A Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 29 March 2021
Janssen Research & Development *
Clinical Protocol
A Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in 
Smoldering Multiple Myeloma
Protocol 54767414SMM2001; Phase 2
AMENDMENT 6
JNJ-54767414  Daratumumab
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen 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.
EudraCT NUMBER: 2014-005139-14
Status:
Approved
Date:
29 March 2021
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-95497760, 10.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient will 
maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or otherwise.
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 29 March 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 24
ABBREVIATIONS ...................................................................................................................................... 37
1.
INTRODUCTION................................................................................................................................ 39
1.1.
Disease Background...................................................................................................................... 39
1.2.
Daratumumab ................................................................................................................................ 39
1.2.1.
Nonclinical Studies ..................................................................................................................... 40
1.2.1.1.
Toxicology................................................................................................................................ 40
1.2.2.
Clinical Studies ........................................................................................................................... 40
1.2.2.1.
Clinical Pharmacokinetics........................................................................................................ 41
1.2.2.2.
Preliminary Efficacy................................................................................................................. 41
1.2.2.3.
Safety and Tolerability............................................................................................................. 41
1.2.2.4.
Daratumumab Subcutaneous.................................................................................................. 42
1.3.
Overall Rationale for the Study...................................................................................................... 43
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 44
2.1.
Objectives ...................................................................................................................................... 44
2.2.
Hypothesis ..................................................................................................................................... 44
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 45
3.1.
Overview of Study Design.............................................................................................................. 45
3.2.
Study Design Rationale.................................................................................................................. 47
4.
SUBJECT POPULATION.................................................................................................................. 51
4.1.
Inclusion Criteria ............................................................................................................................ 51
4.2.
Exclusion Criteria ........................................................................................................................... 53
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 56
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 56
6.1.
Daratumumab Preparation............................................................................................................. 58
6.2.
Daratumumab IV Administration .................................................................................................... 58
6.3.
Daratumumab SC Administration .................................................................................................. 59
6.4.
Guidelines for Prevention of Infusion Reactions............................................................................ 59
6.4.1.
Pre-dose Medication................................................................................................................... 59
6.4.2.
Post-dose Medication ................................................................................................................. 60
6.4.3.
Management of Infusion-related Reactions................................................................................ 60
6.4.3.1.
Infusion-Related Events of Grade 1 or Grade 2...................................................................... 61
6.4.3.2.
Infusion-Related Reactions of Grade 3 or Higher ................................................................... 61
6.4.3.3.
Injection-Site Reactions........................................................................................................... 62
6.5.
Dose Delays................................................................................................................................... 62
6.5.1.
Daratumumab Toxicity Management.......................................................................................... 62
6.5.2.
Daratumumab Delays................................................................................................................. 62
7.
TREATMENT COMPLIANCE............................................................................................................ 63
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Status: Approved,  Date: 29 March 2021
8.
CONCOMITANT THERAPY.............................................................................................................. 63
8.1.
Permitted Therapies....................................................................................................................... 63
8.2.
Prohibited Therapies...................................................................................................................... 63
8.3.
Management of Hepatitis B Virus Reactivation ............................................................................. 64
9.
STUDY EVALUATIONS .................................................................................................................... 64
9.1.
Study Procedures........................................................................................................................... 64
9.1.1.
Overview..................................................................................................................................... 64
9.1.2.
Screening Phase ........................................................................................................................ 64
9.1.3.
Treatment Phase ........................................................................................................................ 65
9.1.4.
Follow-up Phase......................................................................................................................... 66
9.2.
Efficacy........................................................................................................................................... 66
9.2.1.
Evaluations ................................................................................................................................. 67
9.2.1.1.
Assessment of Response........................................................................................................ 67
9.2.1.2.
Assessment of Disease Progression to Multiple Myeloma ..................................................... 68
9.2.1.3.
Free Light Chain Ratio............................................................................................................. 68
9.2.1.4.
CRAB Criteria-Related Laboratory Assessments.................................................................... 69
9.2.1.5.
Myeloma Protein Measurements in Serum and Urine ............................................................ 70
9.2.1.6.
β2-microglobulin ...................................................................................................................... 71
9.2.1.7.
Bone Marrow Examination ...................................................................................................... 71
9.2.1.8.
Assessment of Bone Lesions .................................................................................................. 71
9.2.1.9.
Best Response to First Subsequent Anti-myeloma Therapy .................................................. 72
9.2.2.
Endpoints.................................................................................................................................... 72
9.2.2.1.
Primary Endpoint ..................................................................................................................... 72
9.2.2.2.
Major Secondary Endpoints .................................................................................................... 73
9.2.2.3.
Exploratory Endpoints ............................................................................................................. 73
9.3.
Pharmacokinetics and Immunogenicity ......................................................................................... 73
9.3.1.
Evaluations ................................................................................................................................. 73
9.3.2.
Analytical Procedures................................................................................................................. 74
9.3.3.
Pharmacokinetic Parameters ..................................................................................................... 74
9.3.4.
Immunogenicity Assessments .................................................................................................... 74
9.4.
Biomarkers ..................................................................................................................................... 75
9.5.
Safety Evaluations ......................................................................................................................... 76
9.5.1.
Electrocardiogram (ECG) ........................................................................................................... 76
9.5.2.
Other Safety Evaluations............................................................................................................ 77
9.6.
Sample Collection and Handling.................................................................................................... 80
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 81
10.1.
Completion of Treatment................................................................................................................ 81
10.2.
Completion of Study....................................................................................................................... 81
10.3.
Premature Discontinuation of Study Treatment............................................................................. 81
10.4.
Withdrawal from the Study............................................................................................................. 82
11.
STATISTICAL METHODS................................................................................................................. 82
11.1.
Subject Information ........................................................................................................................ 83
11.2.
Sample Size Determination ........................................................................................................... 83
11.3.
Efficacy Analyses ........................................................................................................................... 83
11.3.1.
Primary Efficacy Endpoint........................................................................................................... 84
11.3.2.
Secondary Efficacy Endpoints.................................................................................................... 84
11.4.
Pharmacokinetic Analyses............................................................................................................. 84
11.5.
Immunogenicity Analyses .............................................................................................................. 85
11.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 85
11.7.
Biomarker Analyses ....................................................................................................................... 85
11.8.
Safety Analyses ............................................................................................................................. 86
11.9.
Interim Analysis.............................................................................................................................. 87
12.
ADVERSE EVENT REPORTING ...................................................................................................... 87
12.1.
Definitions ...................................................................................................................................... 87
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Status: Approved,  Date: 29 March 2021
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 87
12.1.2.
Attribution Definitions.................................................................................................................. 89
12.1.3.
Severity Criteria .......................................................................................................................... 89
12.2.
Special Reporting Situations.......................................................................................................... 89
12.3.
Procedures..................................................................................................................................... 90
12.3.1.
All Adverse Events...................................................................................................................... 90
12.3.2.
Serious Adverse Events ............................................................................................................. 91
12.3.3.
Pregnancy................................................................................................................................... 92
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 92
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 92
13.1.
Procedures..................................................................................................................................... 92
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 93
14.
STUDY DRUG INFORMATION......................................................................................................... 93
14.1.
Physical Description of Study Drug................................................................................................ 93
14.2.
Packaging ...................................................................................................................................... 93
14.3.
Labeling.......................................................................................................................................... 93
14.4.
Preparation, Handling, and Storage............................................................................................... 94
14.5.
Drug Accountability ........................................................................................................................ 94
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 95
16.
ETHICAL ASPECTS ......................................................................................................................... 95
16.1.
Study-Specific Design Considerations........................................................................................... 95
16.2.
Regulatory Ethics Compliance....................................................................................................... 96
16.2.1.
Investigator Responsibilities ....................................................................................................... 96
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 96
16.2.3.
Informed Consent ....................................................................................................................... 97
16.2.4.
Privacy of Personal Data ............................................................................................................ 98
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 99
16.2.6.
Country Selection ....................................................................................................................... 99
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 99
17.1.
Protocol Amendments.................................................................................................................... 99
17.2.
Regulatory Documentation .......................................................................................................... 100
17.2.1.
Regulatory Approval/Notification .............................................................................................. 100
17.2.2.
Required Prestudy Documentation........................................................................................... 100
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 101
17.4.
Source Documentation................................................................................................................. 101
17.5.
Case Report Form Completion .................................................................................................... 101
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 102
17.7.
Record Retention ......................................................................................................................... 102
17.8.
Monitoring .................................................................................................................................... 103
17.9.
Study Completion/Termination..................................................................................................... 103
17.9.1.
Study Completion ..................................................................................................................... 103
17.9.2.
Study Termination..................................................................................................................... 104
17.10.
On-Site Audits .............................................................................................................................. 104
17.11.
Use of Information and Publication.............................................................................................. 104
REFERENCES.......................................................................................................................................... 107
INVESTIGATOR AGREEMENT ............................................................................................................... 117
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Status: Approved,  Date: 29 March 2021
LIST OF ATTACHMENTS
Attachment 1:
ECOG Performance Status Scale ............................................................................ 109
Attachment 2:
Asthma Guidelines ................................................................................................... 110
Attachment 3:
Conversion Table for Glucocorticosteroid Dose....................................................... 112
Attachment 4:
As of Protocol Amendment 5, Study Drug Administration and Required Study 
Evaluations for Subjects Remaining in Treatment Extension or Follow-up ............. 113
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Time and Events Schedule Overview....................................................................................... 30
Table 2:
Time and Events Schedule, QTc Substudy.............................................................................. 34
Table 3:
Time and Events Schedule, Dose Administration .................................................................... 35
Table 4:
International Uniform Response Criteria Consensus Recommendations ................................ 67
Table 5:
Diagnostic Criteria for Multiple Myeloma Requiring Systemic Therapy.................................... 68
Table 6:
Bone Marrow Testing................................................................................................................ 71
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 45
Figure 2:
Daratumumab Maximal Target Suppression ............................................................................ 48
Figure 3:
Schematic Overview of Study Treatment Administration ......................................................... 57
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JNJ-54767414  Daratumumab
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Status: Approved,  Date: 29 March 2021
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
25 November 2014
Amendment 1
20 January 2015
Amendment 2
27 July 2015
Amendment 3
20 June 2017
Amendment 4
28 January 2019
Amendment 5
01 April 2020
Amendment 6
29 March 2021
Amendments are listed beginning with the most recent amendment.
Amendment 6 (29 March 2021)
The overall reason for the amendment: The overall reason for the amendment is to extend the study duration 
up to a maximum of 7 years following Last Patient First Dose (LPFD) by redefining the End of Study. 
Applicable Section(s)
Description of Change(s)
Rationale: The end of the study was extended to collect long-term safety and efficacy data and to allow subjects 
to have the option to continue to receive study treatment.
Synopsis, Overview 
of Study Design 
(including figure); 
3.1. Overview of 
Study Design; Figure 
1; 3.2. Study Design 
Rationale; 9.1.4. 
Follow-up Phase; 
17.9.1. Study 
Completion
The end of study definition was changed to occur up to approximately 7 years after the 
last subject’s first dose, not approximately 5 years. 
Text regarding the evaluation of data from a Phase 3 study to potentially extend drug 
treatment beyond the end of study was deleted.
Rationale: Text was added to specify permitted and prohibited vaccinations.
8.1. Permitted 
Therapies
Text was added indicating vaccinations are allowed per local guidelines with a reference 
to Section 8.2.
8.2. Prohibited 
Therapies
Text was added clarifying the restriction of live attenuated and replication-competent 
viral vector vaccines.
Rationale: Clarified procedures in Attachment 4.
Attachment 4
Clarified that on Day 1 of each cycle, only subjects receiving daratumumab IV may 
require a recalculation of weight and should have vital signs measured.
Added text to the table to indicate that the administration of pre-dose 
methylprednisolone should be administered in the absence of infusion-related adverse 
events in the first 2 doses.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 29 March 2021
Amendment 5 (01 April 2020)
The overall reason for the amendment:  Overall reasons for the amendment are 1) to extend the study duration 
and 2) to provide flexibility for study investigators as it relates to the global coronavirus (COVID-19) pandemic. 
The overall reason for the amendment is to extend the study duration to approximately 5 years following Last 
Patient First Dose (LPFD) by redefining the End of Study. This amendment also reduces required assessments in 
the Time and Events Schedule for ongoing subjects. 
Additionally, this amendment provides flexibility for study investigators to prioritize the safety of their subjects 
during the global coronavirus (COVID-19) pandemic. To ensure continuity of study treatment, while limiting 
subjects’ time spent at the study center, subjects will be given the option to switch from daratumumab 
intravenous (IV) (16 mg/kg) to daratumumab subcutaneous (SC) (1800 mg), at the discretion of the investigator. 
Alternatively, for subjects who continue to receive daratumumab IV, the duration of infusion may be shortened to 
a 90-minute infusion for subjects without a history of an infusion-related reaction after the third dose, at the 
discretion of the investigator. Detailed information regarding daratumumab IV administration, including infusion 
rates and duration, has been removed from the protocol and will only be provided in the Site Investigational 
Product Procedures Manual (SIPPM).
Applicable Section(s)
Description of Change(s)
Rationale: A new formulation of daratumumab for SC administration has been developed to avoid the long 
infusion time with IV administration of daratumumab and to lessen the rate and severity of infusion-related 
reactions (IRRs) observed with daratumumab IV. The SC formulation of daratumumab has been evaluated in the 
Phase 3 randomized Study 54767414MMY3012 (COLUMBA), which compared efficacy, pharmacokinetics, and 
safety of SC vs IV daratumumab in 522 subjects which met the predefined non-inferiority criteria, demonstrating 
that daratumumab SC is non-inferior to IV. As such, subjects who are being treated in the Treatment Extension 
Phase at the time of this amendment will have the option to switch to SC daratumumab dosing (1800 mg dose) at 
the discretion of the investigator.
Synopsis Overview of Study Design, Dosage 
and Administration; 3.1 Overview of Study 
Design; 6 Dosage and Administration; 9.1.3 
Treatment Phase; 10.1 Completion of 
Treatment
Text has been added to describe the option of daratumumab SC 
administration for subjects receiving daratumumab IV.
1.2.2.4 Daratumumab Subcutaneous (new); 
1.3 Overall Rationale for the Study; 3.2 
Study Design Rationale; 6.3 Daratumumab 
SC Administration (new)
Sections, sub-sections, and text have been added to support 
daratumumab SC dosing including background information 
regarding the SC formulation of daratumumab, rationale for 
daratumumab SC dose regimen, and daratumumab SC dose 
administration.
6.4.2 Post-dose Medication
Instruction for post-dose medications for subjects who switch 
from daratumumab IV to daratumumab SC was added.
14.1 Physical Description of Study Drug
Text was added to describe the physical characteristics of 
daratumumab SC supplied to the site.
14.2 Packaging
Text was added to provide details on the packaging of 
daratumumab IV and daratumumab SC.
14.4 Preparation, Handling, and Storage
Text was added to provide instruction on the preparation, 
handling, and storage of daratumumab SC.
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Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Throughout the protocol (including 6.4.1 
Pre-dose Medication; 6.4.2 Post-dose 
Medication; 6.4.3.1 Infusion-related Events 
of Grade 1 or Grade 2 and 6.4.3.2 Infusion-
related 
Reactions of Grade 3 or Higher)
Language and terminology were updated to differentiate between 
IV infusion and SC administration. 
Rationale: Daratumumab SC is co-formulated with rHuPH20 and sorbitol.
Synopsis Overview of Study Design, Dosage 
and Administration; 1.2.2.4 Daratumumab 
Subcutaneous; 3.1 Overview of Study 
Design; 6 Dosage and Administration; 6.3 
Daratumumab SC Administration; 9.1.3 
Treatment Phase; 10.1 Completion of 
Treatment
Subjects with known allergies/intolerance to sorbitol will not be 
allowed to switch from daratumumab IV to daratumumab SC.
Rationale: Infusion-related reactions are systemic reactions related to daratumumab administration, regardless of 
route of administration.
6.4.3 Management of Infusion-related 
Reactions
Text has been added to describe IRRs and the applicability to 
both daratumumab IV or SC administration.
Rationale: Subcutaneous administration of daratumumab is associated with local injection site reactions.
6.4.3.3 Injection-Site Reactions (new)
Text has been added to describe injection-site reactions and 
management of such events.
Rationale: To obtain longer term safety, overall survival, and progression-free survival data in the Smoldering 
Multiple Myeloma population, the End of Study was redefined. Required assessments were reduced to focus the 
remaining study conduct on the above aspects of data collection and are described in the new Attachment 4.
Synopsis Overview of Study Design; 3.1 
Overview of Study Design; 9.1.4 Follow-up 
Phase; 17.9.1 Study Completion
Extended the end of study to approximately 5 years after the 
last subject’s first dose, following a decision by the sponsor to 
end the study based on data from the smoldering multiple 
myeloma Phase 3 study (54767414SMM3001), or for reasons 
as outlined in Section 17.9.2, whichever occurs first.
3.2 Study Design Rationale
Indicated that long-term data on PFS will be analyzed in the 
final study analysis which is expected to occur approximately 5 
years after the last subject’s first dose.
Synopsis Pharmacokinetic and 
Immunogenicity Evaluations, Biomarker 
Evaluations; 9.3 Pharmacokinetics and 
Immunogenicity; 9.4 Biomarkers
PK, immunogenicity, and biomarker evaluations will not be 
collected.
Synopsis Overview of Study Design, 
Efficacy Evaluations/Endpoints; Table 1; 
Table 2; Table 3; 3.1 Overview of Study 
Design; 3.2 Study Design Rationale; 9.1.1 
Overview; 9.1.3 Treatment Phase; 9.1.4 
Follow-up Phase; 9.2 Efficacy; 9.2.1 
Evaluations; 9.3 Pharmacokinetics and 
Immunogenicity; 9.4 Biomarkers; 9.5.2 
Other Safety Evaluations; 10.3 Premature 
Discontinuation of Study Treatment
Refer investigators and staff to Attachment 4 for a description of 
dose administration and study procedures for subjects who 
continue in the Treatment Extension Phase or who have 
discontinued treatment but remain in Follow-up.
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Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: To specify that a protocol amendment will be issued if treatment beyond the end of study is permitted 
for subjects included in the Treatment Extension Phase (and who have not yet entered the Follow-up period as of 
the end of study). Potential extension of treatment will be based on data from the smoldering multiple myeloma 
Phase 3 study (54767414SMM3001).
Synopsis Overview of Study Design; 3.1 
Overview of Study Design; ; 9.1.4 Follow-up 
Phase; 17.9.1 Study Completion
Added: For subjects included in the Treatment Extension 
Phase (and who have not yet entered the Follow-up period as 
