report 
SUSARs 
to 
the 
appropriate 
Independent 
Ethics 
Committee/Institutional Review (ICE/IRB) that approved the protocol unless otherwise required 
and documented by the IRB/IEC.
The subject (or their designee, if applicable) must be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study indicating the following: 

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Blood type and IAT (as described in Section 9.7, Safety Evaluations).


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12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following:

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.

A standard procedure for protocol therapy administration will not be reported as a serious 
adverse event. In addition, hospitalization due to a longer than anticipated infusion time. 
Hospitalization or prolonged hospitalization for a complication of therapy administration 
will be reported as a serious adverse event.

The administration of blood or platelet transfusions. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event.

A procedure for protocol-related investigations (eg, scans, endoscopy, sampling for 
laboratory tests, bone marrow sampling, pharmacokinetic, or biomarker blood sampling). 


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Hospitalization or prolonged hospitalization for a complication of such procedures remains a 
reportable serious adverse event.
Refer to Attachment 13 for details on serious adverse event reporting after the end of the data 
collection period.
12.3.3.
Disease-Related Events or Outcomes Not Qualifying as Adverse 
Events
Known consequences of the underlying disease under investigation (eg, symptoms) and events 
common in the study population independent of drug therapy are adverse events. If they are 
considered drug-related they will be recorded and reported (if appropriate) as per current 
legislation to Health Authorities and ECs. If they are considered disease-related or not related to 
the study drugs they will be exempt from expedited reporting.
12.3.4.
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported 
to the sponsor by the study-site personnel within 24 hours of their knowledge of the event using 
the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious 
adverse events and must be reported using the Serious Adverse Event Form. Any subject who 
becomes pregnant during the study must be promptly withdrawn from the study and discontinue 
further study treatment unless the subject (or the subject's legally acceptable representative), 
investigator, and sponsor agree the benefits outweigh the risks to the fetus and continuation of 
study treatment is in the best interests of the subject. Because the effect of the study drug on 
sperm is unknown, pregnancies in partners of male subjects included in the study will be reported 
as noted above. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.
Pregnancy reporting will continue as described above after the end of the data collection period.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has 
established procedures in conformity with regulatory requirements worldwide to ensure 


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appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
Dara-SC
The Dara-SC supplied for SC injection in this study is a colorless to yellow liquid and sterile 
concentrate of 120 mg/mL daratumumab + 2000 U/mL rHuPH20 as a liquid in vial. The study 
agent should be essentially free of visible particulate matter at the time of syringe preparation 
and drug product administration. It will be manufactured and provided under the responsibility of 
the sponsor. Refer to the Investigator's Brochure (IB daratumumab10) for a list of excipients. 
Dara-IV
The Dara-IV supplied for IV infusion in this study is a colorless to yellow liquid and sterile 
concentrate of 20 mg/mL as a liquid vial. The study agent should be essentially free of visible 
particulate matter at the time of dosage preparation and drug product administration. It will be 
manufactured and provided under the responsibility of the sponsor.
14.2.
Packaging
Dara-SC
Dara-SC is supplied in glass vials containing daratumumab at a concentration of 120 mg/mL and 
rHuPH20 at a concentration of 2000 U/mL (~20 g/mL). It will be supplied to the site/pharmacy 
as open-label supply.
Dara-IV
Dara-IV is supplied in glass vials containing daratumumab at a concentration of 20 mg/mL. It 
will be supplied to the site/pharmacy as open-label supply. 


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14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each 
vial will contain a study-specific label with a unique identification number.
14.4.
Preparation, Handling, and Storage 
Dara-SC
Dara-SC must be stored in the original carton in a refrigerator at controlled temperatures ranging 
from 2°C to 8°C until it is removed for dose preparation. Dara-SC must not be utilized after the 
expiry date printed on the label. Dara-SC must be protected from light and must not be frozen. 
The product does not contain preservatives; therefore, any unused portion remaining in the vial 
must be discarded. Refer to the IPPI for additional guidance on study drug preparation, handling, 
and storage.
Dara-IV
Dara-IV must be stored in the original carton in a refrigerator at controlled temperatures ranging 
from 2°C to 8°C until it is removed for dose preparation. Dara-IV must not be utilized after the 
expiry date printed on the label. Dara-IV must be protected from light and must not be frozen. 
Dara-IV does not contain preservatives; therefore, any unused portion remaining in the vial must 
be discarded. Refer to the IPPI for additional guidance on study drug preparation, handling, and 
storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study 
drug will be documented on the drug return form. When the study site is an authorized 
destruction unit and study drug supplies are destroyed on-site, this must also be documented on 
the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 


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the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator's Brochure for daratumumab

Investigational Product Preparation Instructions

Site Investigational Product Procedures Manual

Laboratory manual

IWRS Manual

eCRF completion guidelines

Sample ICF

Modified-CTSQ and PRO training materials

Subject identification wallet card, including space for blood type and IAT result

Subject diaries for recording predose and postdose medications that are administered at 
home (Section 6.3, Predose and Postdose Medications)

Other manuals and guidance documents as needed
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
As discussed in Section 1.4, Overall Rationale for the Study, preliminary efficacy data suggest 
that SC administration of Dara-SC may provide comparable or better response rates compared 
with IV administration of Dara-IV. Additional benefits of Dara-SC compared with Dara-IV 
include:

Potential reduction in the incidence rate and severity of IRRs (compared with IV infusion), 
due to slower absorption of daratumumab into systemic circulation 

Shorter administration time (approximately 3 to 5 minutes compared with 4 to 7 hours for 
IV infusion)

Reduced administration volume (SC administration of approximately 15 mL instead of 
500 mL to 1000 mL IV infusion), which may be clinically meaningful for elderly patients 
with comorbid cardiac or renal insufficiency 
The primary safety profile of Dara-IV is consistent with IRRs; see Section 6.3, Predose and 
Postdose Medications, 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 study drug administration. CD38 is distributed in erythrocytes and 
platelets. A significant reduction of platelets was reported in an animal study. In a human clinical 


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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.
In a previous study with SC administration of daratumumab (MMY1004), a lower incidence of 
IRRs was observed compared to IRR rate reported from studies with IV administration of 
daratumumab. However, IRRs may still occur and may develop at a later time point than 
previously observed with IV administration due to the more gradual absorption. Subjects will 
therefore be observed for at least 6 hours on their first day of SC daratumumab administration. 
Apart from IRRs, a similar toxicity profile has been shown for SC versus IV administration for 
anemia, thrombocytopenia, and other toxicities. During this study local tolerability at the SC 
injection site will be closely monitored as well. 
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 maximum blood volume for a subject who completes 8 cycles and the post-treatment 
assessments is approximately 490 mL. The total blood volume to be collected is estimated at 
approximately 34 mL for Screening, 100 mL for Cycles 1 and 2, 161 mL for Cycles 3-6, 21 mL 
at each subsequent cycle, 55-85 mL for pharmacokinetics (depending on treatment group), 5 mL 
when CR is suspected or maintained, and 50 mL at the End-of-Treatment visit. In the Follow-up 
Phase, subjects who discontinue study drug prior to PD will continue to have approximately 20 mL 
blood drawn every 2 months 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.


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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 
Independent Ethics Committee/Institutional Review Board [IEC/IRB] with current and complete 
copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of 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 
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
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. The reapproval should be documented in writing (excluding the ones that are purely 
administrative, with no consequences for subjects, data, or study conduct). At the end of the 
study, the investigator (or sponsor where required) will notify the IEC/IRB about the study 
completion (if applicable, the notification will be submitted through the head of investigational 
institution). 
16.2.3.
Informed Consent 
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved 
by both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read 
and understand. The informed consent should be in accordance with principles that originated in 
the Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
participation in the study may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time. They will be informed 
that choosing not to participate will not affect the care the subject will receive for the treatment 
of his or her disease. Subjects will be told that alternative treatments are available if they refuse 
to take part and that such refusal will not prejudice future treatment. Finally, they will be told 
that the investigator will maintain a subject identification register for the purposes of long-term 
follow up if needed and that their records may be accessed by health authorities and authorized 
sponsor personnel without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) or regulations. By signing the ICF the subject or legally acceptable 
representative is authorizing such access, which includes permission to obtain information about 
his or her survival status, and agrees to allow his or her study physician to recontact the subject 
for the purpose of obtaining consent for additional safety evaluations and subsequent disease-
related treatments, if needed, or to collect information about his or her survival status.


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The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject. Where local regulations require, a separate ICF may be used for the 
required DNA component of the study.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the objectives of the study. These data must be collected 
and processed with adequate precautions to ensure confidentiality and compliance with applicable 
data privacy protection laws and regulations. Appropriate technical and organizational measures to 
protect the personal data against unauthorized disclosures or access, accidental or unlawful 
destruction, or accidental loss or alteration must be put in place. Sponsor personnel whose 
responsibilities require access to personal data agree to keep the identity of subjects confidential.
The informed consent obtained from the subject (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her original medical records (source data/documents) for study-
related monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also 
addresses the transfer of the data to other entities and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory DNA, biomarker, and immunogenicity research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.


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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 and
rHuPH20, to understand multiple myeloma, to understand differential drug responders, and to 
develop tests/assays related to daratumumab. The research may begin at any time during the 
study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research (refer to Section 10.3, Withdrawal From the Use of Samples in Future 
Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design 
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB (where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative listed in the Contact Information page(s), which will be provided as a separate 
document. Except in emergency situations, this contact should be made before implementing any 
departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.


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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

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


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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth (as allowed by local regulations). In cases where the subject is not randomized 
into the study, the date seen and date of birth (as allowed by local regulations) will be used. The 
investigator must also complete a subject screening log, which reports on all subjects who were 
seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all adverse events and follow-up of adverse events; concomitant medication; 
drug receipt/dispensing/return records; study drug administration information; and date of study 
completion and reason for early discontinuation of study drug or withdrawal from the study, if 
applicable. 
The author of an entry in the source documents should be identifiable.
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 and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 


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the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If the electronic source system is utilized, references made to 
the eCRF in the protocol include the electronic source system but information collected through 
the electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study-site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct. The study data will be transcribed by study-site personnel from the source 
documents onto an electronic eCRF, if applicable. Study-specific data will be transmitted in a 
secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents. Data must be entered into 
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the 
forms should be available for review at the next scheduled monitoring visit. All subjective 
measurements (eg, pain scale information or other questionnaires) will be completed by the same 
individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the electronic data capture (eDC) tool. If corrections to 
an eCRF are needed after the initial entry into the eCRF, this can be done in either of the 
following ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
There will be no data collection in the eCRF after the database is locked for the final analysis. 
Attachment 13 describes procedures for subjects who continue study treatment after the end of 
the data collection period.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data into the sponsor's data base. 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 eCRF for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 


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with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques central, remote, or on-site 
monitoring to monitor this study. The sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study site visit log that 
will be kept at the study site. The first post-initiation visit will be made as soon as possible after 
enrollment has begun. At these visits, the monitor will compare the data entered into the eCRF 
with the source documents (eg, hospital/clinic/physician's office medical records). The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded data are consistent with the original source data. Findings from this 
review will be discussed with the study-site personnel. The sponsor expects that, during 


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monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
End of Data Collection/Study Completion
The end of the data collection period will be approximately 24 months after the last subject was 
randomized or when median overall survival for both arms has been reached, whichever occurs
first. Only data collected in the eCRF during the data collection period will be included in the 
final study analysis. The final data from the study site will be sent to the sponsor (or designee) 
after completion of the final subject assessment at that study site, in the time frame specified in 
the Clinical Trial Agreement.
The sponsor will ensure that subjects benefiting from treatment with either the IV or SC 
formulation of daratumumab are able to continue receiving daratumumab treatment after the end 
of the data collection period (final analysis) until the applicable formulation is commercially 
available or available from another source, or the study is complete. After the end of the data 
collection period, the clinical database will be closed, and no additional data will be collected in 
the eCRF. Attachment 13 describes data collection and reporting procedures for subjects who 
continue study treatment after the end of the data collection period. 
The study will be considered complete when all subjects still receiving study drug have 
commercial or alternative access to the appropriate formulation of daratumumab, have stopped 
receiving daratumumab treatment, or at approximately 5 years after the last subject was 
randomized, whichever occurs first.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development


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17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including biomarker research data, generated as a result of 
this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 


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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 disclose the existence of and the results of clinical studies as 
required by law.