of the end of study) as described in Amendment 4, potential 
drug treatment beyond the end of study will be evaluated 
after data from the smoldering multiple myeloma Phase 3 
study (54767414SMM3001) are available. A protocol 
amendment will be issued if further treatment is permitted.
Rationale: To eliminate the possibility of inconsistency between the NCI-CTCAE version numbering used in the 
protocol and the standard grade descriptions included in the protocol.
12.1.3 Severity Criteria
Severity Criteria Section:
Eliminated definitions of severity criteria; the definitions are 
specified in NCI-CTCAE version 4.
Rationale: Results reported from assessments facilitated by central laboratories will not be required. Results 
from the primary analysis have been described in a clinical study report and additional data have been collected 
for approximately 3 years. Use of local laboratories will continue as described in the newly added Attachment 4.
Attachment 4
Added: central laboratory evaluations are not applicable
Rationale: Changes for clarity/consistency noted in the protocol were corrected.
Synopsis Overview of Study Design; 3.1 
Overview of Study Design
Clarified that the data collected at the end of the study will be 
reported in a clinical study report.
Synopsis Efficacy Evaluations/Endpoints; 
9.2.2.2 Major Secondary Endpoints; 11.3.2 
Secondary Efficacy Endpoints
Updated the secondary endpoint of overall survival rate to 
exclude the 4-year time period.
Table 2
Clarified that as of Amendment 4, the QTc substudy was 
considered complete and the data collection outlined was not 
applicable.
Synopsis Overview of Study Design; 3.1 
Overview of Study Design
Added a statement to cross-reference Section 6.4 which details 
guidelines to prevent infusion-related reactions.
6.4.3 Management of Infusion-related 
Reactions
Included tracheostomy equipment as an example of resources 
necessary for resuscitation. 
6.5.1 Daratumumab Toxicity Management
Clarified that Grade 3 thrombocytopenia with bleeding is a 
criterion for a dose delay.
9.1.3 Treatment Phase
Specified that due to the addition of the treatment extension 
outlined in Amendment 4, it is possible for subjects to have 2 
EOT visits with the requirement to complete 2 EOT visit CRFs.
9.1.4 Follow-up Phase
Added: If included in the Treatment Extension Phase, it is 
possible that subjects will have 2 Follow-up Phase portions of 
the study (1 after the planned 20 cycles, and 1 after the last 
dose in the treatment extension). As of Amendment 5, these 
additional protocol-specified Follow-up assessments should 
be conducted as specified in Attachment 4.
9.5.2 Other Safety Evaluations
Added information detailing the conduct for subjects with 
evidence of positive HBV serology.
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
14.1 Physical Description of Study Drug
Added additional detail regarding the physical appearance of the 
daratumumab IV liquid supplied to the site.
14.4 Preparation, Handling, and Storage
Added additional detail regarding the preparation, handling, and 
storage of daratumumab IV.
Rationale: Daratumumab IV infusion rates were redefined with added flexibility.
Synopsis Dosage and Administration; 6.2 
Daratumumab IV Administration
Indicated that daratumumab IV infusion rates have been 
redefined with added flexibility and may be shortened to a 90-
minute infusion for subjects without a history of an infusion-
related reaction after the third dose, at the discretion of the 
investigator.
Removed Table 4 Infusion Rates for Daratumumab; renumbered 
subsequent tables.
Rationale: Minor errors were noted.
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 4 (28 January 2019)
The overall reason for the amendment: The overall reason for the amendment is to allow extended treatment 
with IV daratumumab (Q8W) after 20 treatment cycles in long intense (Arm A) and intermediate arm (Arm B) if, 
as per investigator discretion, there is a positive benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, 
and at least stable disease has been achieved. In the case of subjects who already completed EOT and the end of 
Cycle 20 occurred <6 months, these subjects can continue receiving IV daratumumab administrations every 8 
weeks. Additionally, modifications have been made in response to identification of a new important risk 
(hepatitis B virus [HBV] reactivation), and text related to evaluation of circulating multiple myeloma cells as an 
exploratory objective or biomarker has been modified.
Applicable Section(s)
Description of Change(s)
Rationale: Instructions for extension of IV daratumumab treatment beyond Cycle 20 were provided.
Synopsis; Table 1 
(footnote c); 3.1 
Overview of Study 
Design; Figure 1; 6 
Dosage and 
Administration; 6.2 
Daratumumab 
Administration; 9.1.3 
Treatment Phase; 
10.1 Completion of 
Treatment; 
Added the following text: For subjects in Arm A (long intense) and Arm B 
(intermediate), there is a possibility to extend treatment with IV daratumumab 
(Q8W) after the end of Cycle 20 if, as per investigator discretion, there is a positive 
benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, and at least 
stable disease has been achieved. In the case of subjects who already completed 
EOT and end of Cycle 20 occurred <6 months, these subjects can also continue 
receiving IV daratumumab administrations every 8 weeks.
6.2 Daratumumab 
Administration; Table 
4 (footnote f); 
Provided clarification regarding treatment re-initiation relative to EOT: If EOT took 
place ≥3 months but < 6months before re-initiation, the same instructions on 
infusion rates are applicable as per table 4, meaning that slower infusion rates are 
to be applied during the first infusion, with acceleration during the subsequent 
infusions to avoid the occurrence of IRR.
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JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
11
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Table 1 footnote b; 
6.2 Daratumumab 
Administration
Provided clarification on the timing of disease assessment: The assessment of disease 
progression will be based on the last disease evaluation performed. In case last 
disease evaluation was performed ≥5 months at treatment re-initiation, a new 
disease evaluation is to be performed to make sure that patient has not progressed. 
Every case of treatment re-initiation is to be discussed with the medical monitor 
prior to re-initiation.
Synopsis; 3.1 
Overview of Study 
Design; 9.1.4 
Follow-up Phase
Clarified the language for the Follow-up Phase: The Follow-up Phase will begin once 
subjects complete the planned number of cycles, and no treatment extension will be 
given as per investigator’s discretion. In case of treatment extension or treatment 
re-initiation, the same procedures are to be followed as outlined in Section 9.1.3 
and TABLE 1.
9.1.4 Follow-up 
Phase; 17.9.1 Study 
Completion
Added the following text: For subjects that will continue treatment or re-initiate 
treatment as part of treatment extension, the duration of treatment extension will
be re-evaluated at the time of the interim analysis of the Phase 3 study (Study 
54767414SMM3001), evaluating subcutaneous daratumumab in patients with high 
risk smoldering myeloma.
Table 1; Table 3; 
6.4.2 Daratumumab 
Delays; 9.1.3 
Treatment Phase; 9.2 
Efficacy; 10.3 
Premature 
Discontinuation of 
Study Treatment
Added text to indicate that instructions also pertain to treatment extension or re-
initiation.
Rationale: Added instructions for assessment of hepatitis B prior to treatment re-initiation. 
Table 1 (and footnote 
a)
Added to Table 1 Laboratory Assessments, instructions for HBV serology and HBV 
DNA testing prior to treatment re-initiation. 
4.2 Exclusion Criteria 
(Criterion 6)
Updated and added text regarding subjects who are:
•
known to be seropositive for human immunodeficiency virus (HIV).
•
known to have a history of hepatitis C.
•
seropositive for hepatitis B (defined by a positive test for hepatitis B surface 
antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or 
antibodies to hepatitis B surface antigen [anti-HBs]) must be tested 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 (antiHBs 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.
For subjects who enter extension treatment period, HBV serology (HBsAg, anti-
HBs, and anti-HBc) testing is to be performed locally prior to re-initiation. HBV 
serology is not required at re-initiation if this was performed as part of standard of 
care within 3 months prior to the re-initiation or the start of extension treatment is 
within 3 months of last daratumumab dose.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
12
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
8.3 Management of 
Hepatitis B Virus 
Reactivation
Added the following text to the new Section 8.3: 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 9.5.2.
For subjects who are diagnosed with HBV reactivation while on treatment, study 
treatment should be interrupted until the infection is adequately controlled. If the 
benefits outweigh the risks, study treatment may be resumed with concomitant 
antiviral prophylaxis as per local standard of care. Consult a liver disease specialist 
as clinically indicated.
9.5.2 Other Safety 
Evaluations
Added instructions for HBV Serology and DNA testing.
Rationale: Evaluation of circulating multiple myeloma cells (CMMCs) is no longer performed.
Table 1 Time and 
Events Schedule; 9.4 
Biomarkers
Added the following text: As of Amendment 4, these samples will no longer be 
collected.
Amendment 3 (20 June 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To incorporate changes from practical experience with implementing 
study evaluations and to address feedback from investigators and the steering committee. The resulting changes 
include the clarification that a subject with disease progression, assessed by serum FLC only, may continue to 
receive study treatment if the subject continues to show clinical benefit per investigator assessment and if agreed 
upon by the sponsor.
Applicable Section(s)
Description of Change(s)
Rationale: In a subset of subjects, daratumumab disproportionally decreases the uninvolved light chain. It was 
unanticipated at the time of writing the protocol that this would lead to artificially elevated FLC ratios. The 
artificially elevated FLC ratios have led to ambiguous cases in interpretation of disease progression. To allow for 
investigator clinical judgment, clarification was made to allow a subject to remain on study treatment following 
disease progression which is based only on FLC criteria.
9.2.1.3. Free Light 
Chain Ratio
Added a new section and the text in bold:
In a subset of subjects, daratumumab disproportionally decreases the uninvolved 
light chain, thus artificially skewing the FLC ratio. The artificially elevated FLC 
ratios have led to ambiguous cases in interpretation of disease progression. In cases 
where the subject’s disease progresses solely based on FLC criteria, if the subject 
continues to benefit from the study treatment based on investigator assessment, the 
subject is allowed to continue the study treatment if agreed by the sponsor. The 
investigator or designee must consult with the subject and discuss the 
considerations for recommending continuation of study treatment. The agreement 
of the subject to continue treatment with daratumumab must be documented in the 
medical record. Disease evaluations must continue at a frequency of at least every 
8 weeks.
Renumbered subsequent sections.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
13
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: MRD assessment via whole blood samples is no longer proceeding because it has been confirmed that 
whole blood MRD is not sensitive enough for the depth of MRD negativity that is being determined in this study.
Synopsis, Overview 
of Study Design;
3.1. Overview of 
Study Design
Deleted text in strikethrough:
An assessment of MRD will be conducted on whole blood and bone marrow aspirate 
samples.
Synopsis, Biomarker 
Evaluations
In addition, blood samples will be obtained for assessment of MRD, CMMCs, 
immunophenotyping, and plasma and PBMC biomarker assessments.
Table 1 Time and 
Events Table
Deleted the row for Blood sample for MRD
3.2 Study Design 
Rationale, Rationale 
for Biomarker 
Evaluations, 
MRD assessment
In the present study, we will assess for MRD in both blood and bone marrow aspirate 
when samples are obtained at screening, at confirmation of CR, and at 12 months and 
18 months after first dose for subjects who maintain CR.
9.4 Biomarkers
Baseline bone marrow aspirates and a whole blood sample will be subjected to DNA 
sequencing in order to establish the myeloma clone for MRD monitoring. A fresh bone 
marrow aspirate and whole blood sample at Screening is required if at all possible, for 
MRD assessment.
For subjects who achieve a CR or sCR, additional bone marrow aspirate and a whole 
blood sample will be utilized for assessment of MRD by next-generation sequencing 
(NGS) of immunoglobulin heavy and light chains (Vij 2014)24. For subjects who 
maintain a CR, MRD will also be assessed at 12 and 18 months after first dose in bone 
marrow aspirate and whole blood.
Rationale: After the End-of-Treatment Visit, clinic visits are limited to disease evaluations by laboratory tests 
only. Therefore, ECOG assessments cannot be performed.
Table 1 Time and 
Events Table, ECOG
Added text in bold:
Once a subject discontinues or completes therapy prior to PD, ECOG will only be 
assessed at the End-of-Treatment Visit and additionally when PD is suspected.
Replaced text in strikethrough with text in bold:
Week 5, Week 9, and then every 8 weeks in the first year, thereafter q16wk until PD 
during the Treatment Phase
Rationale: Clarified timing of repeated urine UPEP analysis for a subgroup of subjects to minimize urine 
collections to increase subject adherence.
Table 1 Time and 
Events Table, Urine 
disease evaluations 
(UPEP);
9.2.1.5 Myeloma 
Protein 
Measurements in 
Serum and Urine
Added text in bold:
In subjects with baseline UPEP result below the level of quantification, UPEP analysis 
will be repeated only (1) at the time of disease progression and (2) to confirm a CR.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
14
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Corrected typographical errors from Amendment 2 (value for anemia should be >2 g/dL, not ≥2 g/dL) 
and added a missing symbol for anemia value (should be >2 g/dL).
4.2. Exclusion 
Criteria #1d
Replaced text in strikethrough (≥) with text in bold (>):
Anemia, defined as hemoglobin <10 g/dL and/or ≥>2 g/dL below LLN in the absence of 
transfusion support or concurrent treatment with erythropoietin stimulating agents 
(ESAs)
9.2.1.4. CRAB 
Criteria-Related 
Laboratory 
Assessments, 
Hemoglobin
Added text in bold (>):
Development of anemia (according to CRAB criteria; hemoglobin <10 g/dL or >2 g/dL 
lower than LLN) indicates progression to symptomatic MM if it is not attributable to any 
other cause.
Rationale: To comply with Janssen protocol template standards, the Company Sponsorship Statement was 
updated, language in Case Report Form Completion was updated, and the version number was added to the 
EDMS number.
Title page
Added text in bold:
Deleted strikethrough text:
Janssen Pharmaceutica NV;
Janssen Sciences Ireland UC; Janssen R&D Ireland;
Janssen Infectious Diseases BVBA;
EDMS-ERI-95497760, 5.0
17.5. Case Report 
Form Completion
Deleted sentence:
All data relating to the study must be recorded in eCRFs prepared by the sponsor.
Rationale: Footnote letters were added to the text descriptions to match the letters in a table which were missing 
in previous editions of this protocol.
6.2. Daratumumab 
Administration,
Table 4
Added text in bold:
Added footnote letters “a, b, c, d, e” to the text descriptions at the bottom of the table.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
15
Status: Approved,  Date: 29 March 2021
Amendment INT-2 (27 July 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.  
The overall reason for the amendment: To address feedback from health authorities and investigators. The 
resulting changes include the clarification of requirements for radiologic assessment to reduce exposure, addition 
of a disease evaluation to capture early response, adjustment of the entry criteria and visit windows, as well as 
other minor edits throughout the protocol.  
Applicable Section(s)
Description of Change(s)
Rationale: Clarified the requirement for radiologic assessment during the study in order to reduce radiation 
exposure to asymptomatic patients.
Table 1, Time and Events Table, 
Disease Evaluations, Skeletal 
radiography or low-dose CT; 
9.2.1.7. Assessment of Bone 
Lesions
Added text in bold. 
Use same methodology during study as used at screening: Skeletal 
radiography or low-dose CT q12 months and at biochemical progression 
(eg, increase of SPEP >25%) or at suspected PD.;or low dose CT q6 
months for the first year, then q12 months, and at suspected PD. For 
subjects with (1) negative MRI results at baseline, (2) M-protein 
increase ≤25%, and (3) no other signs of clinical progression, only an 
MRI needs to be performed. For these subjects, low-dose whole body 
CT or skeletal survey does not need to be repeated unless focal lesions 
have been identified by MRI. 
Rationale: Added one additional disease evaluation at Cycle 1 Week 5 to capture early response and provide a 
more accurate measure of the duration of response. This timepoint was selected because the median time to 
response for daratumumab is 4 weeks for relapse and refractory MM. 
Synopsis, Efficacy 
Evaluations/Endpoints; Table 1 
Time and Events Table, Heading, 
ECOG, Serum disease evaluations 
(SPEP), Urine disease evaluations 
(UPEP), Serum free light chain, 
Calcium, albumin; 9.2. Efficacy
Disease assessments will be performed at Week 5, Week 9, and then
every 8 weeks in the first year, thereafter and then every 16 weeks until 
disease progression.
Rationale: Updated information on the statistical hypotheses to be tested.
Synopsis, Objectives and 
Hypothesis and Statistical Methods; 
2.2. Hypothesis; 11.2. Sample Size 
Determination
Replaced text in strikethrough with text in bold. 
Two hypotheses will be tested:
1. H0: CR rate ≤ 15% 
Ha: CR rate ≥ 35%
2. H0: PD/death rate ≥ 0.346/patient-year (median PFS < 24 
months)
Ha: PD/death rate ≤ 0.185/patient-year (median PFS > 45 
months)
1. The CR rate at 6 months after the last subject is 
randomized is greater than or equal to 35%. 
2. The disease progression [PD]/death rate one year after 
the last subject is randomized is less than or equal to 
0.185 
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
16
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Added clarification that the antihistamine administered preinfusion and postinfusion is an H1-
antihistamine. 
Synopsis; Overview of Study 
Design; Table 3 Time and Events 
Table Dose Administration; 3.1. 
Overview of Study Design; 6.3.1. 
Preinfusion Medication; 6.3.2. 
Postinfusion Medication; 6.3.3. 
Management of Infusion-related 
Reactions
Added text in bold. 
H1-antihistamine
Rationale: Changed allowable time window for disease evaluations from 5 days to 7 days. 
Synopsis; Efficacy 
Evaluations/Endpoints; Table 1, 
Time and Events Table, Disease 
Evaluations Heading; 9.2. Efficacy; 
9.2.1.1. Assessment of Response
Replaced text in strikethrough with text in bold. 
A window of ±57 days before the scheduled assessment date is allowed.
Rationale: Clarified the definition of PFS.
Synopsis Efficacy 
Evaluations/Endpoints; 9.2.2.2 
Major Secondary Endpoints
Added text in bold:
PFS, defined as the time from the date of randomization to the date of 
initial documented PD according to the CRAB criteria, myeloma defining 
events, or date of death, whichever occurs first.
Rationale: Added that the pregnancy test for women of childbearing potential must be performed within 14 days 
prior to randomization to the Time and Events table for consistency within the protocol. 
Table 1, Time and Events Table, 
Laboratory Assessments
Added text in bold. 
For women of childbearing potential only within 14 days prior to 
randomization.
Rationale: Added time window of 7 days for the End-of-Treatment Visit.
Table 1, Time and Events Table, 
EOT Heading; 3.1 Overview of 
Study Design; 9.1.3. Treatment 
Phase, End of Treatment Visits
Replaced text in strikethrough with text in bold. 
Unless a subject withdraws consent for study participation or is lost to 
follow up, an End-of-Treatment Visit is to occur withinat 28 ±7 days after 
the last dose of all study treatments.
Rationale: Removed the requirement for a FEV1 test for subjects with asthma during screening.
Table 1, Time and Events Table, 
Procedures; 9.5.2. Other Safety 
Evaluations, Pulmonary Function 
Test
Deleted strikethrough text. 
Subjects with known or suspected COPD or asthma must have a FEV1 test 
during screening.
Rationale: Clarified language for samples needed for MRD assessment. 
Table 1 Time and Events Table, 
Disease Evaluations, Bone marrow 
aspirate/biopsy; 9.2.1.6. Bone 
Marrow Examination, Table 7, 
Screening, Central Testing; 9.4. 
Biomarkers
Added text in bold.
If a fresh bone marrow aspirate will not be performed at screening because 
a sample is available within 56 days prior to randomization, then 
unstained, non-decalcified diagnostic tissue [bone marrow aspirate slides, 
touch prep from biopsy (rolled biopsy) slides, or clot specimen slides
or FFPE tissue)] should must be collected for MRD assessment.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
17
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Added that MRI can be performed on a yearly basis starting three years after the first dose of 
daratumumab.
Table 1, Time and Events Table, 
Disease Evaluations, MRI of spine 
and pelvis; 9.2.1.7. Assessment of 
Bone Lesions
Added text in bold. 
q6 months for the first 3 years, then q12 months, and at biochemical 
progression (eg, increase of SPEP >25%) or at suspected PD; whole 
body MRI per local practice or when clinically indicated. 
Rationale: Added monteleukast as an optional preinfusion medication, to be used based upon investigator 
discretion.
Table 3, Time and Events Table 
Dose Administration, Preinfusion 
Medication; 6.3.1 Preinfusion 
Medication
Added text in bold.
Monteleukast 10 mg approximately 1 hr prior to every infusion of 
daratumumab; use is optional per investigator discretion.
Rationale: Added cetirizine as an example of a H1-antihistamine that can be used preinfusion and postinfusion.
Table 3, Time and Events Table 
Dose Administration, Preinfusion 
Medication; 6.3.1 Preinfusion 
Medication
Added text in bold.
An H1-antihistamine (diphenhydramine 25-50 mg IV or PO, cetirizine 
10 mg PO, or equivalent) approximately 1 hour prior to daratumumab  
infusion 
6.3.2. Postinfusion Medication
Added text in bold.
H1-antihistamine (diphenhydramine, cetirizine, or equivalent) on the 2 
days following all daratumumab infusions (beginning the day after the 
infusion)
Rationale: Added lactate dehydrogenase to the list of clinical laboratory tests to be performed by the local 
laboratory.
Table 3 Time and Events Schedule 
Dose Administration, Other Study 
Procedures; 9.5.2. Other Safety 
Evaluations, Clinical Laboratory 
Tests
Added text in bold.
Serum Chemistry Panel: lactate dehydrogenase (LDH)
Rationale: Clarified that the specified laboratory tests need to be drawn for infusions 2 through 8 during Cycle 1, 
and not for each infusion during Cycle 1.
Table 3 Time and Events Schedule 
Dose Administration, Other Study 
Procedures; 9.5.2. Other Safety 
Evaluations, Clinical Laboratory 
Tests
Replaced text in strikethrough with text in bold.
At Screening and during Cycle 1 only, before each the second through 
eighth infusions of daratumumab
Rationale: Amended inclusion criteria to allow enrollment of subjects with light chain only myeloma.
4.1 Inclusion Criteria #3.1
Added text in bold.  
-
The absolute involved serum free light chain (sFLC) is ≥100 mg/L 
with abnormal FLC ratio (<0.126 or >8). 
Rationale: Clarified the duration of contraceptive administration in the inclusion criteria. 
4.1 Inclusion Criteria #6.1
Added text in bold.
Contraception must begin prior to dosing and continue until 4 months 
after the last dose of daratumumab.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
18
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Edited exclusion criteria to clarify that subjects who are on corticosteroids with a dose >10 mg 
prednisone per day or equivalent are not allowed in the study, and subjects who are on a stable dose of bone-
protecting agents for a nonmalignant condition are allowed in the study.   
4.2 Exclusion Criteria #3.1
Replaced text in strikethrough with text in bold. 
To concurrent treatment with bone protecting agents (eg, 
bisphosphonates, denosumab) or corticosteroids with a dose not exceeding 
10 mg prednisone per day or equivalent are only allowed if given in a 
stable dose and for a nonmalignant condition. 
-To concurrent treatment with corticosteroids with a dose >10 mg 
prednisone per day or equivalent.
-To concurrent treatment with bone-protecting agents (eg, 
bisphosphonates, denosumab) for treatment of SMM or MM. The 
subjects who are on a stable dose of these medications for a 
nonmalignant condition are allowed in the study.   
Rationale: Updated the url for the website that contains the list of medications known to affect the QT interval, 
which are prohibited during Cycle 1 for subjects in the QTc substudy. Aligned protocol language with 
terminology used in the referenced website.
4.2 Exclusion Criteria #15.1
Replaced text in strikethrough with text in bold. 
Received medications with a known or possible risk of torsades de 
pointes to affect the QT interval (see https://www.crediblemeds.org/) 
within 4 weeks prior to ECG screening day
8.2. Prohibited Therapies
For subjects in the QTc substudy, medications with a known or possible 
risk of torsades de pointes known to affect the QT interval (see 
http://www.azcert.org/ https://www.crediblemeds.org) are prohibited 
during Cycle 1.  
Rationale: Updated information on daratumumab interference with Indirect Antiglobulin Test (IAT) results. 
Streamlined the display of this information by including in only one section of the protocol, and removing 
redundant information elsewhere.
4.3. Prohibitions and Restrictions
Deleted section, which only included information on the IAT. Text on the 
IAT was relocated to Section 9.5.2.
9.5.2. Other Safety Evaluations; 
Daratumumab Interference with 
Indirect Antiglobulin Test (IAT) 
results 
The text for the IAT was updated to be consistent across all daratumumab 
protocols.
Rationale: Added table to show infusion rates for daratumumab over time. Edited text to state that further 
information on daratumumab administration can be found in the SIPPM. 
6.2. Daratumumab Administration
Added Table 4 Infusion Rates for Daratumumab, which shows infusion 
rates for the first, second and subsequent infusions of daratumumab.
Replaced text in strikethrough with text in bold. 
For further information recommendations on daratumumab 
administration infusion rate, please refer to the SIPPM.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
19
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Added the clarification that postinfusion corticosteroids are long- or intermediate-acting 
corticosteroids. 
6.3.2. Postinfusion Medication
Added text in bold.
For the prevention of delayed infusion-related reactions, all subjects will 
receive long- or intermediate-acting corticosteroids orally (20 mg 
methylprednisolone or equivalent in accordance with local standards) on 
the 2 days following daratumumab infusions in Cycle 1 (beginning the day 
after the infusion).
Rationale: Clarified instructions for postinfusion medications for at-risk subjects. 
6.3.2. Postinfusion Medication
Added text in bold.
If, after 4 full doses, an at-risk subject experiences no major infusion-
related reactions, then postinfusion medications (except Cycle 1 
corticosteroids) may be stopped at the investigator’s discretion.
Rationale: Amended instructions for the management of infusion-related reactions.
6.3.3. Management of Infusion-
related Reactions
Removed text in strikethrough.
If an infusion-related reaction develops, then the infusion should be 
temporarily interrupted paused or slowed down.
6.3.3. Management of Infusion-
related Reactions
If an infusion is paused or the infusion rate is decreased, then a longer-
than-anticipated infusion time may occur.
Rationale: Edited criteria for daratumumab dose delay due to toxicity by removing the requirement for bleeding 
with Grade 3 thrombocytopenia. 
6.4.1. Daratumumab Toxicity 
Management
Removed text in strikethrough.
The criteria for a dose delay are:
–
Grade 3 thrombocytopenia with bleeding
Rationale: Reorganized and modified text for cases where consecutive doses of daratumumab are missed.
6.4.2. Daratumumab Delays
Relocated text, and added text in bold. 
If more than 2 consecutive planned doses of daratumumab are missed due 
to daratumumab-related AEs, treatment should be permanently 
discontinued. 
Replaced text in strikethrough with text in bold. 
If 2 consecutive planned doses of daratumumab are missed for any reason 
other than AEs, this should be brought to the attention of the Sponsor at 
the earliest possible time and study treatment should be discontinued, 
unless, upon consultation with the sponsor and the review of safety and 
efficacy, continuation is agreed upon; subject continuation can occur if 
agreed by the Sponsor.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
20
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
Rationale: Edited instructions on prohibited therapies and discontinuation of study drug to allow greater 
flexibility for the retention of subjects in the Treatment Phase. Replaced specific examples of prohibited therapies 
with general classes of medications that are prohibited, to align with text used in the exclusion criteria. 
8.2. Prohibited Therapies
Replaced text in strikethrough with text in bold.
Use of the prohibited treatments listed below is prohibited during the 
study will result in discontinuation of study drug for subjects:

Administration of commercially available agents or agents under 
investigation for SMM or MM, including systemic corticosteroids 
(>10 mg prednisone per day or equivalent other than those given per 
Section 6.3.1 and Section 6.3.2), clarithromycin, interferon, 
bortezomib, thalidomide, or lenalidomide approved or 
investigational treatments for SMM or/and MM (including but 
not limited to conventional chemotherapies, immunomodulatory 
drugs (IMiDs), or proteasome inhibitors).
Rationale: Clarified follow-up phase instructions.
9.1.4. Follow-up Phase
Added text in bold.
Subjects who discontinue before disease progression must continue to 
have disease evaluations at Week 5, Week 9, and then every 8 weeks for 
the first year, thereafter then every 16 weeks according to the Table 1
until confirmed PD, death, the start of a new anticancer therapy, 
withdrawal of consent, lost to follow-up, or the end of the study. 
Replaced text in strikethrough with text in bold. 
Follow-up for subsequent anticancer multiple myeloma therapy 
(including the response to the first subsequent multiple myeloma 
therapy), second primary malignancies, and survival status will be 
obtained at least every 6 months.
Rationale: Edited timepoints to perform β2 microglobulin analysis to be consistent with the Time and Events 
Schedule.
9.2.1.5. β2 microglobulin
Added text in bold.
Blood samples for β2 microglobulin analysis are to be collected at 
Screening and upon disease progression, and will be analyzed by the 
central laboratory
Rationale: Added flow cytometry as a method for disease characterization of bone marrow at screening.
9.2.1.6. Bone Marrow 
Examination, Table 7, Screening, 
Local Testing
Added text in bold.
Disease characterization (morphology and either immunohistochemistry, 
or immunofluorescence, or flow cytometry).
Rationale: Updated section on assessment of bone lesions to improve readability.
9.2.1.7. Assessment of Bone 
Lesions
Reorganized section, added subheadings, and incorporated edits 
throughout, and added text in bold. 
PET-CT can be used as an alternative imaging test to replace MRI.
Rationale: Updated information in the protocol on pharmacokinetic parameters and analyses, as this level of 
detail is unnecessary for the protocol.
9.3.2. Analytical Procedures; 
Removed information on timing of analysis.
9.3.3. Pharmacokinetic Parameters; 
11.4 Pharmacokinetic Analyses
Removed references to calculation of CL and V.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
21
Status: Approved,  Date: 29 March 2021
Applicable Section(s)
Description of Change(s)
11.6 
Pharmacokinetic/Pharmacodynamic 
Analyses
Added text in bold:
If sufficient data are available, pharmacokinetic/pharmacodynamic 
modeling will be performed, including exploring the relationship between 
serum concentrations of daratumumab and endpoints of clinical efficacy 
and safety.
Rationale: Modified language for clarity, and edited the reasons for premature discontinuation of study treatment 
to allow greater flexibility for the retention of subjects in the Treatment Phase. 
10.3. Premature Discontinuation of 
Study Treatment
Replaced text in strikethrough with text in bold.
A subject's study treatment should must be discontinued if:

The subject initiates treatment with a prohibited medication

The subject received concurrent (non-protocol) treatment for SMM

The subject missed more than 2 consecutive planned doses due to of 
daratumumab-related AEs
Rationale: Clarified the instructions that subjects who withdraw from the study need to have the End-of-
Treatment (EOT) Visit assessments performed only if the subject is still in the Treatment Phase, and the 
assessments had not yet been obtained. Subjects who withdraw from the study during the Follow-up Phase do not 
need to have the EOT visit assessments repeated
10.4. Withdrawal From the Study 
Added text in bold. 
If a subject withdraws from the study before the end of the Treatment 
Phase, assessments outlined in the End-of-Treatment Visit should be 
obtained.
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment-1 (20 January 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to add administration of 
steroids for 2 days postinfusion, as a safety precaution and in line with other single agent studies of 
daratumumab.
Applicable Section(s)
Description of Change(s)
Rationale: Additional safety precaution.
Table 3, Time and 
Events Schedule
Added a row for post-infusion medication
Synopsis, Overview 
of Study Design
3.1, Overview of 
Study Design
Added sentence in bold:
Measures to prevent infusion related reactions will include preinfusion medication with 
methylprednisolone, paracetamol, and an antihistamine before each daratumumab 
infusion. Methylprednisolone will also be administered after daratumumab 
infusions in Cycle 1 to prevent delayed infusion reactions.
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Applicable Section(s)
Description of Change(s)
6.3.2, Postinfusion 
Medication
Added paragraph to beginning of section:
For the prevention of delayed infusion-related reactions, all subjects will receive 
corticosteroid orally (20 mg methylprednisolone or equivalent in accordance with 
local standards) on the 2 days following daratumumab infusions in Cycle 1 
(beginning the day after the infusion). In the absence of infusion related AEs after 
Cycle 1, postinfusion corticosteroids will be administered per investigator 
discretion.
Added text in bold to first bullet:
•
Antihistamine (diphenhydramine or equivalent) on the 2 days following all 
daratumumab infusions (beginning the day after the infusion).
Rationale: Correction regarding provision of study medication.
6.2, Daratumumab 
Administration
Deleted sentence:
Daratumumab (16 mg/kg) will be administered by IV infusion to subjects (1) in Arm A 
once every week in Cycle 1, every other week in Cycle 2 and Cycle 3, every 4 weeks in 
Cycle 4 to Cycle 7, and from Cycle 8 to Cycle 20 on Day 1 of each cycle; (2) in Arm B 
once every week in Cycle 1, and then on Day 1 of each cycle from Cycle 2 to Cycle 20; 
or (3) in Arm C once every week in Cycle 1 only. This schedule is presented 
schematically in Figure 3. After the end of the study, the sponsor will ensure that 
subjects benefiting from treatment with daratumumab will be able to continue treatment
Rationale: Clarification of biomarker evaluations in subjects with genetic modifications
Table 1, Time and 
Events Table, Bone 
marrow aspirate/ 
biopsy
Replaced strikethrough with text in bold:
A fresh aspirate is requested for high risk profiling assessment of genetic 
modifications…
Synopsis, Biomarker 
Evaluations
9.4, Biomarkers
…to determine the clinical benefit (ORR, PFS, and OS) of daratumumab in high risk 
molecular subtypes subjects with genetic modifications…
3.2, Study Design 
Rationale (DNA and 
Biomarker 
Collection)
9.4, Biomarkers
…using DNA/RNA sequencing of MM cells to allow for assessment of high-risk 
genomics genetic modifications such as…
9.2.1.6, Bone Marrow 
Examination
Added below Table 6:
A portion of the bone marrow aspirate at baseline and at disease progression when 
feasible will be utilized for DNA/RNA sequencing to characterize subjects (t(4;14), 
del17p, t(14;16), UAMS70, etc) and to evaluate potential mechanisms of resistance 
(CD38 mutations, expression of  CD38 and CD59).
Rationale: Clarification for subjects participating in QTc substudy
9.5.1, 
Electrocardiogram, 
QTc Evaluation 
Substudy
Replaced text in strikethrough with text in bold:
For the first 30 subjects receiving daratumumab eligible for the QTc substudy at sites 
participating in the QTc evaluation substudy…
Synopsis, Sample 
Size Determination, 
11.2, Sample Size 
Determination
Added test in bold:
To ensure 25 subjects are evaluable, the QTc substudy will enroll approximately 30 
subjects
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Applicable Section(s)
Description of Change(s)
Rationale: Adjustments of various study procedures to improve clarity.
Table 1, Time and 
Events Schedule
made the following clarifications:
serum and urine IFE should be done at screening, 
serum free light chain should be done when CR is suspected or maintained
CMMC blood sample to be obtained at screening, not C1D1
MRI of spine and pelvis required, whole body MRI per local practice or when 
clinically indicated
4.3, Prohibitions and 
Restrictions
Added following sentence to section on blood type and IAT results:
Please refer to SIPPM and IB for details.
6.3.3, Management of 
Infusion-related 
Reactions
deleted phrase in strikethrough:
in case of any infusion reactions occurring, and resources necessary for resuscitation 
(eg, agents such as epinephrine and aerosolized bronchodilator, also medical equipment 
such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available at 
the bedside.
9.2.1.7, Assessment 
of Bone Lesions
Deleted text in strikethrough and added text in bold:
An MRI should also of spine and pelvis will be regularly performed to assess focal 
bone lesions; whole body MRI should be performed per local practice or if 
clinically indicated.
9.5.2, Other Safety 
Evaluations
Added footnote “b” to serum chemistry table, with instruction to calculate creatinine 
clearance as per Section 9.2.1.3.
10.3, Premature 
Discontinuation of 
Study Treatment
deleted phrase in strikethrough:
The subject experiences disease progression (please see below). Relapse from CR is not 
considered as disease progression.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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SYNOPSIS
A Randomized Phase 2 Trial to Evaluate Three Daratumumab Dose Schedules in Smoldering Multiple 
Myeloma
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a unique 
epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor 
cells that express high levels of CD38, such as plasma cells from patients with multiple myeloma (MM). 
This target is distinct from those of other approved agents for MM therapy.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objectives are:

To evaluate if daratumumab can effectively decrease M protein in subjects with intermediate or 
high-risk smoldering MM (SMM) as assessed by CR rate

To determine if daratumumab reduces the progression/death rate in subjects with intermediate or high-
risk SMM
Secondary Objectives
The secondary objectives are:

To evaluate preliminary efficacy, including Overall Response Rate (ORR) and PFS 

To evaluate the MRD negative rate 

To evaluate the pharmacokinetics and immunogenicity of daratumumab

To assess the safety profile of daratumumab given in 3 different dosing schedules

To determine if daratumumab has an effect on QT interval
Exploratory Objectives
The exploratory objectives are:

To explore biomarkers predictive of response to daratumumab

To evaluate the utility of CMMCs (circulating MM cells) to predict SMM progression to MM 
Hypothesis
Two hypotheses will be tested:
1.
H0: CR rate ≤ 15% 
Ha: CR rate ≥ 35%
2.
H0: PD/death rate ≥ 0.346/patient-year (median PFS < 24 months)
Ha: PD/death rate ≤ 0.185/patient-year (median PFS > 45 months)
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, 3-arm, multicenter study in subjects at least 18 years old with intermediate 
or high-risk SMM. Approximately 120 subjects will be enrolled in this study with 40 subjects planned per 
treatment arm.
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* 
Every 8 weeks (Q8W) beyond Cycle 20 (in case of treatment extension or treatment re-initiation if applicable), as per 
investigator’s discretion. As of Amendment 5, subjects continuing in the Treatment Extension Phase may switch to 
daratumumab 1800 mg SC Q8W at the discretion of the investigator. Subjects with a known allergy/intolerance to sorbitol 
will not be eligible to switch to daratumumab SC.
Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. The 
Screening Phase will be up to 28 days before Cycle 1, Day 1. Treatment cycles are 8 weeks in length. For 
subjects randomized to Arm A or Arm B, the Treatment Phase will extend from Cycle 1 to Cycle 20. In 
Arm A, daratumumab will be administered weekly in Cycle 1, every other week in Cycle 2 and Cycle 3, 
every 4 weeks in Cycle 4 to Cycle 7, and from Cycle 8 to Cycle 20 on Day 1 of each cycle. In Arm B, 
daratumumab will be administered weekly in Cycle 1 and then on Day 1 of each cycle from Cycle 2 to 
Cycle 20. For subjects in Arm A (long intense) and Arm B (intermediate), there is a possibility to extend 
treatment with IV daratumumab (Q8W) after the end of Cycle 20 if, as per investigator discretion, there is 
a positive benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, and at least stable disease has 
been achieved. In the case of subjects who already completed EOT and end of Cycle 20 occurred <6 months, 
these subjects can also continue receiving IV daratumumab administrations every 8 weeks.
For subjects randomized to Arm C, the Treatment Phase consists of Cycle 1 only, when daratumumab will 
be administered weekly. Randomization will be stratified based on the number of risk factors for 
progression to symptomatic MM (<2 vs ≥2) as described in Section 5. 
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Measures to prevent infusion-related reactions will include pre-dose medication with methylprednisolone, 
paracetamol, and an H1-antihistamine before each daratumumab administration. Methylprednisolone will 
also be administered after daratumumab administration in Cycle 1 to prevent delayed infusion reactions.
More information on the guidelines to prevent infusion-related reactions are provided in Section 6.4.
The Follow-up Phase will begin once a subject completes the planned number of cycles, or in the case of 
treatment extension, the investigator decides to end the treatment and the End-of-Treatment visit at 4 weeks 
after last dose (±7 days) is completed. Other reasons for premature discontinuation of treatment are listed 
in Section 10.3. Subjects who discontinue before disease progression must continue to have disease 
evaluations according to the Time and Events Schedule (As of Amendment 5, refer to the Time and Events 
Schedule in Attachment 4). The Follow-up Phase will continue until death, lost to follow up, consent 
withdrawal, or study end, whichever occurs first. 
Three data cutoff timepoints are planned:

The first data cutoff is for an interim analysis 6 months after the last subject is randomized. This will 
be the basis for the analysis of the primary study endpoint of CR. All available data at the time of this 
data cutoff may be included in the interim analysis.

The second data cutoff will occur 12 months after the last subject is randomized. This will be the basis 
for the analysis of the primary study endpoint of PD/death rate. All available data at the time of this 
data cutoff will be included in the Clinical Study Report.

A third data cutoff will occur at the end of the study. The data collected will be reported in a Clinical 
Study Report.
The end of the study will occur up to approximately 7 years after the last subject’s first dose, following a 
decision by the sponsor to end the study based on data from the smoldering multiple myeloma Phase 3 study 
(54767414SMM3001 [SMM3001]), or for reasons as outlined in Section 17.9.2, whichever occurs first.
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be 
conducted on bone marrow aspirate samples. Safety evaluations will include AE monitoring, physical 
examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters (hematology and 
chemistry), vital sign measurements, and Eastern Cooperative Oncology Group (ECOG) performance 
status. A QTc substudy will be conducted in a subpopulation of subjects at selected sites. Blood samples 
will be drawn for assessment of pharmacokinetic and biomarker parameters.
SUBJECT POPULATION
Key eligibility criteria include the following: subjects who are 18 years of age, have a confirmed diagnosis 
of intermediate or high-risk SMM, and an Eastern Cooperative Oncology Group (ECOG) performance 
status score of 0 or 1.
DOSAGE AND ADMINISTRATION
Daratumumab (16 mg/kg) will be administered by IV infusion to subjects (1) in Arm A once every week 
in Cycle 1, every other week in Cycle 2 and Cycle 3, every 4 weeks in Cycle 4 to Cycle 7, and from Cycle 8 
to Cycle 20 on Day 1 of each cycle; (2) in Arm B once every week in Cycle 1, and then on Day 1 of each 
cycle from Cycle 2 to Cycle 20; or (3) in Arm C once every week in Cycle 1 only. For subjects in Arm A 
(long intense) and Arm B (intermediate), there is a possibility to extend treatment with IV daratumumab 
(Q8W) after the end of cycle 20 if, as per investigator discretion, there is a positive benefit/risk ratio, absence 
of Grade ≥3 treatment related toxicity, and at least stable disease has been achieved. In the case of subjects 
who already completed EOT and end of Cycle 20 occurred <6 months, these subjects can also continue 
receiving IV daratumumab administrations every 8 weeks.
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To minimize the time subjects spend in the clinic due to the coronavirus (COVID-19) pandemic, subjects 
who are being treated in the Treatment Extension Phase as of Amendment 5 will be given the option to 
switch to SC daratumumab dosing (1800 mg dose) at the discretion of the investigator (see Section 6 for 
details). Subjects with a known allergy/intolerance to sorbitol will not be eligible to switch to daratumumab 
SC. 
Alternatively, for subjects who continue to receive daratumumab IV, the duration of infusion may be 
shortened to a 90-minute infusion for subjects without a history of an infusion related reaction (IRR) after 
the third dose, at the discretion of the investigator. More information is provided in the Site Investigational 
Product Procedures Manual (SIPPM). See Section 6 for more details.
EFFICACY EVALUATIONS/ENDPOINTS
Disease assessments will be performed at Week 5, Week 9, and then every 8 weeks in the first year, 
thereafter every 16 weeks until disease progression (as of Amendment 5, refer to Attachment 4). A window 
of ±7 days before the scheduled assessment date is allowed. For subjects with treatment delays, disease 
assessments should be performed at the time of daratumumab administration, but do not need to be repeated 
if they were performed within 14 days before the actual treatment date.
There are two co-primary endpoints:

Complete Response (CR) rate, defined as the proportion of subjects with a CR, as defined in 
Section 9.2.1.1

PD/Death rate, defined as the proportion of subjects that have progressed to MM or died per 
patient-year (number of events (PD or death)/total follow-up for all subjects).
Secondary endpoints are:

Minimal residual disease negative rate

Time to next treatment defined as, the time from the date of randomization to the date of the first 
subsequent MM treatment

Overall Response Rate defined as CR+PR rate

PFS, defined as the time from the date of randomization to the date of initial documented PD according 
to the CRAB criteria, myeloma defining events, or date of death, whichever occurs first. For subjects 
who are progression-free and are alive at the time of data cutoff for an analysis, PFS will be censored 
at their last disease assessments on or before initiation of subsequent anti-MM therapy, lost to follow-
up, or withdrawal of consent if any of them occurred, or last disease assessments if none of them 
occurred. PFS will be censored at the date of randomization if there is no postbaseline disease 
evaluation recorded.