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Abetz L, Coombs JH, Keininger DL, et al. Development of the cancer therapy satisfaction questionnaire: Item 
generation and context validity testing. Value in Health. 2005; 8:S41-S53.
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Becker N. Epidemiology of multiple myeloma. Recent Results Cancer Res, 2011;183:25-36.
3.
Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd Edition, Philadelphia; WB Saunders: 1998.
4.
Chapuy CI, Aguad MD, Nicholson RT, et al; DARA-DTT Study Group* for the BEST Collaborative. 
International validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with 
blood compatibility testing. Transfusion. 2016;56:2964-2972.
5.
Chapuy CI, Nicholson RT, Aguad MD, et al. Resolving the daratumumab interference with blood
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6.
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal 
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7.
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. 
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Investigator's Brochure: JNJ-54767414 (daratumumab). Edition 13; Janssen Research & Development 
(06Oct2016).
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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.
12.
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after 
therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 
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Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in 
renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145:247-254.
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Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple 
myeloma. N Engl J Med. 2015;373:1207-1219.
15.
Lonial S, Weiss B, Usmani S, et al. Daratumumab monotherapy in patients with treatment-refractory multiple 
myeloma (SIRIUS): an open-label, randomized, phase 2 trial. Lancet. 2016;387:1551-1560.
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Moreau P, San Miguel J, Ludwig H, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Annals Oncol. 2013; 24 Suppl 6:vi133-7.
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National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines): Multiple Myeloma, version 2.2014. 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 
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Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor 
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Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-1060.
21.
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for 
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Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical 
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Usmani S, Ahmadi T, Ng Y, et al. Analysis of real-world data on overall survival in multiple myeloma patients 
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Attachment 1: International Myeloma Working Group Diagnostic Criteria
Multiple myeloma is defined as clonal bone marrow plasma cells 10% or biopsy-proven bony or 
extramedullary plasmacytomaa and any one or more of the following myeloma defining events:

Myeloma defining events:

Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative 
disorder, specifically:
o
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of 
normal or >2.75 mmol/L (>11 mg/dL)
o
Renal insufficiency: creatinine clearance <40 mL per minb or serum creatinine 
>177 μmol/L (>2 mg/dL)
o
Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin 
value <100 g/L 
o
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc,d

Any one or more of the following biomarkers of malignancy: 

Clonal bone marrow plasma cell percentagea 60%

Involved:uninvolved serum free light chain ratioe 100

>1 focal lesions on MRI studiesf
a.
Clonality 
should 
be 
established 
by 
showing 
κ/λ-light-chain 
restriction 
on 
flow 
cytometry, 
immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be 
estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the 
highest value should be used.
b.
Measured or estimated by validated equations. 
c.
If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish 
from solitary plasmacytoma with minimal marrow involvement.
d.
PET-CT=18F-fluorodeoxyglucose positron emission tomography with computed tomography.
e.
These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The 
involved free light chain must be 100 mg/L. 
f.
Each focal lesion must be 5 mm or more in size.
(Rajkumar 201421)


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Attachment 2: Prior Cancer Therapy for Multiple Myeloma
A line of therapy is defined as one or more cycles of a planned treatment program. This may consist of 
one or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of 
treatments administered in a planned manner. For example, a planned treatment approach of induction 
therapy followed by autologous stem cell transplantation, followed by maintenance is considered one line 
of therapy. A new line of therapy starts when a planned course of therapy is modified to include other 
treatment agents (alone or in combination) as a result of disease progression, relapse, or toxicity. A new 
line of therapy also starts when a planned period of observation off therapy is interrupted by a need for 
additional treatment for the disease. 
Source: Rajkumar 201122


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Attachment 3: Eastern Cooperative Oncology Group Performance Status Score
Grade 
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature (eg, light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair (Oken 198218). 


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Attachment 4: Modified Diet in Renal Disease Formula
For creatinine in mg/dL, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal 
disease (MDRD) formulas is: 
e-GFR (MDRD) mL/min per 1.73m2= 175 × [serum creatinine (mg/dL)]-1.154 × [age]-0.203 × [1.212 if 
black] × [0.742 if female]
For creatinine in µmol/L, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal 
disease (MDRD) formulas is:
e-GFR (MDRD) mL/min per 1.73m2= 175 x [serum creatinine (µmol/L)/88.4]-1.154 × [age]-0.203 × 
[1.212 if black] × [0.742 if female]
(Levey 200613)


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Attachment 5: Serum Calcium Corrected for Albumin
If calcium is expressed in mg/dL and albumin is expressed in g/dL:
Corrected calcium (mg/dL) = 
serum calcium (mg/dL) + 0.8 × (4 - serum albumin [g/dL])
If calcium is expressed in mmol/L and albumin is expressed in g/L:
Corrected calcium (mmol/L) = 
serum calcium (mmol/L) + 0.02 × (40 - serum albumin [g/L])
(Burtis 19983)


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


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Attachment 7: 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
Daily
Several time per day
Interference with 
normal activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% 
Normal
N/A
60-80%
75-80%
60-80% 
Reduced 5%
N/A
< 60%
< 75%
< 60% 
Reduced
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting
>1 day and risk factors
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in 6
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 exacerbations in
6 months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors 
for persistent asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
Recommended
Step for
Initiating Treatment
Step 1
Step 2
Step 3 and consider 
short course of oral 
steroids
Step 3: 
medium
dose ICS
and 
consider
short 
course of
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 
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
Recommended Action
for
Treatment
• Maintain current step
• Regular follow-up every 
1-6 months
• Consider step down if well 
controlled for at least 3 
months
Step up 1 
step
Step up at 
least 1 step
• Step up
1 step
• Reevaluate
in 2-6 
week
s
• For side 
effects, 
consider 
alternativ
e 
treatment 
options
• Consider short course
of oral steroids
• Step up 1-2 steps
• Consider 
short course 
of oral 
steroids
• Step up 1-2 
steps
• Reevaluate 
in 2 weeks
• For side
effects, 
consider 
alternative 
treatment 
options
• Before step up:
Review adherence to medication,
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred
treatment for that step.
• Reevaluate the level of asthma
control in 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative 
diagnoses or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.
• Before step up:
Review adherence to medication,
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred
treatment for that step.
• Reevaluate the level of asthma
control in 2-6 weeks to achieve 
control.
0-4 years: If no clear benefit is observed 
in
4-6 weeks, consider alternative 
diagnoses or adjusting therapy.
5-11 years: Adjust therapy accordingly.
• For side effects, consider
alternative treatment options.


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Attachment 8: New York Heart Association (NYHA) Functional Classification
NYHA Class
Symptoms
I
Cardiac disease, but no symptoms and no limitation in ordinary physical activity 
(eg, shortness of breath when walking or climbing stairs).
II
Mild symptoms (mild shortness of breath or angina) and slight limitation during 
ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary activity 
(eg, walking short distances [20–100 m]).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients.


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Attachment 9: Antihistamines That May Be Used Predose
The following antihistamines may be used predose, before Dara-IV infusion or Dara-SC injection 
(including, but not limited to):

Diphenhydramine

Cetirizine

Fexofenadine

Loratadine

Clemastine

Dexchlorpheniramine

Promethazine*
* The IV use of promethazine should be avoided. 


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Attachment 10: Interpretation of The SEBIA Hydrashift 2/4 Daratumumab IFE Interference Test
Background: Clinical response assessment in myeloma relies on serum protein electrophoresis (SPEP) 
and immunofixation electrophoresis (IFE). As daratumumab is a monoclonal IgG kappa antibody, the 
SPEP and IFE can be positive for daratumumab at the serum levels anticipated during this protocol. 
Implementation: To mitigate this interference, the sponsor will use the SEBIA Hydrashift 2/4 
Daratumumab IFE Interference test to distinguish a positive SPEP/IFE due to the presence of 
daratumumab versus the presence of the underlying (endogenous) monoclonal protein. The SEBIA 
Hydrashift 2/4 Daratumumab IFE Interference test will be sent automatically to the central laboratory if a 
subject with IgG kappa multiple myeloma has an SPEP at or below 0.2 g/dL on 2 or more consecutive
cycles. In addition, the SEBIA Hydrashift 2/4 Daratumumab IFE Interference test will be sent 
automatically to the central laboratory if a subject has an SPEP of zero, but persistently positive IFE for 
IgG kappa on 2 or more occasions.
Interpretation of results:
The results will be available to the investigator via the central laboratory interface and will be reported as 
follows:
DARAHydra Impress1:  result defined as “DARA detected”, “DARA not detected”, OR “DARA 
indeterminate”
DARAHydra Impress2:  result defined as “M-protein not detected” OR the specific protein 
detected (i.e. “IgG,k” or “IgA”)
DARAHydra Impress3: result defined as “M-protein not detected” OR the specific protein 
detected (i.e. “IgG,k” or “IgA”)

If Impress1 result is “DARA detected” and Impress2 and 3 results are “M-protein not detected”, 
the patient may be in complete response (CR) if the other criteria for CR (including negative 
bone marrow aspirate/biopsy) are achieved.

If Impress1 result is “DARA not detected” or “DARA indeterminate”, the patient is still 
positive for underlying (endogenous) monoclonal protein and Impress2 and 3 can inform as to 
the type of endogenous protein still present. Therefore, this patient is not in a complete response 
(CR), because the CR response criteria requires a negative SPEP and serum IFE.

If Impress1 result is “DARA detected” but there is also protein present and reported by 
Impress2 or 3, the patient is still positive for underlying (endogenous) monoclonal protein and 
Impress2 and 3 can inform as to the type of endogenous protein still present. Therefore, this 
patient is not in a complete response (CR), because the CR response criteria requires a negative 
SPEP and serum IFE.


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Attachment 11:
Modified Cancer Therapy Satisfaction Questionnaire


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Attachment 12:
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events:

Bleeding

Bone diseases

Hypercalcaemia

Hyperuricemia

Hyperviscosity syndrome

Infection

Renal failure or insufficiency
Reporting of Anticipated Events
All adverse events will be recorded in the eCRF 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 criteria will be reported to the sponsor as described in Section 12.3.2, Serious 
Adverse Events. Each anticipated event will be assessed by the investigator at the individual case level 
and if considered to be drug-related will undergo expedited reporting (if appropriate) as per applicable 
clinical trial legislation to Health Authorities and IRB/IECs. If an anticipated event is considered disease-
related or not related to study drug the event will be exempt from expedited reporting. 
To meet US regulatory clinical trial legislation, the sponsor will perform aggregate review of anticipated 
events as outlined below, and if determined to be drug-related will implement expedited reporting of these 
events to Health Authorities and IRBs/ECs. If an interim analysis of trial results leads to an unblinded, 
aggregate review of safety data by the study team, the sponsor may terminate the review of pre-specified 
anticipated events outlined above.
Safety Assessment Committee (SAC)
An SAC will be established to perform reviews of pre-specified anticipated events at an aggregate level. 
The SAC is a safety committee within the sponsor's organization that is independent of the sponsor's 
study team. The SAC will meet to aid in the recommendation to the sponsor's study team as to whether 
there is a reasonable possibility that an anticipated event is related to the study intervention based on a 
review of the aggregate data by arm.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).


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Attachment 13:
Continuation of Treatment After Clinical Cutoff for the Final Analysis (End of the 
Data Collection Period)
Protocol Amendment 3 will allow those subjects who are benefitting from daratumumab treatment after 
the clinical cutoff date for the final analysis (end of the data collection period) to continue receiving study 
drug. The sponsor will ensure that subjects will be able to continue receiving the appropriate formulation 
of IV or SC daratumumab after the data collection period has ended until the applicable formulation is 
commercially available or available from another source, or until the study is complete (see 
Section 17.9.1). The following limited schedule is applicable. 
Documentation of assessments performed is required only in the subject file/source notes.
Dosage and Administration
Daratumumab will be administered according to the regimen established prior to Amendment 3 (see 
Section 6).
Treatment Period
Once the sponsor has notified investigators that the clinical cutoff for the final analysis has been achieved 
(end of the data collection period), subjects may continue treatment with daratumumab until PD per 
investigator evaluation, unacceptable toxicity, withdrawal of consent, the investigator decides to stop 
treatment, or the start of subsequent anticancer therapy. Post-treatment follow-up is not applicable for 
subjects who discontinue study treatment in this period, except for HBV DNA testing as described below. 
Efficacy Evaluations
Investigators should monitor and assess subjects for response to treatment or disease progression 
according to local institutional practice. The assessments and outcome should be entered in the subject 
file/source notes.
Safety Laboratory Assessments
Once the data collection period has ended, local hematology labs, chemistry labs, and assessment of vital 
signs should still be performed on Day 1 of each dosing cycle for consistency with previous cycles and in 
accordance with good clinical practice. These local laboratory results do not need to be reported to the 
sponsor. 
Safety Reporting
Once the data collection period has ended, serious adverse events that occur while the subject is receiving 
study drug and within 30 days after the last dose of study drug will be collected and reported to the 
sponsor’s global medical safety database only via the same serious adverse event reporting process used 
over the course of the study (see Section 12.3.2). Serious adverse events that occur between the end of the 
30-day post-dose period and completion of the study should be reported using the same process if 
considered by the investigator to be related to study drug. Serious adverse events should also be 
documented in the subject file/source notes. 
Pregnancy reporting should continue as described in Section 12.3.4. The pregnancy should be 
documented in the subject file/source notes.
HBV DNA Tests
Subjects who are positive for anti-HBc or anti-HBs will undergo testing for HBV DNA by PCR every 
4 weeks (±1 month) after entering this treatment period. Testing will continue for 6 months after the last 
dose of study treatment. Subjects with serologic findings suggestive of HBV vaccination (anti-HBs 
positivity as the only serologic marker) and a known history of prior HBV vaccination do not need to be 
tested for HBV by PCR.


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Sample Collection and Handling
There are no PK, immunogenicity, or biomarker assessments during this treatment period, and any sample 
collection or test for safety or disease evaluation should comply with standard local institution practice.
Please note that local bone marrow analysis is required for the assessment of CR.
Case Report Form Completion
No data will be collected in the eCRF during this treatment period. 
Source Documentation
At a minimum, the type and level of detail of source data collected should be consistent with that 
commonly recorded at the site as a basis for standard medical care. This should include: subject 
identification and study identification, study discussion, documentation of the informed consent process 
including the date, dates of visits, drug dispensing/return records, and study drug administration 
information.


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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed):
Ming Qi
Institution:
Janssen Research & Development
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ming Qi
01Apr2020, 13:22:26 PM, UTC
Document Approval

SAP_001.pdf: 
1
Janssen Research & Development
Statistical Analysis Plan
A Phase 3 Randomized, Multicenter Study of Subcutaneous vs. Intravenous 
Administration of Daratumumab in Subjects With Relapsed or Refractory Multiple 
Myeloma 
Protocol 54767414MMY3012; Phase 3
Amendment 1
JNJ-54767414  (daratumumab)
Status:
Approved
Date:
12 February 2019
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-155979312
[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.
NCT03277105


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Statistical Analysis Plan 54767414MMY3012
2
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 8
1.1.
Trial Objectives ............................................................................................................................. 8
1.2.
Trial Design................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives ................................................................................... 9
1.3.1.1.
Statistical Hypotheses for ORR................................................................................................. 9
1.3.1.2.
Statistical Hypotheses for Maximum Ctrough............................................................................. 10
1.4.
Non-inferiority Margins Justification............................................................................................ 10
1.5.
Sample Size Justification............................................................................................................ 11
1.6.
Randomization and Blinding....................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 12
2.1.
Visit Windows................................................................................................................................. 12
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 12
2.3.
Study Drug ..................................................................................................................................... 12
2.4.
Baseline Definitions........................................................................................................................ 12
2.5.
Unique Lab Value........................................................................................................................... 13
2.6.
Analysis Sets.................................................................................................................................. 13
2.7.
Imputation of Missing Data ............................................................................................................ 14
2.7.1.
Adverse Event Start and End Date............................................................................................. 14
2.7.2.
Prior and Concomitant Medication/Therapy Start and End Date ............................................... 15
2.7.3.
Multiple Myeloma Diagnosis Date .............................................................................................. 15
2.7.4.
First Subsequent Anticancer Therapy Start Date....................................................................... 16
2.8.
General Analysis Method............................................................................................................... 16
2.9.
Other General Definitions............................................................................................................... 17
2.9.1.
Measurable Disease of Multiple Myeloma at Baseline and Measurable Type........................... 17
2.9.2.
Type of Multiple Myeloma........................................................................................................... 17
2.9.3.
International Staging System (ISS)............................................................................................ 17
2.9.4.
Hepatic Function......................................................................................................................... 18
2.9.5.
Relapsed Disease....................................................................................................................... 18
2.9.6.
Refractory Disease ..................................................................................................................... 18
2.9.7.
High Risk/Standard Risk Cytogenetics....................................................................................... 18
2.9.8.
Time since Initial Multiple Myeloma Diagnosis........................................................................... 18
2.9.9.
End of Follow-up and Duration of Follow-up .............................................................................. 18
2.10.
Definition of Subgroups.................................................................................................................. 19
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 19
4.
SUBJECT AND TREATMENT INFORMATION................................................................................ 19
4.1.
Subject Disposition......................................................................................................................... 20
4.2.
Demographics and Baseline Characteristics ................................................................................. 20
4.3.
Medical History............................................................................................................................... 21
4.4.
Prior Therapies............................................................................................................................... 21
4.4.1.
Prior Multiple Myeloma Therapies .............................................................................................. 21
4.4.2.
Refractory Status to Prior Systemic Therapy ............................................................................. 21
4.5.
Prior and Concomitant Medications ............................................................................................... 22
4.6.
Subsequent Anticancer Therapies................................................................................................. 22
4.7.
Extent of Exposure......................................................................................................................... 22
4.8.
Protocol Deviations ........................................................................................................................ 23
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Statistical Analysis Plan 54767414MMY3012
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5.
EFFICACY ......................................................................................................................................... 23
5.1.
Analysis Specifications ............................................................................................................... 24
5.1.1.
Level of Significance................................................................................................................... 24
5.1.2.
Computerized Algorithm ............................................................................................................. 24
5.1.3.
Data Handling Rules................................................................................................................... 25
5.2.
Primary Efficacy Endpoint(s) ...................................................................................................... 25
5.2.1.
Definition..................................................................................................................................... 25
5.2.2.
Estimand..................................................................................................................................... 25
5.2.3.
Analysis Methods........................................................................................................................ 25
5.3.
Major Secondary Endpoints ....................................................................................................... 26
5.3.1.
Progression-free Survival ........................................................................................................... 26
5.3.1.1.
Definition.................................................................................................................................. 26
5.3.1.2.
Analysis Methods .................................................................................................................... 27
5.3.2.
Response Rate of VGPR or Better............................................................................................. 28
5.3.2.1.
Definition.................................................................................................................................. 28
5.3.2.2.
Analysis Methods .................................................................................................................... 28
5.3.3.
Response Rate of CR or Better.................................................................................................. 28
5.3.3.1.
Definition.................................................................................................................................. 28
5.3.3.2.
Analysis Methods .................................................................................................................... 28
5.3.4.
Time to Next Therapy ................................................................................................................. 28
5.3.4.1.
Definition.................................................................................................................................. 28
5.3.4.2.
Analysis Methods .................................................................................................................... 29
5.3.5.
Overall Survival........................................................................................................................... 29
5.3.5.1.
Definition.................................................................................................................................. 29
5.3.5.2.
Analysis Methods .................................................................................................................... 29
5.3.6.
Time to Response....................................................................................................................... 29
5.3.6.1.
Definition.................................................................................................................................. 29
5.3.6.2.
Analysis Methods .................................................................................................................... 29
5.3.7.
Duration of Response................................................................................................................. 30
5.3.7.1.
Definition.................................................................................................................................. 30
5.3.7.2.
Analysis Methods .................................................................................................................... 30
5.4.
Other Efficacy Endpoints/Variables ............................................................................................ 30
5.4.1.
Best M-protein/dFLC Response ................................................................................................. 30
5.4.1.1.
Definition.................................................................................................................................. 30
5.4.1.2.
Analysis Methods .................................................................................................................... 31
5.4.2.
Progression-free Survival on Next Line of Therapy (PFS2) ....................................................... 31
5.4.2.1.
Definition.................................................................................................................................. 31
5.4.2.2.
Analysis Methods .................................................................................................................... 31
5.5.
Subgroup Analysis for Efficacy Endpoints.................................................................................. 31
6.
SAFETY............................................................................................................................................. 32
6.1.
Adverse Events........................................................................................................................... 32
6.1.1.
Overview of TEAEs..................................................................................................................... 33
6.1.2.
All TEAEs.................................................................................................................................... 33
6.1.3.
Toxicity Grade 3 or 4 TEAEs ...................................................................................................... 33
6.1.4.
Treatment-related TEAEs........................................................................................................... 33
6.1.5.
Serious TEAEs ........................................................................................................................... 33
6.1.6.
TEAEs Leading to Treatment Discontinuation............................................................................ 34
6.1.7.
TEAEs Leading to Treatment Modifications ............................................................................... 34
6.1.8.
TEAEs with Fatal Outcome......................................................................................................... 34
6.2.
Deaths......................................................................................................................................... 34
6.3.
Adverse Events of Clinical Interest............................................................................................. 34
6.3.1.
Infusion-related Reactions.......................................................................................................... 34
6.3.1.1.
Rate of Infusion-related Reactions .......................................................................................... 34
6.3.1.2.
Summary of Infusion-related Reactions .................................................................................. 34
6.3.2.
Injection-site Reactions............................................................................................................... 35
6.3.3.
Infections and Infestations.......................................................................................................... 35
6.3.4.
Hemorrhage Events.................................................................................................................... 35
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6.3.5.
Tumor Lysis Syndrome............................................................................................................... 35
6.3.6.
Second Primary Malignancies .................................................................................................... 35
6.3.7.
Adverse Events by Subgroups ................................................................................................... 35
6.4.
Clinical Laboratory Tests ............................................................................................................ 36
6.5.
Vital Signs and Physical Examination Findings.......................................................................... 36
6.6.
Electrocardiogram....................................................................................................................... 36
6.7.
ECOG Performance Status ........................................................................................................ 37
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS .......................................... 37
7.1.
Pharmacokinetics ....................................................................................................................... 37
7.1.1.
Maximum Ctrough.......................................................................................................................... 37
7.1.2.
Other Pharmacokinetic Parameters ........................................................................................... 38
7.2.
Immunogenicity........................................................................................................................... 38
7.3.
Pharmacokinetic/Pharmacodynamics Analyses......................................................................... 39
8.
BIOMARKER..................................................................................................................................... 39
9.
PATIENT-REPORTED OUTCOMES................................................................................................. 39
9.1.
Modified-CTSQ Scoring ................................................................................................................. 40
9.2.
Analysis Method............................................................................................................................. 41
10.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 41
REFERENCE .............................................................................................................................................. 42
ATTACHMENT 1: ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT HEMAR......................... 43
ATTACHMENT 2: MULTIPLE MYELOMA IMWG COMPUTERIZED ALGORITHM ................................ 44
ATTACHMENT 3: MODIFIED CANCER THERAPY SATISFACTION QUESTIONNAIRE ...................... 55
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AMENDMENT HISTORY
SAP Version
Issue Date
Original SAP
6 February 2018
Amendment 1
12 February 2019
The following is a summary of the major changes from the original version of the SAP:
1. Updates on the data cutoff and primary analysis strategy according to the Protocol 
Amendment 2 to allow Japan to enroll beyond the initially planned 480 subjects;
2. Updated and clarified on the Statistical Hypotheses Section 1.3 and Efficacy Section 5, added 
a new Section 1.4 of Non-inferiority Margins Justification to address FDA’s comments on 