Incidence of symptomatic MM with adverse prognostic features, which include International Staging 
System (ISS) Stage III (based on β2-microglobulin and albumin) and adverse cytogenetic 
characteristics

Response to first subsequent MM treatment

Overall survival rate 
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Samples to assess both the serum concentration (pharmacokinetics) of daratumumab and the generation of 
antibodies to daratumumab (immunogenicity) will be obtained from all subjects according to Table 1. At 
specified timepoints, venous blood samples (5 mL per sample) will be collected to determine serum 
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concentration of daratumumab and the serum will be divided into 3 aliquots (1 aliquot for pharmacokinetic 
analysis, 1 aliquot for antibodies to daratumumab analysis [when appropriate], and 1 aliquot as a backup). 
As of Amendment 5, these samples will not be collected.
BIOMARKER EVALUATIONS 
Biomarker assessments will focus on 4 main objectives including evaluating the ability of daratumumab to 
reduce MRD in SMM subjects who achieve a complete response, to determine the clinical benefit (ORR, 
PFS, and OS) of daratumumab in subjects with genetic modifications, to evaluate the immunophenotype of 
SMM patients for potential immune cell contributions to daratumumab response, and to evaluate the 
contribution of CMMCs to progression of disease. All biomarker assessments will be performed centrally.
Bone marrow aspirates will be collected at screening and following treatment. In addition, blood samples 
will be obtained for assessment of CMMCs, immunophenotyping and plasma and PBMC biomarker 
assessments. 
As of Amendment 5, these samples will not be collected.
SAFETY EVALUATIONS
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign measurements, physical 
examination findings, and assessment of ECOG performance status score. A QT substudy will be conducted 
in 30 subjects at selected sites.
STATISTICAL METHODS
Two hypotheses will be tested:
1.
H0: CR rate ≤ 15% 
Ha: CR rate ≥ 35%
2.
H0: PD/death rate ≥ 0.346/patient-year (median PFS < 24 months)
Ha: PD/death rate ≤ 0.185/patient-year (median PFS > 45 months)
This study will enroll 120 subjects (40/arm) in total. With 40 subjects per arm, each arm will have:

90% power to show that the true CR rate is 35% at a one-sided level of 0.05

80% power to show that the true PD/death rate is 0.185/patient year at a one-sided level of 0.1
If two or more treatment schedules are deemed to be effective, with 40 subjects per arm this study would 
have:

85% probability of identifying the arm with the higher CR

80% probability of identifying the arm with the lower PD/death rate
For the QTc substudy, assuming that the intrasubject standard deviation for change from baseline in QTc 
(ΔQTc) is 20 milliseconds and that the true difference in means is 5 milliseconds, a sample size of 
25 evaluable subjects (completers) will have 80% power to show that the upper limit of the two-sided 90% 
confidence interval (1 sided upper 95% confidence interval) for the difference in mean QTc (ΔQTc) at each 
timepoint and baseline will be less than 20 milliseconds. To ensure 25 subjects are evaluable, the QTc 
substudy will enroll approximately 30 subjects.
The first primary efficacy analysis of CR rate will occur 6 months after the last subject has been randomized 
and will be considered as an interim analysis. The purpose of this analysis is to select an appropriate dose 
and schedule and enable the sponsor’s decision to proceed to Phase 3.
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The second primary efficacy analysis of PD/death rate will occur 12 months after the last subject has been 
randomized. The purpose of this analysis is to make a decision to either proceed to Phase 3 if at the interim 
analysis there was not enough evidence to do so or to confirm the decision made after the interim analysis 
to proceed to Phase 3.
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.
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imaging; PBMC= peripheral blood mononuclear cell ; PK=pharmacokinetics; PD= disease progression; SAE=serious adverse event; SOC=standard of care; SPEP=serum M-protein 
quantitation by electrophoresis; UPEP=urine M-protein quantitation by electrophoresis; Wk=week
a
Includes HBsAg, anti-HBs, and anti-HBc. For subjects who enter extension treatment period, HBV serology (HBsAg, anti-HBs, and anti-HBc) testing is to be performed locally prior 
to re-initiation. HBV serology is not required at re-initiation if this was performed as part of standard of care within 3 months prior to the re-initiation or the start of extension 
treatment is within 3 months of last daratumumab dose.  
b
If study subject already discontinued study drug and EOT took place < 6 months, treatment can be re-initiated again if there is no disease progression at the time of re-initiation of the 
treatment. The assessment of disease progression will be based on the last disease evaluation performed. If last disease evaluation was performed ≥5 months at treatment re-initiation, 
a new disease evaluation is to be performed to make sure that subject has not progressed. Every case of treatment re-initiation is to be discussed with the medical monitor prior to re-
initiation.
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ABBREVIATIONS
ADCC
antibody-dependent cell-mediated cytotoxicity
ADCP
antibody-dependent cellular phagocytosis
AE
adverse event
AL amyloidosis
immunoglobulin light chain amyloidosis
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
CDC
complement-dependent cytotoxicity
CL
total systemic clearance
Cmax
maximum observed concentration
Cmin
minimum observed concentration
CMMCs
circulating multiple myeloma cells
COPD
chronic obstructive pulmonary disease
CR
complete response
CT
computed tomography
Ctrough
maximum trough concentrations
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EOT
end of treatment
EU
European Union
FEV
forced expiratory volume
FFPE
formalin fixed paraffin embedded
FLC
free light chain
GCP
Good Clinical Practice
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HR
hazard ratio
IAT
indirect antiglobulin test (also known as indirect Coombs test)
IB
Investigator Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IFE
immunofixation
Ig
immunoglobulin
IgG1
immunoglobulin G1 kappa
IMiD
immunomodulatory agent
IMWG
International Myeloma Working Group
IPPI
Investigational Product Preparation Instructions
IRB
Institutional Review Board
IRR
infusion-related  reaction
ISS
International Staging System
IV
intravenous
IWRS
interactive web response system
LLN
lower limit of normal
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MGUS
monoclonal gammopathy of undetermined significance
MM
multiple myeloma
MR
minimal response
MRD
minimal residual disease
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
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NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS
next generation sequencing
NK
natural killer
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PC
plasma cell
PD
disease progression
PET-CT
positron emission tomography-computed tomography
PFS
progression free survival
PK
pharmacokinetics
PO
per os
PQC
Product Quality Complaint
PR
partial response
Q8W
every 8 weeks
RBC
red blood cell
rHuPH20
recombinant human hyaluronidase PH20 
SAE
serious adverse event
SC
subcutaneous
sCR
stringent complete response
SIPPM
Site Investigational Product Procedures Manual (or equivalent document)
SMM
smoldering multiple myeloma
SPEP
serum M-protein quantitation by electrophoresis
TTP
time to progression
ULN
upper limit of normal
UPEP
urine M-protein quantitation by electrophoresis
US
United States
V
volume of distribution
VGPR
very good partial response
VMP
VELCADE-melphalan-prednisone
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1.
INTRODUCTION
1.1.
Disease Background
Multiple myeloma (MM) is a mostly incurable malignant plasma cell disorder diagnosed annually 
in approximately 20,000 patients in the US [Weiss 2009]25. In a majority of patients 
[Landgren 2009]11, MM evolves from premalignant, asymptomatic plasma cell disorders such as 
non IgM monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple 
myeloma (SMM), which are characterized by monoclonal plasma cell proliferation in the bone 
marrow and absence of end-organ damage such as renal failure, anemia, and lytic bone lesions 
[Weiss 2009; Kyle 2009; Kyle 2010]25,8,7. Smoldering multiple myeloma accounts for 13% to 15% 
of all myeloma patients [SEER, Kantar Health] and progresses to symptomatic MM at a rate of 
10% per year for the first 5 years, decreasing to 3% per year over the following 5 years [ESMO 
Clinical Practice Guidelines]. 
Currently there are no approved treatment options for patients with SMM outside of clinical trials 
and clinical management involves close monitoring until development of symptomatic disease 
[Landgren 2013]10. Some early studies that investigated treatment for SMM with various 
chemotherapy regimens (melphalan-prednisone, thalidomide) or bisphosphonates did not show 
consistent clinical benefit and were often poorly tolerated [Dispenzieri 2013; Landgren 2013]3,10. 
Data from a recent Phase 3 study of lenalidomide and dexamethasone (Len-dex, n=57) compared 
with observation (n=62) in high-risk SMM patients showed that lenalidomide-based treatment was 
associated with a significant delay in progression to symptomatic myeloma [Mateos 2013]18. With 
a median follow- up of 40 months, the median time to progression (TTP) was significantly longer 
in the treatment group than in the observation group (median not reached vs. 21 months)(hazard 
ratio [HR] for progression, 0.18; p<0.001). Additionally, lenalidomide plus dexamethasone 
resulted in response rates of 14% complete response (CR) in the induction phase and 26% CR in 
the maintenance phase. However, treatment-related toxicities may preclude the long-term use of 
this regimen in a preventive setting. Therefore, further study in this population is needed to identify 
novel therapeutic agents that delay or prevent the onset of symptomatic MM, and demonstrate a 
favorable safety profile over prolonged treatment durations.
1.2.
Daratumumab
Daratumumab is a human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody (mAb) that 
binds with high affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is a 
targeted immunotherapy directed towards tumor cells that express high levels of CD38, in a variety 
of hematological malignancies including MM, leukemia, and non-Hodgkin’s lymphoma (NHL).
Daratumumab induces lysis of CD38-expressing tumor cells, 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 2011;
Overdijk 2013]2,20.
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For the most comprehensive nonclinical and clinical information as well as Reference Safety 
Information regarding daratumumab, refer to the latest version of the Investigator's Brochure 
[Daratumumab IB].
1.2.1.
Nonclinical Studies
Preliminary pharmacodynamic studies suggest that daratumumab utilizes multiple effector cell 
functions, resulting in immune mediated killing of CD38-expressing tumor cells. In ex vivo 
experiments utilizing human bone marrow stromal cells co-cultured with primary 
CD38-expressing MM cells, complement-dependent cytotoxicity (CDC) occurs rapidly and 
demonstrates maximal myeloma cell killing by daratumumab within 1 hour of antibody-mediated 
activation of the complement proteins (de Weers 2011)2. Daratumumab-induced antibody-
dependent cell-mediated cytotoxicity (ADCC) is slower in its action, with maximal ADCC by 
daratumumab observed at 4 hours in vitro (de Weers 2011)2. Daratumumab has also been shown 
to induce antibody-dependent cellular phagocytosis (ADCP) in the presence of macrophages 
within 4 hours in vitro (Overdijk 2013)20. Further, in vitro studies indicated that daratumumab 
inhibited the cyclase activity of CD38 and stimulated the CD38 hydrolase activity 
(Study No. GMB 3003-013).
Studies on proliferation of and release of cytokines in human blood cells have indicated that 
daratumumab does not exert target-specific agonistic activity. The cytokine release observed is 
mainly caused by the Fc-portion of IgG1 and comparable to that of approved therapeutic antibodies 
already in clinical use. Specific binding of daratumumab was detected in multiple tissues of both 
human and chimpanzee origin. 
1.2.1.1.
Toxicology
Toxicology data have been derived from studies with daratumumab in chimpanzees and with a 
surrogate anti-CD38 antibody in cynomolgus monkeys. The primary toxicities identified in 
chimpanzees were infusion-related reactions (IRRs) during the first, but not subsequent, 
daratumumab infusions and thrombocytopenia. Anemia was observed in cynomolgus monkeys. 
The binding affinity of daratumumab is significantly higher for chimpanzee platelets than for 
human platelets, suggesting that thrombocytopenia may be less pronounced in humans. The effect 
on platelets and red blood cells (RBCs) was reversible.
Depletion of specific lymphocyte phenotypic cell populations, as expected, based on the intended 
pharmacological effect of daratumumab, was observed in both chimpanzees and cynomolgus 
monkeys. No genotoxicity, chronic toxicity, carcinogenicity, or reproductive toxicity testing has 
been conducted.
1.2.2.
Clinical Studies
Preliminary data as of 31 July 2014 from 5 ongoing clinical studies are summarized. For further 
details and the most up-to-date information, please refer to the Daratumumab IB.
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As of 31 July 2014, approximately 300 subjects have been treated across 5 ongoing clinical studies 
of daratumumab in subjects with MM: Studies GEN501, GEN503, 54767414MMY1001, 
54767414MMY1002, and 54767414MMY2002 (hereafter referred to as MMY1001, MMY1002, 
and MMY2002, respectively). Single-agent daratumumab has been administered to 232 subjects 
in Studies GEN501, MMY1002, and MMY2002; 41 subjects have been treated with daratumumab 
in combination with lenalidomide and dexamethasone in Study GEN503, and 25 subjects have 
been treated with daratumumab in combination with VELCADE-containing regimens 
(VELCADE-dexamethasone [VD], VELCADE-thalidomide-dexamethasone [VTD], VELCADE-
melphalan-prednisone 
[VMP]) 
and 
pomalidomide-dexamethasone 
[Pom-dex] 
in 
Study MMY1001. In addition, as of the clinical cutoff date, 16 subjects have been randomized in 
Study 54767414MMY3003 (MMY3003). 
1.2.2.1.
Clinical Pharmacokinetics
Pharmacokinetic (PK) data are available from Study GEN501 Part 1. The doses ranged from 0.005 
to 24 mg/kg. The PK profile was consistent with target mediated disposition (TMD) with rapid 
target-related clearance at low doses and slower clearance at higher doses. Following long-term 
treatment, clearance may decrease as the tumor burden decreases. The preliminary PK data in 
Studies GEN501 Part 2 and MMY2002 are consistent with the PK profile obtained in GEN501 
Part 1. Preliminary PK data from Study GEN503 show that following both the first dose and 
multiple repeated doses, the PK profile of daratumumab in combination with lenalidomide and 
dexamethasone is similar to what was observed in Study GEN501 following the same dose and 
schedule. The data suggest that lenalidomide and dexamethasone do not affect the PK profile of 
daratumumab. 
1.2.2.2.
Preliminary Efficacy
Preliminary efficacy data for Study GEN501 Parts 1 and 2 were presented at the 2013 and 2014 
American Society of Clinical Oncology (ASCO) Annual Meetings, respectively. As the study is 
still ongoing, and data reconciliation activities are underway, the data should be considered 
preliminary. Among 12 subjects treated with daratumumab in Part 1 at doses ≥4 mg/kg, 5 partial 
responses (PRs) and 3 minimal responses (MRs) were observed. Seven (7) of these subjects had a 
50 to 100% concomitant reduction in bone marrow plasma cells. Among 29 subjects treated with 
8 mg/kg daratumumab in Part 2, 3 subjects (10%) had a PR; the response rate was 10%. Among 
20 subjects treated with 16 mg/kg, 2 subjects (10%) had a CR, 1 subject (5%) had a very good 
partial response (VGPR), and 4 subjects (20%) had a PR; the response rate was 35%. 
1.2.2.3.
Safety and Tolerability
In general, daratumumab is tolerated well. Maximum tolerated dose (MTD) has not been reached 
following intravenous (IV) infusions up to 24 mg/kg monotherapy and 16 mg/kg in combination 
studies. The most frequently reported adverse events (AEs) across the daratumumab program have 
been IRRs following single agent therapy. Among all subjects treated in ongoing studies 
(monotherapy and combination therapy), IRRs have been reported in 49% of subjects; among 
151 subjects treated with 16 mg/kg daratumumab monotherapy in Studies GEN501 and 
MMY2002, the percentage of subjects with a reported IRR was identical (49%) to what was 
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observed across all treated subjects. The most frequently reported AEs (reported in ≥5% of 
subjects) reported as IRRs were rhinitis allergic (8%), cough (7%), and nasal congestion (6%). 
Among subjects treated with 16 mg/kg daratumumab monotherapy, the most commonly reported 
IRRs were nasal congestion (8%), cough (7%), and rhinitis allergic and throat irritation (5% each). 
Grade 3 or higher IRRs were reported in 5% of subjects treated with 16 mg/kg daratumumab as 
monotherapy, with bronchospasm and hypertension being the most frequently reported Grade 3 or 
higher IRRs (1% each). 
Across all ongoing studies, bronchospasm was reported in 10 subjects. Early in daratumumab 
development, in Study GEN501, 2 cases of bronchospasm were reported 24-48 hours following 
the second full-dose infusion of daratumumab. With the exception of those 2 cases, which had a 
delayed onset, all other reported bronchospasm events occurred following the first dose. All of the 
events occurring during the infusion period resolved quickly after standard treatments were 
administered. The daratumumab infusion was restarted, and no new onset of bronchospasm 
occurred. Most of the subjects who experienced bronchospasm had underlying respiratory diseases 
(asthma, chronic obstructive pulmonary disease [COPD], and others). 
Among the 151 subjects treated with 16 mg/kg daratumumab as monotherapy in Studies GEN501 
and MMY2002, the most frequently reported AEs (reported in >10% of subjects) were fatigue 
(29%); anemia (23%); nausea (19%); back pain (18%); cough (17%); thrombocytopenia (16%); 
decreased appetite (13%); pyrexia, dyspnea, upper respiratory tract infection (12% each); nasal 
congestion and neutropenia (11% each). Grade 3 and higher AEs were reported in 48% of subjects 
treated with 16 mg/kg monotherapy daratumumab. The most frequently reported Grade 3 or higher 
AEs were anemia (13%) and thrombocytopenia (9%). All other Grade 3 and higher AEs were 
reported in <5% of subjects. No deaths due to daratumumab-related AEs have been reported in 
any ongoing study.
1.2.2.4.
Daratumumab Subcutaneous 
A new formulation of daratumumab for subcutaneous (SC) administration has been developed to 
avoid the long infusion time that frequently requires hospitalization with IV administration of 
daratumumab and to lessen the rate and severity of IRRs observed with daratumumab IV. A 
recombinant human hyaluronidase PH20 (rHuPH20) was used to facilitate the SC administration 
of daratumumab to decrease the volume required for SC administration.
To minimize the time subjects spend in the clinic during the coronavirus (COVID-19) pandemic, 
subjects who are being treated in the Treatment Extension Phase as of Amendment 5 will be given 
the option to switch to SC daratumumab dosing (1800 mg dose, every 8 weeks [Q8W]) at the 
discretion of the investigator. Subjects with a known allergy/intolerance to sorbitol will not be 
eligible to switch to daratumumab SC.
This 
SC 
formulation 
of 
daratumumab 
has 
been 
evaluated 
in 
the 
Phase 
3 
Study 54767414MMY3012 (MMY3012; COLUMBA), which compared efficacy, PK, and safety 
of SC vs IV daratumumab in 522 subjects. Adults with relapsed/refractory multiple myeloma were 
randomized 1:1 to SC (1800 mg; co-formulated with rHuPH20; n=263) or IV (16 mg/kg; n=259) 
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daratumumab. Randomization was stratified by body weight, prior therapy lines, and myeloma 
subtype. Primary objectives were to demonstrate non-inferiority of SC vs. IV administration in 
overall response rate (ORR; at least partial response) and maximum trough concentrations (Ctrough) 
(Cycle 3, Day 1).
Co-primary endpoints ORR and Ctrough met predefined non-inferiority criteria, demonstrating that 
daratumumab SC is non-inferior to IV. ORR was 41% and 37% with SC and IV daratumumab 
administration, respectively (relative risk, 1.11; 95% CI, 0.89–1.37). Geometric mean ratio for 
Ctrough was 107.93% (90% CI, 95.74–121.67). Median duration of injection was 5 minutes (range 
1–18) for the first, second, and subsequent SC administrations vs. 7 hours (1–14), 4.3 hours 
(3-10.5), and 3.4 hour (2–7.7) for corresponding IV infusions. Infusion-related reactions were 
reported in 13% of subjects receiving daratumumab SC versus 35% receiving daratumumab IV 
(odds ratio, 0.28; 95% CI, 0.18–0.44, p<0.0001). Daratumumab SC offers consistent efficacy and 
exposure to standard IV administration, with significantly shorter infusion times and an improved 
safety profile.   
1.3.
Overall Rationale for the Study
Daratumumab is a targeted immunotherapy that binds to tumor cells that overexpress CD38, a 
transmembrane glycoprotein. Plasma cells in patients with SMM express high levels of CD38, 
similar to plasma cells in symptomatic MM [Tiedemann 2010]23. Daratumumab, as a single agent, 
has shown clinical activity at 16 mg/kg in patients with relapsed/refractory MM who have already 
failed a number of prior therapies and whose myeloma clones have become resistant to many 
therapies [Lokhorst 2014]15. Daratumumab has also demonstrated an acceptable and manageable 
safety profile.
Patients with SMM are asymptomatic and relatively immunocompetent. In current practice, the 
standard of care for subjects with SMM is watchful waiting. For high-risk patients, treatment under 
clinical trials has been recommended [Landgren 2013]10. As an immunotherapy, daratumumab’s 
immediate and effective cell-mediated (and potentially direct) cytotoxic effects against MM cells 
may be an ideal mechanism for providing disease interception and early intervention at the SMM 
stage. Furthermore, the low risk of serious side effects increases the appeal of daratumumab as a 
treatment option to prevent and/or delay transition to symptomatic MM.
This study is designed to evaluate whether daratumumab as a single agent is effective in delaying 
the transition from an intermediate or high-risk premalignant condition (SMM) to symptomatic 
MM, and to find the optimal schedule of treatment administration. Three different treatment 
schedules will be investigated. An intensive daratumumab treatment schedule, similar to the 
schedule proposed for Arm A, has demonstrated clinical activity and an acceptable safety profile 
in subjects with relapsed/refractory MM [Lokhorst 2014]15. However, in this asymptomatic patient 
population, a less intensive but still efficacious treatment schedule would be more attractive to 
patients and providers. In Study 501, subjects with relapsed or refractory MM received 2 pre and 
7 full doses of daratumumab over a 9 week treatment period. Even with this abbreviated schedule, 
clinical activity (5 PRs and 3 MRs) was observed and the response was durable after stopping 
daratumumab [Lokhorst 2013]16. These data suggest that 8 weekly infusions of daratumumab (as 
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proposed for Arm C) might be sufficient to delay the onset of symptomatic MM in this relatively 
immunocompetent patient population. A third alternative will be tested in Arm B, with an intensive 
treatment schedule once a week for 8 weeks followed by maintenance infusions once every 
8 weeks.
As of Amendment 5, which was implemented to minimize the time subjects spend in the clinic 
during the coronavirus (COVID-19) pandemic, subjects continuing in the Treatment Extension 
Phase may switch to daratumumab 1800 mg SC, Q8W, at the discretion of the investigator. The 
SC formulation of daratumumab has been evaluated in the Phase 3 randomized Study MMY3012 
(COLUMBA), which compared efficacy, PK, and safety of SC vs IV daratumumab in 522 subjects 
which met pre-defined non-inferiority criteria, demonstrating that daratumumab SC is non-inferior 
to IV.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective

To evaluate if daratumumab can effectively decrease M protein in subjects with intermediate 
or high-risk SMM as assessed by CR rate

To determine if daratumumab reduces the progression/death rate in subjects with intermediate 
or high-risk SMM 
Secondary Objectives
The secondary objectives are:

To evaluate preliminary efficacy, including ORR and progression-free survival (PFS) 

To evaluate the minimal residual disease (MRD) negative rate 

To evaluate the PK and immunogenicity of daratumumab

To assess the safety profile of daratumumab given in 3 different dosing schedules

To determine if daratumumab has an effect on QT interval
Exploratory Objective

To explore biomarkers predictive of response to daratumumab

To evaluate the utility of circulating MM cells (CMMCs) to predict SMM progression to MM 
2.2.
Hypothesis
Two hypotheses will be tested:
1.
H0: CR rate ≤ 15% 
Ha: CR rate ≥ 35%
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2.
H0: PD/death rate ≥ 0.346/patient-year (median PFS < 24 months)
Ha: PD/death rate ≤ 0.185/patient-year (median PFS > 45 months)
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, open-label, 3-arm, multicenter study in subjects at least 18 years old with 
intermediate or high-risk SMM. Approximately 120 subjects will be enrolled in this study with 
40 subjects planned per treatment arm.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
* 
Every 8 weeks (Q8W) beyond Cycle 20 (in case of treatment extension or treatment re-initiation if applicable), as per
investigator’s discretion. As of Amendment 5, subjects continuing in the Treatment Extension Phase may switch to 
daratumumab 1800 mg SC Q8W at the discretion of the investigator. Subjects with a known allergy/intolerance to sorbitol 
will not be eligible to switch to daratumumab SC.
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Subject participation will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. 
The Screening Phase will be up to 28 days before Cycle 1, Day 1. Treatment cycles are 8 weeks in 
length. For subjects randomized to Arm A or Arm B, the Treatment Phase will extend from Cycle 1 
to Cycle 20. In Arm A, daratumumab will be administered weekly in Cycle 1, every other week in 
Cycle 2 and Cycle 3, every 4 weeks in Cycle 4 to Cycle 7, and from Cycle 8 to Cycle 20 on Day 1 
of each cycle. In Arm B, daratumumab will be administered weekly in Cycle 1 and then on Day 1 
of each cycle from Cycle 2 to Cycle 20. For subjects in Arm A (long intense) and Arm B 
(intermediate), there is a possibility to extend treatment with IV daratumumab (every 8 weeks 
[Q8W]) after the end of Cycle 20 if, as per investigator discretion, there is a positive benefit/risk 
ratio, absence of Grade ≥3 treatment related toxicity, and at least stable disease has been achieved. 
In the case of subjects who already completed EOT and end of Cycle 20 occurred <6 months, these 
subjects can also continue receiving IV daratumumab administrations every 8 weeks. Per 
Amendment 5, subjects continuing in the study will follow the modified Time and Events schedule 
detailed in Attachment 4.
For subjects randomized to Arm C, the Treatment Phase consists of Cycle 1 only, when 
daratumumab will be administered weekly. Randomization will be stratified based on the number 
of risk factors for progression to symptomatic MM (<2 versus ≥2) as described in Section 5. 
Measures to prevent IRRs will include pre-dose medication with methylprednisolone, 
paracetamol, 
and 
a 
H1-antihistamine 
before 
each 
daratumumab 
administration. 
Methylprednisolone will also be administered after daratumumab administration in Cycle 1 to 
prevent delayed infusion reactions. More information on the guidelines to prevent IRRs are 
provided in Section 6.4.
The Follow-up Phase will begin once a subject completes the planned number of cycles or in case 
of treatment extension, the investigator decides to end the treatment and the End-of-Treatment visit 
at 4 weeks after last dose (±7 days) is completed. Reasons for premature discontinuation of 
treatment are listed in Section 10.3. Subjects who discontinue before disease progression must 
continue to have disease evaluations according to the Time and Events Schedule (as of 
Amendment 5, refer to the Time and Events Schedule in Attachment 4). The Follow-up Phase will 
continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first. 
Three data cutoff timepoints are planned:

The first data cutoff is for an interim analysis 6 months after the last subject is randomized. 
This will be the basis for the analysis of the primary study endpoint of CR. All available data 
at the time of this data cutoff may be included in the interim analysis.

The second data cutoff will occur 12 months after the last subject is randomized. This will be 
the basis for the analysis of the primary study endpoint of PD/death rate. All available data at 
the time of this data cutoff will be included in the Clinical Study Report.

A third data cutoff will occur at the end of the study. The data collected will be reported in a 
Clinical Study Report.
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
The end of the study will occur up to approximately 7 years after the last subject's first dose, 
following a decision by the sponsor to end the study based on data from the smoldering 
multiple myeloma Phase 3 study (SMM3001), or for reasons as outlined in Section 17.9.2, 
whichever occurs first.
Assessment of tumor response and disease progression will be conducted in accordance with the 
International Myeloma Working Group (IMWG) response criteria. An assessment of MRD will be 
conducted on bone marrow aspirate samples. Safety evaluations will include AE monitoring, 
physical examinations, electrocardiogram (ECG) monitoring, clinical laboratory parameters 
(hematology and chemistry), vital sign measurements, and Eastern Cooperative Oncology Group 
(ECOG) performance status. A QTc substudy will be conducted in a subpopulation of subjects at 
selected sites. Blood samples will be drawn for assessment of PK and biomarker parameters.
3.2.
Study Design Rationale
Rationale for Study Design
Randomization in the assignment of subjects to a dosing schedule will allow assessment of
preliminary efficacy and safety across all 3 arms. To further minimize imbalance across treatment 
arms and to allow for important subgroup analyses, subjects will be stratified according to the 
number of risk factors present at screening (<2 versus ≥2) using the criteria of Dispenzieri (2013)3.
These risk factors will include: abnormal free light chain (FLC) ratio (<0.126 or >8), serum 
M-protein ≥3 g/dL, urine M-protein >500 mg/24 hours, IgA subtype, and immunoparesis (at least 
1 uninvolved immunoglobulin [IgG, IgA, IgM] decreased more than 25% below lower limit of 
normal [LLN]). Stratification factors will be based on central laboratory analyses.
The treatment effect, evaluating whether initial response will reduce the rate of progression to 
symptomatic MM or death in subjects with intermediate or high-risk SMM, will be measured using 
the endpoint of PFS, defined as the time between randomization and progression to symptomatic 
MM or death. Given that the median time to progression in the high-risk SMM patient population 
is about 2 years, assessment of PFS rate approximately 1 year after the last subject is randomized 
should provide an early indication of treatment effect. However, all subjects will continue to be 
followed, and in the final study analysis (expected up to approximately 7 years after the last 
subject’s first dose), long-term data on PFS will be analyzed.
The criteria for efficacy (both response and follow up to progression to symptomatic MM, as 
defined by the IMWG, are objective and will be measured in all 3 treatment dosing schedules. The 
CR rate is defined as the proportion of subjects with CR. In a recent Phase 3 study of lenalidomide 
and dexamethasone in high-risk SMM patients, CR rate in the maintenance phase was 26% 
[Mateos 2013]18. A correlation between CR and time to symptomatic MM has been demonstrated
in simulation models conducted by the Janssen statistical team. A CR rate of 35% was chosen as 
the alternative hypothesis for this study, since a CR rate of at least 30% is considered to be most
likely to translate into delay of progression to myeloma. 
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Even if a therapeutic approach is able to delay the progression to symptomatic MM, it will be 
important to establish whether the delayed symptomatic MM has a similar biology, responsiveness 
to standard therapy approaches, and outcomes as compared with watchful waiting. Within the 
constraints of a randomized Phase 2 design, data (including cytogenetics) will be collected on the 
biologic characteristics of the myeloma, the response to frontline therapy, and overall survival 
(OS).
Rationale for IV Daratumumab Dose Selection
CD38, the target for daratumumab, is expressed on NK cells and clinical data have shown NK cell 
suppression to be a marker of on target drug activity. Clinical PK data have shown the 16 mg/kg 
dose to be the lowest dose that results in nearly complete target suppression at all timepoints. This 
dose and schedule continuously suppressed NK cells throughout dosing. Daratumumab maximal 
target suppression is presented in Figure 2.
Figure 2:
Daratumumab Maximal Target Suppression 
8 mg/kg: Observed trough concentration 
values below predicted 90% suppression
throughout dosing
16 mg/kg: Observed trough concentration 
values at 90% suppression throughout 
dosing
The ORR appeared higher for the 16 mg/kg dose compared with the 8 mg/kg dose, based on early 
preliminary data from Part 2 of Study GEN501 and from Study MMY2002 (both ongoing studies) 
as of a cutoff date of 24 January 2014. In Study GEN501, the ORRs (ie, PR or greater) were 11% 
and 40% for the 8 mg/kg (n=28) and 16 mg/kg (n=15) dose regimens, respectively. For 
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Study MMY2002, the unconfirmed ORRs for the 8 mg/kg and 16 mg/kg dose regimens were 
similar to those observed in GEN501. In addition, VGPRs were observed for 7 of 30 subjects 
treated with the 16 mg/kg dose in the 2 studies. VGPR had not been observed at lower dose levels. 
These preliminary data support that full target saturation at the 16 mg/kg dose is needed to achieve 
higher and deeper response.
Rationale for Daratumumab SC Dose Regimen
The clinical pharmacology assessment of daratumumab SC monotherapy data are available from 
daratumumab SC-dosed subjects in a Phase 1/1b study (54767414MMY1004 [MMY1004; 
Part 2]), a Phase 3 study (MMY3012), and population PK and exposure-response analyses.
In MMY1004, the 1800 mg dose achieved maximum Ctrough (Cycle 3 Day 1 pre-dose) values that 
were similar or greater than the maximum Ctrough observed for the approved 16 mg/kg IV dose 
following the same dose schedule. The PK data from Part 2 supported the daratumumab SC 
1800 mg dose selection for the Phase 3 study. The PK data from MMY3012 study demonstrated 
that daratumumab SC 1800 mg is non-inferior to daratumumab IV 16 mg/kg in terms of maximum 
Ctrough (Cycle 3 Day 1 pre-dose), with the lower bound of the 90% CI for the geometric means ratio 
for daratumumab SC versus daratumumab IV for maximum Ctrough (Cycle 3 Day 1 pre-dose) 
exceeding 80%, thereby meeting the predefined non-inferiority criterion. 
Additionally, daratumumab SC 1800 mg monotherapy consistently produced lower peak-to-trough 
fluctuations, similar or slightly higher trough levels over time, and lower peak concentrations 
compared with daratumumab IV 16 mg/kg monotherapy. Overall, consistent daratumumab 
concentrations were observed across the body weight ranges. As expected, slightly higher 
concentrations were observed for subjects with lower body weights.
There was no apparent relationship between exposure and safety endpoints (serious adverse events 
[SAEs], Grade 3 or higher treatment-emergent adverse events and neutropenia).
Overall, daratumumab SC was well-tolerated with manageable side effects and a significantly 
reduced incidence of IRRs relative to daratumumab IV. The safety profile of daratumumab 
administered SC at a flat dose of 1800 mg continues to be generally comparable to that of the 
16 mg/kg IV formulation.
Rationale for QTc Study
In addition to expression on immune cell populations, CD38 is also expressed on cardiomyocytes. 
Daratumumab inhibits the cyclase activity of CD38, which is involved in the modulation of ER 
calcium release. The resulting lower intracellular calcium concentrations could potentially affect 
the function of cardiomyocytes. 
In a limited toxicology study in chimpanzees, no ECG findings were noted. No other 
cardiovascular safety pharmacology data are available, and generation of further nonclinical safety 
data would be challenging given the lack of suitable animal models other than the chimpanzee, 
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since daratumumab does not bind to CD38 of species typically used for nonclinical toxicology 
testing (mouse, rat, rabbit, pig, cynomolgus monkey, or rhesus monkey).
Preliminary clinical data from study GEN501 Part 2 showed that QTc prolongation was observed 
upon administration of daratumumab at 16 mg/kg; however, these were not time-matched 
observations. The pre-to-post dosing increase for QTcF was approximately 10 msec. No subject 
had a post-dose absolute QT above 500 msec and no subject had an increase from baseline that 
was more than 60 msec. In addition, no infusion-related cardiac arrhythmia was observed.
To further investigate the potential effect of daratumumab on QTc prolongation, a QTc substudy 
will be included in this study. This study is suitable for evaluation of QTc since daratumumab is 
given as a single agent in a relatively healthy population of SMM patients.
Rationale for Pharmacokinetic and Immunogenicity Evaluations
The PK data from this study will be used for PK/pharmacodynamic modeling to aid in the selection 
of a Phase 3 dosing schedule. 
The demographic characteristics of the SMM population differ significantly from previously 
studied daratumumab patient populations and may impact the PK profile. Therefore, samples will 
be obtained from all subjects to determine the PK profile, and the derived PK parameters will 
provide information about the determinates of inter subject variability in this population.
Immunogenicity to daratumumab is possible, and the incidence of anti-drug antibody generation 
in subjects with SMM may be different from previously studied populations because these subjects 
are expected to be less immune compromised. Therefore, samples to determine the presence of 
antibodies to daratumumab (immunogenicity) will be collected from all subjects during treatment 
and after the last dose in the study according to the Time and Events Schedule. As of 
Amendment 5, refer to Attachment 4 for required assessments.
Rationale for Biomarker Evaluations
MRD assessment:
Minimal Residual Disease (MRD) assessment allows evaluation of the depth of clinical response 
beyond the standard IMWG CR/sCR response category. There are multiple methods to assess 
MRD in MM, including next-generation sequencing (NGS)/PCR of immunoglobulin genes in 
bone marrow or whole blood [Ladetto 2014]9. Several studies have demonstrated that MRD status 
is correlated with PFS and OS in MM [Martinez-Lopez 2014]17. In the present study, we will 
assess for MRD in bone marrow aspirate when samples are obtained at screening, at confirmation 
of CR, and at 12 months and 18 months after first dose for subjects who maintain CR. As of 
Amendment 5, refer to Attachment 4 for required assessments.
DNA and Biomarker Collection:
Biomarker samples will be collected to evaluate the depth of clinical response to daratumumab 
through evaluation of MRD, using DNA sequencing of immunoglobulin genes, and to determine 
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response rates in specific molecular subgroups of MM, using DNA/RNA sequencing of MM cells 
to allow for assessment of genetic modifications such as deletion 17p, t(4;14), t(14;20), t(14;16), 
deletion13, GEP signatures such as UAMS-70, and mutations in p53, BRAF, FGFR, IGH, PI3K, 
or other molecular subtypes associated with disease progression. As of Amendment 5, refer to 
Attachment 4 for required assessments.
Exploratory biomarkers
In previous MM daratumumab studies, NK cell counts were reduced significantly following the 
first dose of daratumumab and maintained at low levels while patients were on therapy. Other 
immune cell populations (T and B cells) were not susceptible to decreases and were maintained at 
levels similar to baseline counts. Given that SMM precedes MM, and MM patients present with 
deficiencies in humoral and cell mediated immune function [Laubach 2011]12, these immune cell 
populations will be examined in SMM patients to determine whether a similar response is seen in 
NK, T, and B cells, and to evaluate the role of immune subpopulations (MDSC, cytotoxic T cells, 
regulatory T cells) in daratumumab response in this premalignant condition. Bone marrow MM 
cells may be evaluated for expression of CD38 expression and complement inhibitor proteins 
(CD46, CD55, CD59) which show association with response in previous clinical studies. 
Circulating MM cells (CMMCs) appear to be associated with response and can potentially serve 
as a prognostic marker for SMM patients who will progress to symptomatic MM. Seventy percent 
of MGUS, SMM and symptomatic MM patients have been reported to present with CMMCs and, 
furthermore, median TTP for patients with increasing CMMCs was significantly decreased 
compared to those who had stable counts [Witzig 1994; Kumar 2005; Ghobrial 2012]26,6,5. In 
addition, CMMCs may be characterized for other assessments, such as RNA profiling, to compare 
to MM cells in the bone marrow niche. As of Amendment 5, refer to Attachment 4 for required 
assessments.
4.
SUBJECT POPULATION
Screening for eligible subjects will be performed within 28 days before randomization.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, Sample 
Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be at least 18 years of age (and satisfying the legal age of consent in the 
jurisdiction in which the study is taking place).
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2.
Diagnosis of SMM for <5 years.
3.
Criterion modified per Amendment INT-2.
3.1.
Diagnosis of intermediate or high-risk SMM.  Potential subject must meet both of the 
following criteria:

Bone marrow plasma cells ≥10% and

At least 1 of the following:

Serum M-protein ≥3 g/dL [except IgA ≥2 g/dL], or

Urine M-protein >500 mg/per 24 hours, or

Abnormal FLC ratio (<0.126 or >8) and serum M-protein <3 g/dL but >1 g/dL, 
or

The absolute involved serum free light chain (sFLC) is ≥100 mg/L with
abnormal FLC ratio (<0.126 or >8). 
4.
Subject must have an ECOG performance status score of 0 or 1 (refer to Attachment 1)
5.
Subject must have pretreatment clinical laboratory values meeting the following criteria 
during the Screening Phase:
a) absolute neutrophil count (ANC) 1.0 x 109/L (ie, ≥1000/µL);
b) platelet count 75 x 109/L (not permissible to transfuse a subject to reach this 
level);
c) aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN);
d) alanine aminotransferase (ALT) ≤2.5 x ULN;
e) total bilirubin ≤1.5 x ULN, except in subjects with congenital bilirubinemia, 
such as Gilbert syndrome (in which case direct bilirubin ≤1.5 x ULN required).
6.
Criterion modified per Amendment INT-2.
6.1.
Women of childbearing potential must commit to either abstain continuously from 
heterosexual sexual intercourse or to use 2 methods of reliable birth control 
simultaneously. This includes one highly effective form of contraception (tubal ligation, 
intrauterine device [IUD], hormonal [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 prior to dosing and continue until 4 months after the last dose 
of daratumumab. Reliable contraception is indicated even where there has been a 
history of infertility, unless due to hysterectomy or bilateral oophorectomy. During the 
study and for 4 months after receiving the last dose of daratumumab, a woman must 
agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
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7.
A woman of childbearing potential must have a negative serum or urine pregnancy test 
within 14 days prior to randomization. 
8.
A man who is sexually active with a woman of childbearing potential must agree to 
always use condom during sexual intercourse, and all men must also not donate sperm 
during the study and for 4 months after receiving the last dose of study drug.
9.
Each subject (or their legally acceptable representative) must sign an informed consent 
form (ICF) indicating that he or she understands the purpose of and procedures required 
for the study and are willing to participate in the study. Subject must be willing and able 
to adhere to the prohibitions and restrictions specified in this protocol, as referenced in 
the ICF.
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study. 
1.
Active MM, requiring treatment, defined by any of the following:
1.
Bone lesions (one or more osteolytic lesions on skeletal radiography, computed 
tomography (CT), or positron-emission tomography [PET]-CT)
3.
Hypercalcemia (serum calcium >0.25 mmol/L (>1 mg/dL) higher than ULN or 
>2.75 mmol/L (>11 mg/dL)
2.
Renal insufficiency (see Section 9.2.1.4; preferably determined by creatinine 
clearance <40 mL/min measured or estimated using validated equations [MDRD 
or CKD-EP formulae recommended], or serum creatinine >177 µmol/L 
[>2 mg/dL])
3.
Anemia, defined as hemoglobin <10 g/dL and/or >2 g/dL below LLN in the 
absence of transfusion support or concurrent treatment with erythropoietin 
stimulating agents (ESAs)
4.
Clonal bone marrow plasma cell percentage ≥60%
5.
Serum free light chain involved:uninvolved ratio ≥100
6.
More than 1 focal lesion by magnetic resonance imaging (MRI)
2.
Primary systemic AL (immunoglobulin light chain) amyloidosis
3.
Criterion modified per Amendment INT-2.
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3.1
Prior or concurrent exposure to any of the following: 

To approved or investigational treatments for SMM or/and MM (including but not 
limited to conventional chemotherapies, immunomodulatory drugs (IMiDs), or 
proteasome inhibitors).

To daratumumab or other anti CD-38 therapies 

To concurrent treatment with corticosteroids with a dose >10 mg prednisone per 
day or equivalent. 

To concurrent treatment with bone-protecting agents (eg, bisphosphonates, 
denosumab) for treatment of SMM or MM. The subjects who are on a stable dose 
of these medications for a nonmalignant condition are allowed in the study.   

Received an investigational drug (including investigational vaccines) or used an 
invasive investigational medical device within 4 weeks before Cycle 1, Day 1
4.
Subject has a history of malignancy (other than SMM) within 3 years before the date of 
randomization, except for the following if treated and not active: basal cell or 
nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, ductal 
carcinoma in situ of breast, or International Federation of Gynecology and Obstetrics 
(FIGO) Stage 1 carcinoma of the cervix.
5.
a)
Subject has known chronic obstructive pulmonary disease (COPD) with a Forced 
Expiratory Volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 
testing is required for patients suspected of having COPD and subjects must be 
excluded if FEV1 <50% of predicted normal.
b)
Subject has known moderate or severe persistent asthma within the past 2 years 
(see Attachment 2), or currently has uncontrolled asthma of any classification. 
(Note that subjects who currently have controlled intermittent asthma or controlled 
mild persistent asthma are allowed in the study).
6.
Criterion modified per Amendment 4.
6.1 Subject is: 

known to be seropositive for human immunodeficiency virus (HIV).

known to have a history of hepatitis C.

seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen 
[HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative 
but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies 
to hepatitis B surface antigen [anti-HBs]) must be tested 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 (antiHBs 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.
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For subjects who enter extension treatment period, HBV serology (HBsAg, 
anti-HBs, and anti-HBc) testing is to be performed locally prior to re-initiation. 
HBV serology is not required at re-initiation if this was performed as part of 
standard of care within 3 months prior to the re-initiation or the start of extension 
treatment is within 3 months of last daratumumab dose.
7.
Subject has any concurrent medical or psychiatric condition or disease (eg, autoimmune 
disease, active systemic disease, myelodysplasia) that is likely to interfere with the 
study procedures or results, or that in the opinion of the investigator, would constitute 
a hazard for participating in this study.
8.
Subject has clinically significant cardiac disease, including significant ischemic 
coronary disease, congestive heart failure (New York Heart Association [NYHA] 
Class III or IV), unstable arrhythmias, myocardial infarction or unstable angina within 
6 months before randomization, a history of additional risk factors for torsades de 
pointes (eg, electrolyte abnormalities, family history of Long QT Syndrome), or a 
family history of sudden cardiac death before age 40.
9.
Screening QT interval as corrected by Fridericia’s formula (QTcF) >470 msec.
10.
Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies 
or human proteins, or their excipients (refer to Daratumumab IB), or known sensitivity 
to mammalian-derived products.
11.
Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration
12.
Subject is known or suspected of not being able to comply with the study protocol 
(eg, because of alcoholism, drug dependency, or psychological disorder). Subject has 
any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the subject (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments. Subject is taking any prohibited 
medications as per Section 8.2
13.
Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant 
while enrolled in this study within 4 months after the last dose of daratumumab. Or, 
subject is a man who plans to father a child while enrolled in this study within 4 months 
after the last dose of daratumumab.
14.
For subjects in the QTc substudy, screening 12-lead ECG based on a central laboratory 
reading showing any of the following:

QTcF >470 msec, based on the mean of 3 tracings

QRS interval of ≥110 milliseconds, based on the mean of 3 tracings
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
PR interval ≥200 milliseconds, based on the mean of 3 tracings

Pulse rate <45b pm or >90 bpm
15.
Criterion modified per Amendment INT-2.
15.1
For subjects in the QTc substudy, the following additional exclusion criteria apply:

Skin condition likely to interfere with ECG electrode placement, breast 
implant, or thoracic surgery likely to cause abnormality in electrical 
conduction