alpha level, estimand and non-inferiority margins;
3. Refined the parameters for the biomarker analysis;
4. Added exploratory endpoint and analyses for PFS2 (Section 5.4.2);
5. Added attachments of IMWG computerized algorithm and additional exploratory analysis to 
support HEMAR.
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ABBREVIATIONS
AE
adverse event
ALB
albumin
ALKY
alkylating agent
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCT
autologous stem cell transplant 
AST
aspartate aminotransferase
B2MG
beta2 microglobulin
BUN
blood urea nitrogen
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CR
complete response
CT
cancer therapy
CTSQ
Cancer Therapy Satisfaction Questionnaire
Dara IV
daratumumab for intravenous infusion
Dara SC
daratumumab administered subcutaneously
DMC
Data Monitoring Committee
DOR
duration of response
DPS
Data Presentation Specifications
ECG
electrocardiograms
ECOG
European Cooperative Oncology Group
eCRF
electronic case report form
FLC
free light chain
FM
Farrington-Manning
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
GM
geometric mean 
HLT
high level term
ICH
International Conference on Harmonization
LDH
lactic acid dehydrogenase
LLN
lower limit normal
IMiD
immunomodulatory drug
IMWG
International Multiple Myeloma Working Group
IRR
infusion-related reaction
ISS
International Staging System
ITT
intent-to-treat
IV
intravenous
IWRS
Interactive Web Response System
MDSCs
myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
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MM
multiple myeloma
MR
minimal response
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NE
not evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression free survival
PI
proteasome inhibitor
PK
pharmacokinetic
PP
per-protocol 
PR
partial response
PT
preferred term
rHuPH20
recombinant human hyaluronidase
SAE
serious adverse event
SAP
Statistical Analysis Plan
sCR
stringent complete response
SD
stable disease
SMQ
standardized MedDRA queries 
SOC
system organ class
SWT
satisfaction with therapy
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome 
TNT
time to next therapy
TTR
time to response
ULN
upper limit normal
VGPR 
very good partial response
WBC
white blood cell
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis set(s), derived variables 
and statistical methods for the primary analysis of the open-label, active-controlled, multicenter, 
Phase 3 study to demonstrate that the efficacy and pharmacokinetics for Dara SC are not inferior 
to those for Dara IV in subjects with relapsed or refractory multiple myeloma who have received 
at least 3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory 
drug (IMiD), or whose disease is double refractory to both a PI and an IMiD.
1.1.
Trial Objectives
Primary Objectives
-
To show that subcutaneous (SC) administration of daratumumab co-formulated with 
recombinant human hyaluronidase PH20 (Dara SC) is non-inferior to intravenous 
administration of daratumumab (Dara IV) in terms of the overall response rate (ORR)
-
To show that Dara SC is non-inferior to Dara IV in terms of the maximum trough 
concentration (Ctrough)
Secondary Objectives
-
To assess the pharmacokinetics and immunogenicity of Dara SC and Dara IV
-
To evaluate the safety of Dara SC and Dara IV
-
To evaluate the clinical benefit of Dara SC and Dara IV
-
To evaluate the immunogenicity of rHuPH20 following Dara SC administration
-
To evaluate patient-reported satisfaction with Dara SC and Dara IV
1.2.
Trial Design
This is a phase 3, randomized (1:1), open-label, active-controlled, multicenter study to 
demonstrate that the efficacy and pharmacokinetics for Dara SC are not inferior to those for Dara 
IV in subjects with relapsed or refractory multiple myeloma who have received at least 3 prior 
lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or 
whose disease is double refractory to both a PI and an IMiD. Approximately 480 subjects will be 
assigned randomly to the Dara SC group or the Dara IV group in a 1:1 ratio. The randomization 
will be stratified by body weight at baseline (65 kg, 66 kg to 85 kg, >85 kg), number of prior 
lines of therapy (4 prior lines versus >4 prior lines), and type of myeloma (IgG versus non-
IgG).
The study consists of 3 phases: Screening Phase, Treatment Phase, and Follow-up Phase. The 
Screening Phase will be up to 28 days before randomization. The Treatment Phase will extend 
from randomization until discontinuation of treatment with study drug. Each subject will be 
treated until the sponsor confirms that disease progression has occurred for that subject, the 
subject has unacceptable toxicity, or other reasons. The Follow-up Phase begins immediately 
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following the End-of-Treatment Visit, and will continue until death, loss to follow up, consent 
withdrawal for study participation, or study end, whichever occurs first.
Treatment cycles are 28 days in length. The dosing schedule for both groups will be weekly for 
Cycles 1 and 2, every 2 weeks for Cycles 3 to 6, and every 4 weeks thereafter. Subjects who are 
assigned to the Dara SC
group will receive a fixed
dose of Dara SC
1800 mg 
(daratumumab 1800 mg co-formulated with rHuPH20 2000 IU/ml). Dara SC will be delivered by 
SC injection in the abdominal wall in left/right locations, alternating between individual doses. 
All subjects in the Dara SC group will be observed for at least 6 hours after the end of the SC 
injection during Cycle 1 Day 1 and, if deemed necessary by the investigator, after consecutive 
injections. Subjects who are assigned to the Dara IV group will receive Dara IV 16 mg/kg by IV 
infusion pump. 
Assessment of disease response will be conducted in accordance with the International Myeloma 
Working Group (IMWG) response criteria using a computerized algorithm. The primary analysis 
will occur approximately 6 months after the planned 480 subjects have been randomized. 
However, to support local submission in Japan, the study extended the local enrollment to reach 
the targeted number of Japanese subjects after the planned 480 subjects were all randomized. 
Additional subgroup analysis for Japanese subjects may be conducted approximately 6 months 
after the last Japanese subject has been randomized. The study is considered completed 
approximately 18 months after the last subject is randomized. At the end of the study, subjects 
who are benefiting from study treatment with daratumumab can continue to receive treatment 
after the end of the study.
1.3.
Statistical Hypotheses for Trial Objectives
The clinical and pharmacokinetic hypotheses are that the ORR and maximum Ctrough for Dara SC
1800 mg are not inferior to the ORR and maximum Ctrough, respectively, for Dara IV 16 mg/kg in 
subjects with multiple myeloma who have received at least 3 prior lines of therapy including a PI 
and an IMiD, or whose disease is refractory to both a PI and an IMiD. Both the null hypotheses 
for clinical and PK need to be rejected to declare non-inferiority.
1.3.1.1.
Statistical Hypotheses for ORR
For this study, the clinical non-inferiority of Dara SC relative to Dara IV is defined using 60% 
retention of the ORR (i.e., a non-inferiority margin of 40%). The non-inferiority hypothesis for 
ORR can be stated as:
H0: ORRSC / ORRIV < 60%                   
H1: ORRSC / ORRIV 60% (non-inferiority)
The primary analysis will use the non-inferiority test for non-unity null according to Farrington 
and Manning (1990)1. The relative risk and its two-sided 95% CI will be provided. In order to 
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declare non-inferiority, the lower bound of the two-sided 95% CI of the relative risk needs to be 
60%.
1.
If the lower bound of the two-sided 95% CI of the relative risk is ≥100%, superiority of 
Dara SC relative to Dara IV will be concluded.
1.3.1.2.
Statistical Hypotheses for Maximum Ctrough
For the co-primary endpoint of maximum Ctrough, which is defined as the concentration at pre-
dose on Cycle 3 Day 1, non-inferiority of Dara SC relative to Dara IV is defined using a non-
inferiority margin of at least 80% of the ratio of geometric mean (GM) of maximum Ctrough. The 
non-inferiority hypothesis for maximum Ctrough can be stated as:  
H0: GMSC / GMIV < 80%                    
H1: GMSC / GMIV 80% (non-inferiority)
Dara SC will be considered non-inferior to Dara IV on maximum Ctrough if the lower bound of the 
90% CI for the ratio of the geometric means is at least 80%.
1.4.
Non-inferiority Margins Justification
The clinical non-inferiority of Dara SC relative to Dara IV in the current study is defined using a 
60% retention of ORR from previous clinical Study MMY2002, a study of 106 subjects with 
relapsed or refractory multiple myeloma who had received at least 3 prior therapies and who 
were treated with Dara IV 16 mg/kg, an ORR of 29.2% (95% CI: 20.8%, 38.9%) was observed. 
There is no established standard of care for the targeted population, and the recent approvals 
were based on single-arm studies with ORR as the primary endpoint.
The 60% retention will result in minimal loss of benefit in terms of observed ORR. For example, 
if the observed ORR for Dara IV is 30%, then an ORR of at least 25% needs to be observed for 
Dara SC. The clinical relevance of the 60% retention of ORR was justified based on the 
benefit/risk of Dara SC and a strong indication of similar efficacy from early efficacy and 
pharmacokinetics data. Subjects enrolled into MMY2002 had a median of 5 prior lines of 
therapy. Outcomes for this population of patients generally are measured in months. Due to prior 
therapies, these patients also tend to be more frail, with lower organ reserves, compared with 
subjects with newly diagnosed multiple myeloma. A shorter infusion time would reduce time 
spent in a healthcare setting and a lower incidence of IRRs could enable them to stay on therapy 
longer. In addition, in the daratumumab Study MMY1004 Part 1, the ORR was 38% for 45 
subjects receiving Dara-MD 1800 mg, and the maximum Ctrough was similar or higher compared 
to Dara IV, strongly suggesting similar efficacy with Dara SC.
For the co-primary endpoint of maximum Ctrough, the non-inferiority of Dara SC relative to Dara 
IV is defined using a non-inferiority margin of at least 80% of the ratio of geometric mean (GM) 
of maximum Ctrough. Since this is a PK endpoint, the selection of non-inferiority margin and the 
choice of alpha level follow the convention for bioequivalence studies.
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1.5.
Sample Size Justification
There is no established standard of care for the targeted population, and the recent approvals 
were based on single-arm studies with ORR as the primary endpoint. In a previous clinical study 
(MMY2002), of 106 subjects with relapsed or refractory multiple myeloma who had received at 
least 3 prior therapies and who were treated with Dara IV 16 mg/kg, an ORR of 29.2% 
(95% CI: 20.8%, 38.9%) was observed.
Non-inferiority of Dara SC to Dara IV in the current study is defined using a 60% retention of 
the lower bound (20.8%) of the 95% CI from Study MMY2002. The clinical relevance of the 
60% retention of ORR was justified based on the benefit/risk of Dara SC and a strong indication 
of similar efficacy from early efficacy and pharmacokinetics data. The 60% retention will result 
in minimal loss of benefit in terms of observed ORR.
With a planned 1:1 randomization, 480 subjects (n=240 in the Dara SC group and n=240 in the 
Dara IV group) will be needed to demonstrate non-inferiority with a power of 80% and a one-
sided alpha=0.025, assuming that the true ORR is the same for both groups. The sample size 
calculation is based on the methodology for the non-inferiority test for non-unity null, as 
described by Farrington and Manning (1990)1.
The study is also designed to establish comparability of maximum Ctrough between Dara SC and 
Dara IV. The 2 formulations of daratumumab will be considered similar if the lower bound of 
the 90% CI for the ratio of the geometric means of Ctrough on Cycle 3 Day 1 is at least 80% (non-
inferiority margin of 20%). A one-sided test is selected based on previous analyses that 
demonstrated a strong relationship between maximum Ctrough and efficacy. However, there is no 
apparent relationship between drug exposure in the therapeutic dose range and adverse events of 
interest. With a planned 1:1 randomization, 480 subjects and a one-sided alpha=0.05, the power 
will be >95%. This assumes a true ratio of the Ctrough of 1, a non-inferiority margin of at least 
80% of the geometric mean ratio, a coefficient of variation of 0.6. 
1.6.
Randomization and Blinding
Central randomization will be implemented in this study. Subjects will be assigned randomly to 
1 of 2 treatment groups based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. The randomization will be balanced by 
using randomly permuted blocks and will be stratified by body weight at baseline (65 kg, 66 kg 
to 85 kg, >85 kg), number of prior lines of therapy (4 prior lines versus >4 prior lines), and type 
of myeloma (IgG versus non-IgG). An interactive web response system (IWRS) will assign a 
unique treatment code, which will dictate the treatment assignment and matching study drug kit 
for the subject. 
As this is an open-label study, blinding procedures are not applicable.
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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
drug administration data. The start date of a cycle is defined as the first scheduled dose date of 
the study drug for that particular cycle, 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 dose date plus 30 days or subsequent anticancer therapy minus 1 day, if the end 
of treatment visit date is not available. 
In general, if data (e.g., laboratory and vital sign etc.) are collected by cycle, the nominal cycle 
will be used to summarize data. However, due to possible cycle delays, assessment performed in 
the same cycle may not be well aligned in time scale for different subjects. To address this, 
by-week windowing rules may be applied in the overtime data summary by study week.
2.2.
Pooling Algorithm for Analysis Centers
Data from all study centers will be pooled for analyses.
2.3.
Study Drug
In this study, study drug refers to Dara SC or Dara IV. In the Dara SC group, Dara SC will be 
administered by SC injection at a fixed dose of 1800 mg. In the Dara IV group, Dara IV 16 
mg/kg will be administered by IV infusion. Each subject's dose in the Dara IV group will be 
calculated based on the subject's weight rounded to the nearest kilogram, but does not need to be 
recalculated for weight changes that are <10% from baseline.
Dose reduction or increase of Dara IV or Dara SC is not permitted. Dose delay or dose skip is the 
primary method for managing daratumumab-related toxicities.
The first dose date is defined as the earliest date of non-zero dose of study drug. The last dose 
date is defined as the latest date of non-zero dose of study drug.
A subject is considered as treated in a cycle if he/she receives any non-zero dose of study drug in 
that cycle.
2.4.
Baseline Definitions
The baseline value is defined as the last non-missing measurement taken on or prior to the first 
dose administration of study drug (including time if time is available).
Study day is defined as date of assessment – first dosing date + 1 for any assessment done on or 
after first dosing date; otherwise, study day is defined as date of assessment – first dosing date. 
The first dose date is defined as the earliest date of non-zero dose of study drug.
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2.5.
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 
as the unique lab value; c.) multiple records from local lab, select the latest lab value as the 
unique lab value.
2.6.
Analysis Sets
The analysis sets for the study are:
-
Intent-to-treat (ITT) analysis set: defined as all subjects randomized into the study. This 
analysis set will be used for summary of study populations, analyses of disposition, 
demographic, baseline disease characteristics, and analyses of efficacy endpoints including 
time-to-event endpoints. All subjects in ITT analysis set will be analyzed according to their 
randomized treatment group, regardless of the actual treatment received.
-
Safety analysis set: defined as all randomized subjects who receive at least 1 dose of study 
drug (Dara SC or Dara IV). This analysis set will be used for all safety analyses and 
analyses of exposure. All subjects in safety analysis set will be analyzed according to the 
actual treatment that they received.
-
Per-protocol (PP) analysis set: defined as all treated subjects who have measurable disease at 
baseline and have no major protocol deviations with respect to eligibility. The per-protocol 
analysis set will be used for critical sensitivity analyses of ORR in the context of the non-
inferiority design.
-
Response-evaluable analysis set: 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 1 administration of study drug and have at least 1 post baseline 
disease assessment. Measurable disease at baseline is defined in section 2.9.1. This analysis 
set will be used as sensitivity analyses for selective response-related endpoints such as ORR, 
VGPR or better rate, and CR or better rate.
-
Pharmacokinetics analysis set: defined as subjects who received at least 1 administration of 
study drug and have at least 1 pharmacokinetics sample concentration value after the first 
dose administration. All pharmacokinetic parameters except for maximum Ctrough will be 
analyzed based on the pharmacokinetics analysis set.
-
Pharmacokinetics-evaluable analysis set: defined as subjects who received all 8 weekly full
doses of Dara IV or Dara SC in Cycle 1 and Cycle 2 within the dosing time window
according to the Time and Events Schedule in protocol and provided a pre-dose 
pharmacokinetic sample on Cycle 3 Day 1 within the sampling window of 8 hours prior to 
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the start of dose administration. The Pharmacokinetics-evaluable analysis set will be used to 
summarize the maximum Ctrough. 
-
Immunogenicity-evaluable analysis set: 

Daratumumab immunogenicity-evaluable: Immunogenicity-evaluable analysis set 
for antibodies to daratumumab is defined as all subjects who receive at least 1
dose of Dara SC or Dara IV and have appropriate serum samples for detection of 
anti-daratumumab antibodies to daratumumab (at least 1 sample after the start of 
the first dose of daratumumab).

rHuPH20 immunogenicity-evaluable: Immunogenicity-evaluable analysis set for 
anti-rHuPH20 antibodies is defined as all subjects who receive at least 1 dose of 
Dara SC and have appropriate plasma samples for detection of antibodies to
rHuPH20 (at least 1 sample after the start of the first dose of Dara SC).
2.7.
Imputation of Missing Data 
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 anticancer therapy will be imputed.
2.7.1.
Adverse Event Start and End Date
Adverse Event Start Date
If the onset date of an adverse event is completely or partially missing, the following imputation 
rules will be used.

When month and year are present and the day is missing:
o
If the onset month and year are the same as the month and year of first dosing date, 
the day of first dosing or the day-component of the AE end date (possibly imputed) is 
imputed, whichever is earlier; 
o
If the onset month and year are not the same as the month and year of first treatment 
with study drug, the first day of the month is imputed.

When only a year of the onset date is present:
o
If the onset year is the same as the year of first treatment with study drug:

If AE end date is available and is prior to first dosing date, the day and month 
of AE end date are imputed;

Otherwise, the day and month of the first dosing date are imputed. 
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o
If the onset year is different from the year of first treatment with study drug, the 1st of 
January is imputed.

If the onset date is completely missing, the first dosing date is imputed as the onset date.
No imputation will be done for partial or missing AE onset time.
Adverse Event End Date
If the end date of an adverse event is completely or partially missing, 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. 
After the imputation, if the imputed date is later than the date of death (if available) after 
imputation, the date of death will be used as the imputed date.
No imputation will be done for partial or missing AE end time.
2.7.2.
Prior and Concomitant Medication/Therapy Start and End Date
For prior or concomitant medications/therapy, if the start or end date is completely missing, no 
imputation will be performed. If the start or end date is partially missing, the following 
imputation rules will be used. 

If only the day is missing, the 15th day of the month will be used. 

If both the day and month are missing, the 30th of June will be used.
If the medication/therapy was taken prior to study start, and the imputed start date is after first 
dosing date, further adjust the imputed start date as the day prior to first dosing date; if the 
medication/therapy 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/therapy end date so that it is on or after first dosing date.
2.7.3.
Multiple Myeloma Diagnosis Date
If the diagnosis date of multiple myeloma (MM) is completely missing, no imputation will be 
applied. If the diagnosis date is partially missing, the following imputation rules will be applied:

If only the day of the diagnosis date is missing:
o
If the month and year of the diagnosis date are the same as the month and year of the 
start date of the first line of prior MM therapy, and day of the start date of the first 
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line of prior MM therapy is available, impute day of the diagnosis date with the day 
of the start date of the first line of prior MM therapy;
o
Otherwise, impute day of diagnosis date with 15;

If both month and day of the diagnosis date are missing:

If the year of the diagnosis date is the same as the year of the start date of the first line
of prior MM therapy, and the month of the start date of the first line of prior MM 
therapy is available:
o
if both month and day of the start date of the first line of prior MM therapy are
available, impute diagnosis month and day with the month and day of the start date 
of the first line of prior MM therapy; 
o
if only the month of the start date of the first line of prior MM therapy is available, 
impute the month of diagnosis date with the month of the start date of the first line 
of prior MM therapy and the day of the diagnosis date with 15; 
o
Otherwise, impute the month and day of the diagnosis date with June 30.  
2.7.4.
First Subsequent Anticancer Therapy Start Date
If the start date of the first subsequent anticancer therapy is completely missing or the month is 
missing, no imputation will be performed. If only the day of the first subsequent therapy start 
date is missing, the following imputation rules will be applied:

If the month and year of the start date are the same as the month and year of the last dosing 
date, the day of last dosing date +1 or the day-component of the stop date of subsequent 
anticancer therapy will be imputed, whichever is earlier. 

If the month and year of the start date are not the same as the month and year of last dosing 
date, the first day of the month will be imputed.
2.8.
General Analysis Method
In general, continuous variables will be summarized using descriptive statistics such as mean,
standard deviation, median and range. Categorical variables will be summarized using
frequency and percentage. For time-to-event variables, which is defined as from the date of 
randomization to the date of the event, the Kaplan-Meier method will be used for descriptive
summaries. For the calculation of time-to-event and duration-of-event variables, the difference
between the start date and the end date plus 1 day will be used.
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2.9.
Other General Definitions
2.9.1.
Measurable Disease of Multiple Myeloma at Baseline and Measurable 
Type
Measurable disease at baseline is defined by any of the following: 
-
IgG multiple myeloma: Serum M-protein level ≥1.0 g/dL or urine M-protein level ≥200 
mg/24 hours; or
-
IgA, IgD, IgE, 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 the serum or the urine: Serum 
immunoglobulin free light chain (FLC) ≥10 mg/dL and abnormal serum immunoglobulin 
kappa lambda FLC ratio.
If a subject meets the criteria for serum M-protein, the measurable disease type is serum; 
otherwise, if a subject meets the criteria for urine M-protein, the measurable disease type is 
urine; otherwise if a subject meets the criteria for FLC, the measurable disease type is FLC. If a 
subject meets both of the criteria for serum M-protein and urine M-protein, then the measurable 
disease type is “serum and urine”.
2.9.2.
Type of Multiple Myeloma
Type of myeloma for a subject is determined by serum heavy chain or serum FLC or urinary 
FLC. Serum heavy chain refers to serum immunoglobulin of IgG, IgA, IgM, IgD, or IgE. Serum 
and urine FLC refers to kappa or lambda type. 
A subject will be classified as IgG type of myeloma if any reported result contains serum heavy 
chain ‘IgG’ regardless of FLC reported, similarly for IgA, IgM, IgD and IgE type. A subject will 
be classified as the light chain type of myeloma if any reported result is either ‘Lambda light 
chains’ or ‘Kappa light chains’ but without heavy chain reported. A subject will be reported as 
‘biclonal’ if the distinct test results contain different heavy chain values or different FLC values. 
A subject will be classified as “Negative immunofixation” if the reported result is “Not 
Detected” and with no serum heavy chain, serum light chain and urine light chain reported.
2.9.3.
International Staging System (ISS)
ISS staging is based on the combination of serum β2-microglobulin (B2MG) and serum 
albumin (ALB) at baseline.

Stage I:   β2-microglobulin<3.5 mg/L and serum albumin≥ 35 g/L

Stage III: β2-microglobulin ≥ 5.5 mg/L

Stage II:  Neither stage I nor stage III

   (β2-microglobulin<3.5 mg/L but serum albumin< 35 g/L, or β2-microglobulin    

    ≥3.5 mg/L to 5.5 mg/L irrespective of the serum albumin level)
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2.9.4.
Hepatic Function
Hepatic impairment is classified into 4 levels per NCI organ dysfunction criteria, using baseline 
total bilirubin and Aspartate Aminotransferase (AST):
-
Normal: total bilirubin ≤ ULN and AST ≤ ULN 
-
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
2.9.5.
Relapsed Disease
Relapsed disease is defined as an initial response to previous treatment, followed by progressive 
disease (PD) by IMWG criteria >60 days after cessation of treatment.
2.9.6.
Refractory Disease
Refractory disease is defined as <25% reduction in M-protein or confirmed PD by IMWG 
criteria during previous treatment or 60 days after cessation of treatment. 
2.9.7.
High Risk/Standard Risk Cytogenetics
The high risk and standard risk cytogenetics are defined as follows:
-
High risk: subjects that are positive for any of del17p, t(14;16), t(4;14) by 
FISH/Karyotype
-
Standard risk: subjects with sufficient cytogenetic testing to rule out presence of deletion 
of del17p, t(14:16), and t(4:14)
A subject will be classified as “Undetermined” if a subject had either no cytogenetic testing 
performed or had cytogenetic testing performed but risk categorization could not be determined.
2.9.8.
Time since Initial Multiple Myeloma Diagnosis
Time since initial multiple myeloma diagnosis to randomization in years is calculated as date of
randomization – date of initial MM diagnosis + 1, divided by 365.25.
2.9.9.
End of Follow-up and Duration of Follow-up
The end of follow-up is defined as the maximum date of the following study evaluations: labs 
(hematology, chemistry, immunology), adverse events, vital signs, ECOG performance status, 
PRO assessment, bone marrow cytogenetics, lytic bone lesions, extra-medullary plasmacytomas, 
study drug administration, ECG, pre-dose medications, post-dose medications, concomitant 
medications, subsequent therapy, medical encounters, clinical events/disease response per 
investigator and date of last known to be alive. For subjects who died on study, the end of
follow-up is the date of death. For subjects who died after the end of study, the end of follow-up 
will be set to the maximum date derived above.
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Duration of follow-up (in months) = the date of end of follow-up - the date of randomization + 1, 
divided by 365.25/12.
2.10.
Definition of Subgroups 
In general, subgroup analyses on the pre-specified subgroups in Table 1 will be performed for 
the primary efficacy endpoint ORR, major secondary endpoint of rate of infusion-related 
reactions (IRRs), and safety endpoints treatment-emergent adverse event (TEAE). Additional 
exploratory subgroup analyses may be performed for selected efficacy and/or safety endpoints. 
Table 1:
Subgroup Analyses for Efficacy and Safety Endpoints
Subgroup
Definition
Analysis Type
Sex
Male, Female
E, S
Age 
E: <75, ≥75 years
S:  < 65, 65 to < 75, and 75 years
E, S
Race
White, Other
E, S
Region
Asia/Pacific, Other 
E, S
Baseline weight
≤ 65 kg, >65 to 85 kg, and >85 kg
E, S
Baseline renal function 
(Glomerular filtration rate 
[GFR] [mL/min/1.73m2])
E: ≤60, >60 (mL/min/1.73m2)
S: <30, 30 to <60, 60 to <90, and ≥90
(mL/min/1.73m2)
E, S
Baseline hepatic function
Normal, Impaireda
S
ISS staging 
I, II, and III
E 
Number of prior lines of therapy
≤ 4 lines, >4 lines
E
Type of myeloma 
IgG, non-IgG
E
Cytogenetic risk
High risk, Standard risk
E 
ECOG performance score
0, ≥1
E
E: efficacy (ORR); S: safety (TEAEs).
a Includes mild, moderate and severe.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
No interim analysis is planned for this study.
An independent Data Monitoring Committee (DMC), consisting of 2 clinicians and 1 statistician, 
will be established to review safety data periodically during the study. The DMC will review 
comprehensive safety data and provide recommendations concerning the conduct of the study. 
The details will be provided in a separate DMC charter. 
The statistical analysis plan for the DMC will be provided in a separate DMC SAP.
4.
SUBJECT AND TREATMENT INFORMATION
Analyses of subject disposition, demographic and baseline disease characteristics will be 
conducted on ITT analysis set. Analyses on extent of exposure will be conducted on safety 
analysis set. No statistical comparisons between the two treatment groups will be performed.
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4.1.
Subject Disposition
The number of subjects who are randomized, treated, ongoing, and discontinued treatment with 
reasons of discontinuation reported on eCRF will be summarized. The number of subjects who 
discontinued from study with the reported reasons will also be presented. The number of subjects 
who discontinued treatment by cycle with the reported reasons will also be provided.
Subject enrollment will also be summarized by country and site for intent-to-treat analysis set. 
A listing of subjects who discontinued treatment with study drug including reasons for 
discontinuation will be provided. A similar listing will be provided for subjects who discontinued 
study.
4.2.
Demographics and Baseline Characteristics
The following subject demographics will be summarized using descriptive statistics:
-
Age (continuous)
-
Age category (< 65 years, 65 to < 75 years, and ≥75 years)
-
Sex (male, female)
-
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, and Not reported) 
-
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
-
Height (cm)
-
Weight (kg) (65 kg, >65 kg to 85 kg, >85 kg)
-
Baseline ECOG performance status (0, 1, 2)
The following baseline disease characteristics will be summarized using descriptive statistics: 
-
Type of myeloma (IgA, IgD, IgE, IgG, IgM, light chain, biclonal, or negative 
immunofixation)
-
Type of measurable disease (serum and urine, serum, urine, FLC)
-
ISS staging (I, II, III)
-
standard-risk and high-risk cytogenetic abnormalities (del17p, t(4;14), t(14;16))
-
Time since initial diagnosis to randomization (years) 
-
Number of lytic bone lesions (None, 1-3, 4-10, more than 10) 
-
Presence of diffuse myeloma-related osteopenia (Yes, No) 
-
Presence of extramedullary plasmacytomas (Yes, No) 
-
Bone marrow % plasma cells (<10, 10 – 30, > 30) 
In addition, a descriptive summary of selected hematology and chemistry laboratory analytes at 
baseline will be provided for each treatment group and overall. The baseline toxicity grade of
selected laboratory analyte in hematology and chemistry panel will be summarized by treatment 
group using frequency.
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In addition, a summary of stratification factors used in the randomization (body weight at 
baseline, number of prior lines of therapy, and type of myeloma) based on IWRS will be 
provided to evaluate whether or not randomization process was appropriately executed in the 
study.
4.3.
Medical History
General medical history will be summarized by body system organ class and preferred term for 
each treatment group and overall. 
4.4.
Prior Therapies
4.4.1.
Prior Multiple Myeloma Therapies
The number and percentage of subjects who had prior exposure to multiple myeloma therapies 
(systemic therapy, autologous stem cell transplant [ASCT], radiotherapy, cancer-related surgery) 
will be summarized by treatment group. Specifically, for prior systemic therapies, the number of 
prior lines of therapy will be summarized descriptively and summarized by the following 
categories: ≤4 and > 4.
The summary of prior systemic therapies will be presented by therapy class and therapy. The 
therapy classes include proteasome inhibitors (PI), immunomodulatory drugs (IMiD), steroids, 
alkylating agents and anthracyclines. 
-
PI therapy class includes: bortezomib, carfilzomib, oprozomib, ixazomib, and marizomib;
-
IMiD therapy class includes: lenalidomide, pomalidomide, and thalidomide;
-
Steroids therapy class includes: dexamethasone and prednisone, among others.
Further update of the above lists will be specified in the Data Presentation Specifications (DPS). 
The number of subjects who had prior exposure to multiple therapy classes (e.g., PI + IMiD) or 
multiple therapies (e.g., bortezomib + lenalidomide) may be provided, if the number of subjects 
who exposed to those therapy class or therapies is sufficient.
Additionally, the prior systemic therapy will be summarized by therapeutic class, pharmacologic 
class and preferred term.
4.4.2.
Refractory Status to Prior Systemic Therapy
Refractory status (yes, no) to a particular prior systemic therapy class (i.e., PI/IMiD) or prior 
systemic therapy (e.g., bortezomib or thalidomide) will be based on refractory status to each line 
of therapy, or each specific therapy collected on prior systemic therapy CRF page. For each 
subject, refractory to each therapy class/therapy refers to refractory to his/her most recent 
therapy-containing line. 
The number and percentage of subjects’ refractory status to the most recent PI or IMiD therapy 
class will be summarized by the following 4 categories: none (neither PI-refractory nor IMiD-
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refractory), PI only (PI-refractory but not IMiD-refractory), IMiD only (IMiD-refractory only but 
not PI-refractory), both PI and IMiD. Refractory to specific prior therapy, such as bortezomib, 
carfilzomib, ixazomib, lenalidomide, pomalidomide, or thalidomide
and the relevant 
combinations of the aforementioned therapies will be provided separately. 
The incidence of subjects who are refractory to their last line of therapy will be reported. 
4.5.
Prior and Concomitant Medications
Medications administered prior to the first dose date of study drug will be considered as prior 
medications. Concomitant medications are defined as those medications taken on or after the first 
dose date through 30 days after the last dose date.
Prior medications will be summarized on ITT analysis set by therapeutic class, pharmacologic 
class, and preferred term.
Concomitant medications will be summarized on safety analysis set by therapeutic class, 
pharmacologic class, and preferred term. Similar summaries will be provided for subjects who 
received concomitant growth factor support, systemic steroids, antiviral systemic use, and 
prophylactic antiviral medications during the study, respectively.
Pre-dose medications and post-dose medications will also be summarized by therapeutic class, 
pharmacologic class, and preferred term, respectively.
4.6.
Subsequent Anticancer Therapies
The total number of subjects who received subsequent anticancer therapy for multiple myeloma
will be reported for safety analysis set in each treatment group. A summary of subsequent 
anticancer therapy will be presented by therapeutic class, pharmacologic class and preferred 
term.
In addition, for subjects who received subsequent anticancer therapy for multiple myeloma, the 
best response to the first subsequent anticancer therapy will be summarized.  
4.7.
Extent of Exposure
Extent of exposure to study drug will be summarized and presented on safety analysis set.
Treatment duration and the total number of treatment cycles will be summarized descriptively. 
The number and percentage of subjects treated within each cycle will also be summarized by 
treatment group.
Treatment duration in months is derived as last non-zero daratumumab dosing date – first 
non-zero daratumumab dosing date + 1 and then divided by 365.25/12. The maximum number of 
treatment cycles for each subject is the largest cycle number in which a subject receives any non-
zero dose of daratumumab.
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In addition, duration of daratumumab administration in minutes is derived for each visit 
separately. It includes both interruption time and actual dose administration time, and is 
calculated as maximum dose administration end time – minimum dose administration start time. 
Duration of daratumumab administration in minutes will be summarized by first dose 
administration, second dose administration, and subsequent dose administrations. 
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 and summarized for each treatment group. Dose 
intensity will be summarized for both treatment groups in both units of mg/cycle and 
mg/kg/cycle. Additionally, the daratumumab dose intensity will be summarized by Cycles 1-2, 
Cycles 3-6, and Cycle 7+ during the treatment. 
Relative dose intensity (%), which is defined as the ratio of total dose received and total planned 
dose, will be calculated and summarized for each treatment group.  Additionally, the relative
dose intensity will be summarized by Cycles 1-2, Cycles 3-6, and Cycle 7+ during the treatment.
The incidences of treatment cycle delays, dose delays, dose skip and corresponding reasons will 
be provided. The frequencies of actions planned prior to infusion or injection start and taken 
during infusion or injection will be summarized, together with reasons reported on eCRF. In 
addition, a summary of treatment modifications will also be provided by Cycles 1-2, Cycles 3-6, 
and Cycle 7+ during the treatment.
A separate listing including all daratumumab dose administration data will be provided.
4.8.
Protocol Deviations
Major protocol deviations will be summarized for ITT analysis set by the following types of 
deviation for each treatment group: 
-
Entered but did not satisfy criteria 
-
Developed withdrawal criteria but not withdrawn 
-
Received wrong treatment or incorrect dose 
-
Received a disallowed concomitant treatment 
-
Other 
A list of subjects with major protocol deviations including subject ID, type of deviation, and 
reasons for deviation will be provided.
5.
EFFICACY
Assessment of disease will be conducted in accordance with the IMWG response criteria. 
Efficacy evaluations will include the following: measurements of myeloma proteins, bone 
marrow examinations, skeletal surveys and other imaging studies, and serum calcium corrected 
for albumin.
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5.1.
Analysis Specifications
5.1.1.
Level of Significance 
For the co-primary endpoint of ORR, the hypothesis tests will be based on one-sided test at 
significance level of alpha=0.025 to demonstrate the non-inferiority of Dara SC relative to Dara 
IV. If the non-inferiority of the Dara SC relative to Dara IV is claimed and the lower bound of 
the two-sided 95% CI of the relative risk is ≥100%, the superiority of Dara SC relative to Dara 
IV will be concluded.
For the co-primary endpoint of maximum Ctrough, one-sided test at significance level of 
alpha=0.05 is selected to demonstrate the non-inferiority of Dara SC relative to Dara IV in terms 
of the maximum trough concentration. 
Non-inferiority of Dara SC relative to Dara IV will be claimed only if both endpoints of ORR 
and maximum Ctrough meet their criteria. Therefore, the overall type I error will be strictly 
controlled at level of alpha=0.025 (one-sided). In addition, since maximum Ctrough is a 
pharmacokinetic endpoint, the conventional choice of alpha=0.05 (one-sided) is selected.
Once the non-inferiority null hypothesis is rejected for both the ORR and maximum Ctrough, the 
following major secondary endpoints ordered below will be sequentially testing for superiority 
by utilizing a hierarchical procedure to control familywise Type I error rate at a two-sided 
significance level of 0.05. The major secondary endpoints will be sequentially tested in the 
following order:
1) Rate of infusion-related reactions 
2) Progression-free survival 
3) Rate of VGPR or better
4) Overall Survival
5.1.2.
Computerized Algorithm
A validated computerized algorithm (Attachment 2), which is based on the IMWG response 
criteria (Durie 2006, Rajkumar 2011)2,3 and has been used and validated by an independent 
review committee in study MMY2002, also used in MMY3003, MMY3004, MMY3007, 
and MMY3008 will be used to determine response and disease progression for each subject. 
Unless specified otherwise, relapse from CR by positive immunofixation or trace amount 
(defined as less than 0.5 g/dl) of M protein is not considered to be progressive disease in the 
IMWG response criteria. 
The primary efficacy analyses will be based on the computerized algorithm assessments. 
Analyses for the primary endpoint ORR and selected major secondary efficacy endpoints based 
on investigator assessments using the IMWG response criteria will also be performed as 
sensitivity analyses.  
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5.1.3.
Data Handling Rules 
There is no imputation planned for missing efficacy endpoint values.
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
The co-primary endpoint of this study for efficacy is overall response rate, which is defined as 
the proportion of subjects who achieve partial response (PR) or better according to the IMWG 
response criteria, including the subjects with either complete response (including stringent 
complete response [sCR]) or partial response (including VGPR), during or after treatment with 
study drug but at or prior to the start of subsequent anticancer therapy. Subjects with overall 
responses achieved after the start of subsequent anticancer therapy will not be considered as 
responders.
5.2.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is 
defined by the following 4 components:

Population: subjects with relapsed or refractory 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; 

Variable: overall response, which is defined as response if the best response is PR or better 
assessed at or prior to the start of subsequent anticancer therapy and non-response otherwise;

Intercurrent event: Treatment discontinuation is considered as an intercurrent event for 
overall response and treatment policy strategy will be implement, i.e., disease assessments
ignoring the treatment discontinuation will be implemented.

Population-level summary: relative risk of overall response between two treatment groups.
5.2.3.
Analysis Methods
The primary analysis of ORR will be performed on the ITT analysis set. The number and 
percentage of subjects in the following response categories will be tabulated by treatment group: 
sCR, CR, VGPR, PR, minimal response (MR), stable disease (SD), progressive disease (PD), 
and not evaluable (NE). The overall response (including sCR + CR + VGPR + PR), VGPR or 
better (sCR + CR + VGPR), and CR or better (sCR + CR) will also be summarized. For each of 
the above categories, two-sided 95% Clopper-Pearson exact confidence interval (CI) will also be 
presented by treatment group.
Farrington-Manning (FM) test will be used to test the overall response rate. The FM estimate of 
relative risk with its 2-sided 95% confidence interval and p-value will be reported. If the lower 
bound of the 95% CI is ≥ 60%, the non-inferiority of Dara SC relative to Dara IV will be 
concluded. If non-inferiority in ORR is established and the lower limit of the 95% CI of the 
relative risk is ≥100%, the superiority of Dara SC relative to Dara IV will be concluded.
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A sensitivity analysis of ORR based on the per-protocol and response-evaluable analysis sets
will be performed in a similar manner as described above.
A sensitivity analysis of ORR, in which disease response is based on investigator assessment
according to the IMWG response criteria, will also be performed in a similar manner.
A supplementary analysis of ORR based on the first 480 randomized subjects in intent-to-treat 
analysis set will also be performed in a similar manner.
5.3.
Major Secondary Endpoints
The major secondary efficacy endpoints include progression-free survival (PFS), response rate of 
VGPR or better, response rate of CR or better, time to next therapy (TNT), overall survival (OS),
duration of response (DOR), and time to response (TTR).
5.3.1.
Progression-free Survival 
5.3.1.1.
Definition
PFS is defined as the duration from the date of randomization to either progressive disease, 
according to the IMWG response criteria, or death due to any cause, whichever occurs first.
Subjects who start subsequent anticancer 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 the subjects were lost to 
follow-up. Subjects who have not progressed and are still alive at the clinical cut-off date for 
analysis will be censored at the last disease assessment. Subjects without any post-baseline 
disease assessment will be censored at randomization. 
Determination of dates of PFS event and dates for censoring is summarized in Table 2 as 
follows.
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Table 2:
PFS Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No postbaseline disease assessment
Randomization
Censored
Disease progression at or prior to start of
subsequent anticancer therapy
Earliest date that indicates disease progression PFS event
Death at or prior to start of subsequent anticancer
therapy
Date of death
PFS event
Other, such as:
Withdrawal of consent to study participation,
Lost to follow-up
Start of subsequent anticancer therapy prior to 
disease progression or death 
Date of last disease assessment prior to
withdrawal of consent to study participation,
lost to follow-up, or 
start of subsequent anticancer therapy  
Censored
5.3.1.2.
Analysis Methods
Analysis of PFS will be performed on the ITT analysis set. 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. The Kaplan-Meier curve for PFS will also be plotted by treatment 
group.
The PFS distributions between the 2 treatment groups will be compared using the stratified 
log-rank test. The p-value from a stratified log-rank test will be reported. The treatment effect 
(hazard ratio) and its 2-sided 95% CI will be estimated using a stratified Cox regression model 
with treatment as the sole explanatory variable. Stratification factors used in the analyses include 
body weight at baseline (65 kg, 66 kg to 85 kg, >85 kg), number of prior lines of therapy 
(4 prior lines versus >4 prior lines), and type of myeloma (IgG versus non-IgG). 
In addition, the number and percentage of subjects who had a PFS event or were censored will be 
reported. The reasons for progressive disease and censoring of PFS will also be summarized for 
ITT analysis set.
A sensitivity analysis of PFS, in which progressive disease is based on investigator assessment 
according to the IMWG response criteria, will be performed in a similar manner as described
above.
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5.3.2.
Response Rate of VGPR or Better 
5.3.2.1.
Definition
Response rate of VGPR or better is defined as the proportion of subjects with a response of 
VGPR or better (VGPR, CR or sCR) according to IMWG response criteria, during or after
treatment with study drug but at or prior to the start of subsequent anticancer therapy. 
5.3.2.2.
Analysis Methods
The response rate of VGPR or better will be calculated for each treatment group on both ITT and 
response-evaluable analysis sets. The corresponding 95% Clopper-Pearson exact CI will be 
provided. 
Stratified CMH test will be used to test the proportion of subjects who achieved a VGPR or 
better response. The CMH estimate of odds ratio and its 95% confidence interval and p-value 
will be reported. Stratification factors used in the analysis include body weight at baseline (65 
kg, 66 kg to 85 kg, >85 kg), number of prior lines of therapy (4 prior lines versus >4 prior 
lines), and type of myeloma (IgG versus non-IgG).
A sensitivity analysis of response rate of VGPR or better, in which disease response is based on 
investigator assessment according to the IMWG response criteria, will be performed in a similar 
manner as described above.
5.3.3.
Response Rate of CR or Better 
5.3.3.1.
Definition
Response rate of CR or better is defined as the proportion of subjects with a response of a CR or 
better (CR or sCR) according to IMWG response criteria, during or after treatment with study 
drug but at or prior to the start of subsequent anticancer therapy. 
5.3.3.2.
Analysis Methods
The response rate of CR or better will be calculated for each treatment group on both ITT and 
response-evaluable analysis sets. The corresponding 95% Clopper-Pearson exact CI will be 
provided. 
An analysis of response rate of CR or better, in which disease response is based on investigator 
assessment according to the IMWG response criteria, will be performed in a similar manner as 
described above.
5.3.4.
Time to Next Therapy
5.3.4.1.
Definition
Time to next therapy is defined as the time from randomization to the start of subsequent 
anticancer therapy for multiple myeloma. Death due to PD without start of subsequent anticancer
therapy will be considered as event. Subjects who withdrew consent to study or are lost to 
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follow, or die due to causes other than disease progression or subjects without receiving 
subsequent anticancer therapy will be censored at date of death or the last date known to be alive.
5.3.4.2.
Analysis Methods
TNT will be analyzed using similar statistical methods as described in Section 5.3.1.2 for PFS 
analysis.
5.3.5.
Overall Survival
5.3.5.1.
Definition
Overall survival is defined as the time from the date of randomization to the date of the subject’s 
death due to any cause. Death after end of study will also be considered as an OS event.
Subjects who are lost to follow-up will be censored at the time of lost to follow-up. Subject 
who is still alive at the clinical cut-off date for the analysis will be censored at the date of last 
known to be alive. The date of last known to be alive will be determined by the maximum 
collection/assessment date from among selected data domains within the clinical database.
5.3.5.2.
Analysis Methods
OS will be analyzed using similar statistical methods as described in Section 5.3.1.2 for PFS 
analysis.
A summary of reasons for censoring of overall survival will be provided.
5.3.6.
Time to Response
5.3.6.1.
Definition
Time to response (i.e., time to first response) is defined as the time from the date of 
randomization to the date of initial documentation of a response of PR or better based on the 
computerized algorithm for patients who had PR or better as their best response.
5.3.6.2.
Analysis Methods
For the subjects who achieve a response of PR or better, descriptive statistics (n, mean, standard 
deviation, median, and range) will be provided to summarize TTR for the responders in each 
treatment group. 
The similar analyses will be conducted for time to response of VGPR or better and time to 
response of CR or better.
No formal statistical comparison of TTR between the treatment groups will be made.
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5.3.7.
Duration of Response
5.3.7.1.
Definition
Duration of response is 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 according to
IMWG criteria or death due to PD, whichever occurs first, for the subjects who had achieved a 
response of PR or better. 
Subjects who start subsequent anticancer therapies without PD will be censored at the date of the 
last disease assessment prior to the start of subsequent anticancer therapies. Subjects who have 
not progressed or subjects who die due to causes other than disease progression will be censored 
at the last disease assessment date.
5.3.7.2.
Analysis Methods
Analysis of DOR will be based on subjects who achieved a 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 curve for DOR will be plotted by treatment group.
No formal statistical comparison of DOR between the treatment groups will be made.
5.4.
Other Efficacy Endpoints/Variables
Other efficacy endpoints include the proportion of subjects with best M-protein response for 
subjects with measurable disease in serum or urine, and the proportion of subjects with maximal 
reduction of ≥90% and ≥50% from baseline in the difference between involved and uninvolved 
serum FLC (dFLC) for subjects with measurable disease of FLC only, and exploratory efficacy 
endpoint of progression-free survival on next line of therapy (PFS2).
5.4.1.
Best M-protein/dFLC Response
5.4.1.1.
Definition
Serum/urine M-protein or FLC reduction, defined as the percent change from baseline at each 
post-baseline assessment visit in the quantitation of the corresponding serum/urine M-protein or 
FLC, according to the measurable type at baseline. 
Best M-protein response is defined as the maximal percent reduction or the lowest percent 
increase from baseline in serum M-protein for subjects with measurable heavy chain at baseline 
or urine M-protein for subjects without measurable heavy chain, but with measurable light chain 
disease at baseline. 
For subjects without measurable heavy chain and light chain disease at baseline, best response in 
serum dFLC is defined as the maximal percent reduction or the lowest percent increase from 
baseline in the difference between involved and uninvolved serum FLC level.
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5.4.1.2.
Analysis Methods
The number and percentage of subjects in each response category, along with presentation of 
≥90% reduction and ≥50% reduction, will be tabulated for each treatment group. 
5.4.2.
Progression-free Survival on Next Line of Therapy (PFS2)
5.4.2.1.
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, including the deaths after end of study. 
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 3 as 
follows.
Table 3:
PFS2 Event and Censoring Method
Situation
Date of Progression or Censoring
Outcome
No postbaseline 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
5.4.2.2.
Analysis Methods
PFS2 based on investigator assessment on ITT analysis set will be analyzed using similar 
statistical methods as described in Section 5.3.1.2 for PFS analysis.
5.5.
Subgroup Analysis for Efficacy Endpoints
For assessment of internal consistency and investigation of homogeneity of the treatment effect 
across subgroups, a subgroup analysis of the primary efficacy endpoint of ORR based on pre-
specified subgroups defined in Section 2.10 will be conducted.
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A forest plot of subgroup analysis on ORR will be generated. 
Additional exploratory subgroup analyses may be performed for selected efficacy and/or safety 
endpoints.
6.
SAFETY
Analysis of safety data will be provided on the safety analysis set. All subjects will be analyzed 
according to the actual treatment they received.
The safety assessments to be evaluated include AEs, deaths, clinical laboratory tests 
(hematology, chemistry), vital signs, electrocardiogram (ECG) and ECOG performance scores. 
6.1.
Adverse Events
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.  
The relationships to study medication will be recorded as not related, doubtful, possible, 
probable, or very likely on eCRF for all the AEs. Adverse events will be categorized and 
summarized according to their highest relationship to study medication. An adverse event is 
considered as related to study medication if the relationship is recorded as possible, probable or 
very likely.
Treatment-emergent adverse events (TEAEs) are defined as any AE with onset date and time on 
or after that of the first dose through 30 days after the last study drug administration, or the day 
prior to start of subsequent therapy, whichever is earlier; or the follow-up AE (linked to an 
existing TEAE) with onset date and time beyond 30 days after the last study agent administration 
but prior to the start of subsequent therapy; or any AE that is considered related to (very likely, 
probably, or possibly related) study medication 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. 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 study drug administration.
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 
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1 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.
6.1.1.
Overview of TEAEs
An overview of TEAEs reported through the study will be provided for each treatment group.
Overall summary of TEAE will include the subjects with TEAEs, serious TEAEs, TEAEs of 
maximum toxicity grade of 1 to 5, and TEAEs leading to treatment discontinuation.
A similar overview of TEAEs will be presented by treatment cycle.
6.1.2.
All TEAEs
The following summaries will be provided for all TEAEs:
-
TEAEs by system organ class (SOC) and preferred term (PT)
-
Most common (e.g., ≥10%) TEAEs by SOC and PT
-
TEAEs by SOC, PT, and maximum toxicity grade
6.1.3.
Toxicity Grade 3 or 4 TEAEs
The following grade 3 or 4 TEAEs will be summarized:
-
Grade 3 or 4 TEAEs by SOC and PT
-
Most commonly reported (e.g., ≥5%) grade 3 or 4 TEAE by SOC and PT 
A similar summary of grade 3 or 4 TEAEs will be presented by SOC, PT and by treatment cycle.
In addition, a listing of grade 3 or 4 TEAEs will also be provided.
6.1.4.
Treatment-related TEAEs
The following TEAEs will be summarized by relationship to study drug:
-
TEAEs by SOC, PT, and relationship
-
Grade 3 or 4 TEAEs by SOC, PT and relationship
6.1.5.
Serious TEAEs
The incidence of serious TEAEs will be summarized as below:
-
Serious TEAEs by SOC and PT
-
Serious TEAEs by SOC, PT and relationship to study drug
-
Most commonly reported (e.g., ≥2%) serious TEAEs by SOC and PT
A similar summary of serious TEAEs will be presented by SOC, PT and treatment cycle. 
In addition, a listing of serious TEAEs will be provided.
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6.1.6.
TEAEs Leading to Treatment Discontinuation
The TEAEs leading to permanent treatment discontinuation will be summarized by SOC, PT and 
grade 3/4 for those subjects indicated as having discontinued treatment with study drug due to an 
adverse event on the eCRF “End of Treatment” page. 
A listing for subjects who discontinued treatment with study drug due to AE will be provided.
6.1.7.
TEAEs Leading to Treatment Modifications
Incidence of TEAEs leading to treatment modifications (i.e., cycle delay, dose delays, or dose
skip) will be summarized by SOC, PT and grade 3/4 for each treatment group. 
6.1.8.
TEAEs with Fatal Outcome 
The TEAEs with fatal outcome will be summarized by PT and relationship to study drug for each 
treatment group. A listing of TEAEs with fatal outcome will also be provided.
6.2.
Deaths
The number of subjects who died during the study and the primary causes of death will be
summarized for the ITT analysis set. In addition, the similar summaries will be presented for 
all deaths within 30 days of last dose and deaths within 60 days of first dose, respectively.
A listing of subjects who died during the study will be provided.
6.3.
Adverse Events of Clinical Interest 
6.3.1.
Infusion-related Reactions
6.3.1.1.
Rate of Infusion-related Reactions
For the major secondary endpoint of rate of IRRs, the proportion of subjects who have an IRR 
along with its 95% Clopper-Pearson exact CI will be calculated for each treatment group on the 
safety analysis set.  
Stratified CMH test will be used to test the IRR rate. The CMH estimate of odds ratio and its 
2-sided 95% confidence interval and p-value will be reported. Stratification factors used in the 
analysis include body weight at baseline (65 kg, 66 kg to 85 kg, >85 kg), number of prior lines 
of therapy (4 prior lines versus >4 prior lines), and type of myeloma (IgG versus non-IgG). 
A subgroup analysis on rate of IRRs will be conducted for the subgroups of race and baseline 
weight defined in Section 2.10. A forest plot of the subgroup analysis on rate of IRRs will be 
generated.
6.3.1.2.
Summary of Infusion-related Reactions
The incidence of infusion-related reactions (IRRs), as recorded on eCRF, will be presented by 
SOC, PT, and toxicity grade 3/4. In addition, the total number of subjects with IRR in more than 
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1 infusion will be presented. Time to onset of IRR will be summarized descriptively. The timing 
of IRR will also be evaluated through a summary of IRR by event onset time. 
A listing of infusion-related reactions will be provided.
6.3.2.
Injection-site Reactions 
For the Dara SC treatment group, injection-site reactions will be recorded on eCRF. The 
incidence of injection-site reactions will be summarized by SOC, PT, and toxicity grade 3/4. A 
listing of injection-site reactions will be provided.
6.3.3.
Infections and Infestations
Infections and infestations refer to the adverse events with SOC of infections and infestations.
The grade 3 or 4 treatment-emergent infections and infestations will be summarized by preferred 
term and relationship to treatment. Treatment-emergent infections and infestations may also be 
summarized by preferred term and treatment cycles.
6.3.4.
Hemorrhage Events
Hemorrhage events refer to the adverse events defined by Standardized MedDRA Queries 
(SMQ) with the first subcategory SMQ of hemorrhage terms (exclude laboratory terms).
Incidences will be summarized by MedDRA system organ class and preferred term. The
summaries will be presented by all grades and maximum toxicity grade for each treatment
group.
6.3.5.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) events refer to the adverse events defined by narrow SMQ of 
tumor lysis syndrome (e.g., haemorrhagic tumour necrosis, tumour lysis syndrome, or tumour 
necrosis). A listing of subjects who reported any treatment-emergent TLSs during the study will
be provided.
6.3.6.
Second Primary Malignancies
The second primary malignancies during the study will be summarized by cancer type and 
preferred term. A listing of subjects who reported second primary malignancies during the study 
will also be provided. This listing will include diagnosis, study day of diagnosis, recurrence of a 
prior existing malignancy (yes, no) and pathology diagnosis (biopsy, aspirate etc.) information 
whenever a second primary malignancy is observed. In addition, cumulative study drug
exposure, the treatment for second primary malignancy and the outcome information will also be 
presented in the listing.
6.3.7.
Adverse Events by Subgroups
The subgroup analysis for the following TEAEs will be performed based on the subgroups 
specified in Section 2.10:
-
Overview of TEAEs 
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-
Summary of all TEAEs 
-
Grade 3 or 4 TEAEs
-
Serious TEAEs
6.4.
Clinical Laboratory Tests
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes:

Hematology Panel:
-
hemoglobin
-
white blood cell (WBC) count, absolute neutrophil count, and absolute lymphocyte 
count
-
platelet count

Serum Chemistry Panel:
-
AST
-
alkaline phosphatase
-
ALT
-
uric acid
-
total bilirubin
-
blood urea nitrogen (BUN) or urea
-
glucose
-
calcium and albumin-adjusted calcium
-
creatinine
-
lactic acid dehydrogenase (LDH)
-
sodium
-
potassium
Descriptive statistics for values and changes from baseline at each scheduled visit for 
hematology and chemistry laboratory parameters will be provided. 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, and creatinine.
In addition, the worst toxicity grade in hematology and chemistry during the treatment will be 
summarized by treatment group and toxicity grade. Shifts tables from baseline to the worst 
toxicity grade during treatment will be generated.
6.5.
Vital Signs and Physical Examination Findings
Descriptive statistics will be provided for values and changes from baseline over time for vital 
signs (pulse, temperature, systolic and diastolic blood pressure) at each scheduled visit. Similar 
analysis may be performed for weight at Day 1 of each treatment cycle.
Clinically significant physical examination findings occurred at post-baseline were collected as 
AEs, and therefore will not be summarized.
6.6.
Electrocardiogram 
The ECG data will be collected at Screening, visits as clinically indicated during treatment, and 
End-of-Treatment visit.
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The number and percentage of subjects with normal and abnormal either clinically significant or 
not clinically significant ECG results will be summarized for each treatment group.
A listing of subjects who experienced clinically significant abnormal ECGs in either baseline or 
post-baseline will be produced.
6.7.
ECOG Performance Status
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 each treatment cycle and end-of-treatment 
visit. The shift summaries of ECOG performance status from baseline to each scheduled visit, 
including Day 1 of each treatment cycle and end-of-treatment visit, will be provided for each 
treatment group. The shift summary from baseline to the worst performance score during 
treatment will also be presented. 
7.
PHARMACOKINETICS/IMMUNOGENICITY/PHARMACODYNAMICS
Unless specified otherwise, descriptive statistics will be used to summarize pharmacokinetics 
and pharmacodynamics data. In addition, coefficient variation and geometric mean will be 
provided in the pharmacokinetic concentration summary.
7.1.
Pharmacokinetics
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. 
The pharmacokinetic parameters are defined as:
-
Maximum Ctrough - Serum pre-dose concentration of daratumumab on Cycle 3 Day 1
-
Cmin - Minimum observed concentration
-
Cmax - Maximum observed concentration
The Maximum Ctrough, Cmin, and Cmax will be determined based on the assigned collection 
timepoints. If there are sufficient data, population pharmacokinetic analysis of serum 
concentration-time data of daratumumab may be performed using nonlinear mixed effects 
modeling and may include data from other clinical studies. If performed, details will be provided 
in a population pharmacokinetic analysis plan and results of the analysis will be presented in a
separate report.
7.1.1.
Maximum Ctrough
For the co-primary endpoint maximum Ctrough, which is defined as the concentration at pre-dose 
on Cycle 3 Day 1, the summary statistics such as the geometric mean, coefficient of variation, 
median, and range will be provided by treatment group. The ratio of the geometric means and the 
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corresponding 90% confidence interval utilizing logarithmic transformation of Ctrough values will 
be provided. If the lower bound of the 90% CI for the ratio of the geometric means of maximum 
Ctrough is ≥80% (non-inferiority margin of 20%), Dara SC will be considered non-inferior to 
Dara IV.
Box plot of maximum Ctrough will be provided.
The analyses of maximum Ctrough will be performed on the pharmacokinetics-evaluable analysis 
set.
7.1.2.
Other Pharmacokinetic Parameters
The following pharmacokinetic parameters will also be summarized on the pharmacokinetics 
analysis set: 
-
Minimum observed concentration (Cmin): defined as the concentration observed 
immediately before dose administration;
-
Maximum observed concentration (Cmax): defined as the concentration observed after the 
end of dose administration.
The Cmin and Cmax will be determined based on assigned collection timepoint. Descriptive 
statistics will be used to summarize daratumumab serum concentrations at each sampling time 
point specified in protocol. Plot of mean (±standard deviation) daratumumab serum peak and 
trough concentrations over time will be provided.
A scatter plot of daratumumab serum concentration over time will also be provided.
If sufficient data are available, other pharmacokinetic parameters may be calculated and 
analyzed.
7.2.
Immunogenicity
The incidence of anti-daratumumab antibodies along with the titer and incidence of neutralizing 
antibodies will be summarized for all subjects who receive at least 1 dose of Dara SC or Dara IV
and have appropriate samples for detection of anti-daratumumab antibodies (i.e., subjects with at 
least 1 sample obtained after their first dose of daratumumab).
The incidence of anti-rHuPH20 antibodies along with the titer will be summarized for all 
subjects who receive a dose of Dara SC and have appropriate samples for detection of anti-
rHuPH20 antibodies.
Subjects who are positive for anti-daratumumab or anti-rHuPH20 antibodies will be listed. A 
listing of subject status of anti-daratumumab or anti-rHuPH20 antibodies at any time during the 
study with daratumumab concentrations at the time of each immunogenicity sample will also be 
provided.
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7.3.
Pharmacokinetic/Pharmacodynamics Analyses
Pharmacokinetic/pharmacodynamic modeling may be performed, including exploring the 
relationship between serum concentrations of daratumumab and endpoints of clinical efficacy 
and safety. If performed, details and results of the analysis will be presented in a separate report.
8.
BIOMARKER  
Biomarker studies are designed to evaluate if there are any differences with Dara SC and Dara 
IV on biomarkers for daratumumab pharmacodynamics and mechanism of action. Samples for 
biomarker evaluations will be collected as specified in the protocol Time and Events Schedule.
The immunophenotyping analyses including the assessments of natural killer (NK) cells, T cells, 
and B cells in peripheral blood will be performed. The analyses for CD38+ myeloid-derived 
suppressor cells (MDSCs) and CD38+ regulatory T cells will also be performed.
Descriptive statistics for values and changes from baseline at each scheduled visit for absolute 
counts (cells/µl) of total NK cells and percent total NK cells (as a percentage of lymphocytes) in 
peripheral blood will be provided. The plots of absolute counts of total NK cells and percent NK 
cells in blood over time will also be provided. Similar analyses will be performed for CD8+ T 
cells, activated CD8+ T cells, CD3+ T cells, B cells, CD38+ myeloid-derived suppressor cells, 
and CD38+ regulatory T cells as well.
Further analysis of other biomarkers may be performed and the results may be presented in a 
separate report. 
9.
PATIENT-REPORTED OUTCOMES
The modified Cancer Therapy Satisfaction Questionnaire (modified-CTSQ) is a patient-reported 
outcome (PRO) measure to assess patient satisfaction of Dara SC compared with Dara IV in 
support of market access and payer request for patient-reported outcomes data. 
The modified-CTSQ was adapted, with approval from the instrument developer, to contain 9
items specific to satisfaction with therapy and for comparison of IV with SC mode of
administration. Each item asks about the most recent cancer therapy using a 5-point verbal rating 
scale (see Attachment 3). The modified-CTSQ asks about previous administration of 
daratumumab, not the current visit administration. To achieve unbiased assessments, the 
modified-CTSQ should be administered before the subject’s clinical examination, the subject 
receives any tests or test results, and the subject’s health, health data, or emotions are discussed. 
The modified-CTSQ is a secondary endpoint, not part of the statistical hierarchy. Non-inferiority 
will not be analyzed for this endpoint. Type I error control was not applied to patient-reported 
outcome data.
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9.1.
Modified-CTSQ Scoring
For this study, the modified-CTSQ contains 1 multi-item domain (Satisfaction with Therapy 
[SWT]) and 2 single items (Thoughts about Cancer Therapy) as summarized in Table 4, each 
item has 5 response options coded as 1-5. 
Table 4:
Modified-CTSQ Domain Structure and Scoring Information
Modified-CTSQ 
Domain
Description of Items in Domain
Total # of 
Items
Minimum # of 
Completed Items 
Required to Score
Thoughts about Cancer 
Therapy (CT)
Q1: Worth taking even with side effects
Q2: Think about stopping CT
2
No summary score
Satisfaction with 
Therapy
Q3: How worthwhile was CT
Q4: Taking CT as difficult as expected
Q5: Benefits meet expectations 
Q6: Were side effects as expected
Q7: Satisfied with form of CT 
Q8: Satisfied with most recent CT
Q9: Would you take this CT again
7
5 
For most of the items, a higher coded number indicates a more positive response (e.g., 5 is the 
most positive response indicator and 1 is the least positive response indicator). However, for 
items Q2 (think about stopping CT) and Q4 (taking CT as difficult as expected), a higher coded 
number indicates a more negative response. For the analysis purpose, to ensure that a higher 
domain score is associated with a better response outcome and a lower domain score is 
associated with a worse response outcome, we need to reverse-code the response values for these 
two items Q2 and Q4. This is done by subtracting the initial (raw) response value from 6 for each 
of these 2 items. For example, we create 2 new variables Q2R and Q4R which contain reverse-
coded response values for items Q2 and Q4: 
Q2R = 6 – Q2; 
Q4R = 6 – Q4; 
To calculate the domain score for Satisfaction with Therapy (SWT), the minimum number of 
completed items is required, as shown in Table 4. If the number of completed items is greater 
than or equal to the minimum number of completed items required, the domain score is 
calculated using the following formula in general: 
Domain score = [(Sum of completed item responses/Number of completed items) - 1] × 100 / 
(Maximum possible item response value – Minimum possible item response value) 
However, if fewer items are completed than the minimum number indicated in Table 4, then the 
domain is not scored (i.e. a missing value is assigned). 
Since the maximum possible item response value is 5 and the minimum possible response value 
is 1 for all modified-CTSQ items, a simpler way to represent the above formula for the modified-
CTSQ SWT domain is: SWT domain score = (Mean of completed item responses – 1) × 25. For 
Q4 item, the reverse-coded response value Q4R is used in calculating SWT domain score.
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For the modified-CTSQ SWT domain, a higher calculated domain score on a scale of 0 to 100 is
a more positive indicator.
9.2.
Analysis Method
Analysis of PRO data will be performed on ITT analysis set. For subjects with multiple records 
at the same visit, the closest one to the visit date will be selected as scheduled assessment, and 
others will be unscheduled assessments.
At each time point for analysis, the number and percentage of modified-CTSQ assessment forms 
that are expected, received and missing will be tabulated by treatment group. The missing PRO 
assessments are defined as the expected number of assessments for a particular visit minus the 
actual number of assessments received for that visit, the expected number of assessments per 
visit will be determined by subject-level study completion status.
For each modified-CTSQ item score and SWT domain score, descriptive statistics (n, mean, 
standard deviation, median, and range) will be provided for each time point by treatment group.
The mean difference (with its 95% CI) of SWT domain score will be calculated and compared
between treatment groups at each time point.
Line plot of mean scores with standard error over time will be displayed by treatment group for 
each individual item score and SWT domain score.
10.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data associated with medical encounters due to IRRs or injection 
site reactions, primarily hospitalizations, outpatient visits and emergency room visits, will be 
collected in the eCRF by the investigator and study-site personnel for all subjects throughout the 
study.
Medical resource utilization 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, types of adverse 
events if involved, blood product transfusions will be tabulated. The treatment-emergent adverse 
events leading to the hospitalization/outpatient visits and leading to on-study transfusions will 
also be summarized.
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REFERENCE
1.
Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null 
hypothesis of non-zero risk difference or non-unity relative risk. Stat Med. 1990;9:1447-1454.
2.
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.
3.
Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of 
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 4691-4695.
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ATTACHMENT 1: ADDITIONAL EXPLORATORY ANALYSIS TO SUPPORT HEMAR
1.
DEFINITION OF SUBGROUPS
Subgroup analyses will be performed using 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 MR/SD as their best response

For subjects who reached PD as their best response

For subjects who reached MR or better as their best response (i.e. subjects with clinical 
benefit)

For subjects who reached PR or better as their best response

For subjects who reached VGPR or better as their best response 
2.
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

TNT

OS

DOR

PFS2
In addition, as described in Sections 5.3.6 (TTR), 6.3.1 (IRR) and 9.2 (PRO), the following 
endpoints will be evaluated by pre-defined subgroups as defined in section 2.10 and in section 1, 
Appendix:

TTR

IRRs

modified-CTSQ
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ATTACHMENT 3: MODIFIED CANCER THERAPY SATISFACTION 
QUESTIONNAIRE
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