Received medications with a known or possible risk of torsades de pointes 
(see https://www.crediblemeds.org) within 4 weeks prior to ECG screening 
day
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
Section 17.4, describes the required documentation to support meeting the enrollment criteria. 
Subjects who fail to meet the inclusion and exclusion criteria (ie, screen failures) may be 
rescreened once if their condition changes. Rescreening must be discussed with and approved by 
the sponsor on a case-by-case basis. Subjects who are determined to be eligible for rescreening 
must sign a new ICF and will then be assigned a new screening number.
5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Eligible subjects will be stratified based on the number of risk factors for progression to 
symptomatic MM (<2 vs ≥2) using the criteria of Dispenzieri (2013)3. These risk factors will
include: abnormal FLC ratio (<0.126 or >8), serum M-protein ≥3 g/dL, IgA subtype, urine 
M-protein >500 mg/24 hours, and immunoparesis (at least 1 uninvolved immunoglobulin [IgG, 
IgA, IgM] decreased more than 25% below lower limit of normal [LLN]).  Stratification factors 
will be based on central laboratory analyses.
Subjects will then be randomized to treatment in a 1:1:1 ratio to either Treatment Arm A, 
Treatment Arm B, or Treatment Arm C. The method of randomization is randomly permuted 
blocks. An interactive web-based randomization system (IWRS) will be used. Each subject will 
be assigned a unique subject number.
Blinding
As this is an open study, blinding procedures are not applicable.
6.
DOSAGE AND ADMINISTRATION
Daratumumab is to be administered as described in Table 3. Each cycle is 8 weeks in length. The 
start of each cycle may occur ±5 days of the scheduled day in order to accommodate the schedule 
of the site or subject. The start of each cycle should be scheduled relative to Cycle 1 Day 1 and 
should not change if visits have shifted within the allowed window. Subjects will continue to 
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receive daratumumab according to Table 3 until completion of the planned number of cycles. 
Reasons for early discontinuation of treatment are listed in Section 10.3.
For subjects in Arm A (long intense) and Arm B (intermediate), there is a possibility to extend 
treatment with IV daratumumab (Q8W) after the end of Cycle 20 if, as per investigator discretion, 
there is a positive benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, and at least 
stable disease has been achieved. In the case of subjects who already completed EOT and end of 
Cycle 20 occurred <6 months, these subjects can also continue receiving IV daratumumab 
administrations every 8 weeks. As of Amendment 5, subjects continuing in the Treatment 
Extension Phase may switch to daratumumab 1800 mg SC Q8W at the discretion of the 
investigator. Subjects with a known allergy/intolerance to sorbitol will not be eligible to switch to 
daratumumab SC.
A schematic of study treatment administration is provided in Figure 3. For subjects still receiving 
doses in the Treatment Extension Phase as of Amendment 5, daratumumab 16 mg/kg IV may be 
switched to daratumumab 1800 mg SC at the discretion of the investigator on the same dosing 
(Q8W) schedule.
Figure 3:
Schematic Overview of Study Treatment Administration
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6.1.
Daratumumab Preparation
Daratumumab doses will be prepared on the day of the planned administration. Detailed 
instructions for preparation and administration of daratumumab will be supplied in the Site 
Investigational Product Procedures Manual (SIPPM), Investigational Product Preparation 
Instructions (IPPI), or equivalent document.
6.2.
Daratumumab IV Administration
Daratumumab (16 mg/kg) will be administered by IV infusion to subjects (1) in Arm A once every 
week in Cycle 1, every other week in Cycle 2 and Cycle 3, every 4 weeks in Cycle 4 to Cycle 7, 
and from Cycle 8 to Cycle 20 on Day 1 of each cycle; (2) in Arm B once every week in Cycle 1, 
and then on Day 1 of each cycle from Cycle 2 to Cycle 20; or (3) in Arm C once every week in 
Cycle 1 only. This schedule is presented schematically in Figure 3. As of Amendment 5, IV 
daratumumab infusion rates have been redefined with added flexibility and may be shortened to a 
90-minute infusion for subjects without a history of an infusion-related reaction after the third 
dose, at the discretion of the investigator. More information is provided in the SIPPM.    
For subjects in Arm A (long intense) and Arm B (intermediate), in case treatment will be extended 
after cycle 20, study drug will be given at the same frequency as during Cycles 8-20, which is at 
Day 1 of each cycle (Q8W). If a subject has already discontinued study drug and EOT took place 
<6 months, treatment can be re-initiated if, as per investigator’s discretion, there is a positive 
benefit/risk ratio and at least stable disease has been achieved at the time of EOT without any 
evidence of disease progression at the time of re-initiation of the treatment. The assessment of
disease progression will be based on the last disease evaluation performed. If the last disease 
evaluation was performed ≥5 months prior to the time of treatment re-initiation, disease evaluation 
is to be performed to make sure that the subject has not progressed. Every case of treatment re-
initiation is to be discussed with the medical monitor prior to re-initiation. 
If EOT took place ≥3 months but <6 months before re-initiation, the same instructions on infusion 
rates are applicable as per the SIPPM, meaning that slower infusion rates are to be applied during 
the first infusion, with acceleration during the subsequent infusions to avoid the occurrence of IRR.
Each subject’s dose will be calculated based on the subject’s weight rounded to the nearest 
kilogram. There is no cap on the absolute dose allowed, as long as the dose does not exceed 
16 mg/kg. If a subject’s weight changes by more than 10% from baseline, the dose of daratumumab 
will be re-calculated. For further information on daratumumab administration, please refer to the 
SIPPM. Subjects will receive pre-dose medications and post-dose medications as outlined in 
Section 6.4. Every effort should be made to keep subjects on the planned dosing schedule.
As noted in Table 3, vital signs should be monitored extensively on Cycle 1 Day 1 before, during, 
and after the first administration of daratumumab. For all other administrations, vital signs should 
be measured immediately before the start of administration and at the end of the administration. If 
a subject experiences any significant medical event, then the investigator should assess whether 
the subject should stay overnight for observation. 
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6.3.
Daratumumab SC Administration 
If the investigator decides to allow a switch from daratumumab IV to daratumumab SC 
administration, daratumumab SC will be administered by SC injection at a fixed dose of 1800 mg 
once Q8W until documented progression, unacceptable toxicity, or study end. Doses will be 
administered by manual push over 3-5 minutes in the abdominal SC tissue, rotating between the 
four quadrants. The volume of the SC solution will be 15 mL for the 1800 mg dose. Refer to the 
IPPI for additional guidance on SC administration of daratumumab SC. 
The dose of daratumumab will remain constant throughout the study. For subjects who initially 
received daratumumab IV and then switch to daratumumab SC following Amendment 5, it is 
recommended subjects are observed for a period of time deemed appropriate by the investigator 
following the first daratumumab SC dose and, if necessary, after subsequent injections. Reasons 
for continued observation on subsequent daratumumab administrations may include, but are not 
limited to the following: subjects with a higher risk of respiratory complications (eg, subjects with 
mild asthma or subjects with COPD who have an FEV1 <80% at screening or developed FEV1 
<80% during the study without any medical history), subjects with IRR with prior administrations 
of study drug, or subjects with a decreased condition on day of dosing compared to prior dosing 
day.
Subjects with a known allergy/intolerance to sorbitol will not be eligible to switch to daratumumab 
SC.
6.4.
Guidelines for Prevention of Infusion Reactions
6.4.1.
Pre-dose Medication 
Pre-dose medications for subjects receiving daratumumab will be administered as described in 
Attachment 4. On daratumumab administration days (IV or SC), subjects will receive the 
following medications prior to dosing:

Paracetamol (acetaminophen) 650-1000 mg IV or orally (PO) approximately 1 hour prior to 
daratumumab dose

An H1-antihistamine (diphenhydramine 25-50 mg IV, PO, cetirizine 10 mg PO, or equivalent) 
approximately 1 hour prior to daratumumab dose

Approximately 1 hour prior to daratumumab dose, methylprednisolone IV or PO 100 mg for 
the first 2 doses, 60 mg for all subsequent doses (in the absence of infusion-related AEs in the 
first 2 doses). An equivalent intermediate-acting or a long-acting corticosteroid may substitute 
[see Attachment 3 for conversion table]. IV administration is preferred, but oral steroids may 
be substituted.

Montelukast 10 mg approximately 1 hour prior to daratumumab dose; use is optional per 
investigator discretion.
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6.4.2.
Post-dose Medication
For the prevention of delayed IRRs, all subjects will receive long- or intermediate-acting 
corticosteroid orally (20 mg methylprednisolone or equivalent in accordance with local standards) 
on the 2 days following daratumumab doses in Cycle 1 (beginning the day after the 
administration). In the absence of infusion-related AEs after Cycle 1, post-dose corticosteroids 
will be administered per investigator discretion. For subjects previously treated with daratumumab 
IV who switch to daratumumab SC, post-dose medications may be offered in conjunction with the 
first and subsequent dose of daratumumab SC, per investigator discretion, or as required due to an 
IRR experienced previously in the study during Cycle 1.  
For subjects with higher risk of respiratory complications (ie, subjects who have a FEV1 <80% or 
subjects with asthma), the following post-dose medications are recommended:

H1-antihistamine (diphenhydramine, cetirizine, or equivalent) on the 2 days following all 
daratumumab administrations (beginning the day after the administration)

Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 

Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salbutamol ± inhaled corticosteroids for subjects with COPD)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
administration. If subjects are hospitalized, then their FEV1 should be measured before discharge. 
If these subjects are not hospitalized, then a follow up telephone call should be made to monitor 
their condition within 48 hours after all administrations. If the subject has not experienced a 
significant medical event but is hospitalized overnight only for observation, then the 
hospitalization should not be reported as a SAE. Investigators may prescribe bronchodilators, 
H1-antihistamines, and corticosteroids that are deemed necessary to provide adequate supportive 
care in the event a bronchospasm occurs after subjects are released from the hospital/clinic. If, 
after 4 full doses, an at-risk subject experiences no major IRRs, then post-dose medications (except 
Cycle 1 corticosteroids) may be stopped at the investigator’s discretion.
6.4.3.
Management of Infusion-related Reactions
Infusion-related reactions are systemic reactions related to daratumumab administration (IV or 
SC). Subjects should be carefully observed during daratumumab administrations. Trained study 
staff at the clinic should be prepared to intervene in case of any infusion reactions occurring, and 
resources necessary for resuscitation (eg, agents such as epinephrine and aerosolized 
bronchodilator, also medical equipment such as oxygen tanks, tracheostomy equipment, and a 
defibrillator) must be available at the bedside. Attention to staffing should be considered when 
multiple subjects will be dosed at the same time. 
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If an IRR develops during daratumumab administration, then the administration should be paused. 
Subjects who experience AEs during the daratumumab administration must be treated according 
to the investigator’s judgment and best clinical practice. The following guidelines may apply:

Subjects should be treated with acetaminophen, H1-antihistamine, or corticosteroids. 
Intravenous saline may be indicated. For bronchospasm, urticaria, or dyspnea, subjects may 
require H1-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. 
For subjects treated with daratumumab IV, if an infusion is paused, then a longer-than-anticipated 
infusion time may occur. Overnight stays at the hospital because of slow infusion times should not 
be reported as an SAE. However, if the underlying cause of the delayed infusion time is an AE or 
SAE, then that should be reported as such.
6.4.3.1.
Infusion-Related Events of Grade 1 or Grade 2
If the investigator assesses a Grade 1 or 2 AE to be related to daratumumab, then the daratumumab 
administration should be paused. When the subject’s condition is stable, the daratumumab 
administration may be restarted at the investigator’s discretion. For subjects receiving 
daratumumab IV, upon restart, the infusion rate should be half of that used before the interruption. 
Subsequently, the infusion rate may be increased at the investigator’s discretion. 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from the onset, then the subject must be withdrawn from treatment.
6.4.3.2.
Infusion-Related Reactions of Grade 3 or Higher
For infusion-related AEs that are Grade 4, daratumumab should be stopped and treatment with 
daratumumab will be discontinued for that subject.
For infusion-related AEs that are Grade 3, the daratumumab administration must be stopped, and 
the subject must be observed carefully until the resolution of the AE or until the intensity of the 
event decreases to Grade 1, at which point daratumumab may be restarted at the investigator’s 
discretion. For subjects treated with daratumumab IV, upon restart, the infusion rate should be half 
of that used before the interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion.
If the intensity of the AE returns to Grade 3 after restart of daratumumab, then the procedure 
described in this section may be repeated at the investigator’s discretion. Should the intensity of 
the AE increase to Grade 3 for a third time, then treatment with daratumumab will be discontinued 
for that subject.
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6.4.3.3.
Injection-Site Reactions 
In clinical studies, SC administration of daratumumab was associated with local injection site 
reactions, such as induration and erythema, in some subjects. The reactions usually resolved within 
60 minutes. Local injection-site reactions should be managed per institutional standards.
6.5.
Dose Delays
Dose modification of daratumumab is not permitted, but dose delay is the primary method for 
managing daratumumab-related toxicities. 
6.5.1.
Daratumumab Toxicity Management
Refer to Section 6.4 for details on management of IRRs. If any of the following criteria are met, 
the daratumumab administration must be held to allow for recovery from toxicity. The criteria for 
a dose delay are:

Grade 4 hematologic toxicities

Grade 3 thrombocytopenia with bleeding

Febrile neutropenia

Neutropenia with infection, of any grade

Grade 3 or higher nonhematologic toxicities with the following exceptions: 

Grade 3 nausea that responds to antiemetic treatment within 7 days

Grade 3 vomiting that responds to antiemetic treatment within 7 days

Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days

Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab

Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
6.5.2.
Daratumumab Delays
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully 
recovered. 
If 2 consecutive planned doses of daratumumab are missed (also in case of treatment extension or 
treatment re-initiation), this should be brought to the attention of the Sponsor at the earliest possible 
time; subject continuation can occur if agreed by the Sponsor. 
If more than 2 consecutive planned doses of daratumumab are missed (also in case of treatment 
extension or treatment re-initiation) due to daratumumab-related AEs, treatment should be 
permanently discontinued. 
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If a dose delay occurs, then PK and pharmacodynamic assessments should be performed on the 
actual administration day of daratumumab, not on the original scheduled administration day.
7.
TREATMENT COMPLIANCE
Study drug (daratumumab) will be administered by qualified site staff, and the details of each 
administration will be recorded in the electronic case report form (eCRF). Additional details are 
provided in the SIPPM or equivalent document.
8.
CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 8.2. 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 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 post-dose systemic reactions, 
bisphosphonates, and any anticancer therapy (including radiation). Concomitant medications to 
manage AEs and SAEs will be recorded as per Section 12.3.1.
8.1.
Permitted Therapies
Supportive management for infections is strongly recommended, including vaccination with 
pneumococcal vaccine before beginning treatment with daratumumab. Management of IRRs is 
also recommended, as discussed in Section 6.4. Other symptoms may be managed according to 
institutional guidelines provided medications that could potentially prolong the QT interval are not 
administered (see Section 8.2).
Vaccination is allowed per local guidelines (see Section 8.2 for Prohibited Therapies).
8.2.
Prohibited Therapies
For subjects in the QTc substudy, medications with known or possible risk of torsades de pointes 
(see https://www.crediblemeds.org) are prohibited during Cycle 1. Use of such medications may 
result in the subject becoming unevaluable for the assessment of potential effects of daratumumab 
on QT. 
Use of the treatments listed below is prohibited during the study:

Administration of approved or investigational treatments for SMM or/and MM (including but 
not limited to conventional chemotherapies, immunomodulatory drugs (IMiDs), or 
proteasome inhibitors).
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
Other agents that target CD38
Administration of live attenuated and replication-competent viral vector vaccines are prohibited.
8.3.
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 9.5.2.
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should 
be interrupted until the infection is adequately controlled. If the benefits outweigh the risks, study 
treatment may be resumed with concomitant antiviral prophylaxis as per local standard of care. 
Consult a liver disease specialist as clinically indicated.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule (Table 1) summarizes the frequency and timing of efficacy, PK, 
immunogenicity, biomarker, and safety measurements applicable to this study. As of 
Amendment 5, refer to Attachment 4 for a description of study procedures for subjects who 
continue in the Treatment Extension Phase or who have discontinued treatment but remain in 
Follow-up.
Blood collections for PK assessments should be kept as close to the specified time as possible. 
Other measurements may be done earlier than specified timepoints if needed. Actual dates and 
times of assessments will be recorded in the source documentation.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
The maximum blood volume for the study is estimated at approximately 25 mL during screening 
and 340 mL during the first year. In the Follow-up Phase, subjects prior to PD will continue to 
have approximately 20 mL blood drawn every 2 months for serum disease evaluations. This 
includes laboratory assessments associated with safety, efficacy, and PK evaluations, as well as 
scientific research samples. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
9.1.2.
Screening Phase
The signed ICF must be obtained before any study-specific procedures are performed. The 
Screening Phase begins when the first protocol specified screening assessment is performed 
(typically signing of the ICF). During the Screening Phase, eligibility criteria will be reviewed and 
a complete clinical evaluation will be performed as specified in Table 1. Screening procedures will 
be performed within 28 days before randomization; however, chest x-rays and 12-lead ECGs 
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performed up to 42 days before randomization and imaging (skeletal radiography, low-dose CT, 
or MRI) and bone marrow aspirate/biopsy performed up to 56 days before randomization as 
routine standard of care for the subject’s disease can be used. 
Eligibility of the subject is based on central laboratory results of screening serum and urine 
M-protein measurements.
9.1.3.
Treatment Phase
Details of the procedures performed during the Treatment Phase (including treatment extension or 
treatment re-initiation) are outlined in Table 1. As of Amendment 5, refer to Attachment 4 for a 
description of study procedures for subjects who continue in the Treatment Extension Phase or 
who have discontinued treatment but remain in Follow-up. Subjects should start study treatment 
within 5 days after randomization. A window of ±5 days is allowed for visits to the clinic. The 
start of each cycle should be scheduled relative to Cycle 1 Day 1 and should not change if visits 
have shifted within the allowed window. Subjects will be closely monitored for AEs, laboratory 
abnormalities, and clinical response. Clinical evaluations and laboratory studies may be repeated 
more frequently, if clinically indicated. If disease progression is diagnosed, then the subject will 
discontinue study treatment, complete the End-of-Treatment Visit, and enter the Follow-up Phase.
For subjects in Arm A (long intense) and Arm B (intermediate), there is a possibility to extend 
treatment with IV daratumumab (Q8W) after the end of Cycle 20 if, as per investigator discretion, 
there is a positive benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, and at least 
stable disease has been achieved. In the case of subjects who already completed EOT and end of 
Cycle 20 occurred <6 months, these subjects can also continue receiving IV daratumumab 
administrations every 8 weeks. For subjects continuing in the Treatment Extension Phase as of 
Amendment 5, daratumumab 16 mg/kg IV may be switched to daratumumab 1800 mg SC at the 
discretion of the investigator at the same dosing (Q8W) schedule. Subjects with a known 
allergy/intolerance to sorbitol will not be eligible to switch to daratumumab SC.
End of Treatment Visits
Unless a subject withdraws consent for study participation or is lost to follow up, an 
End-of-Treatment Visit is to occur at 28 days ± 7 days after the last dose of all study treatments. 
Every effort should be made to conduct the End-of-Treatment Visit before the subject starts 
subsequent treatment. If a subject is unable to return to the site for the End-of-Treatment Visit, 
then the subject should be contacted to collect information on AEs and concomitant medications 
that occur up to 30 days after the last dose of study treatment. Additional information on reporting 
of AEs is presented in Section 12. Due to the addition of the treatment extension outlined in 
Amendment 4 which allowed some subjects to resume daratumumab treatment if within 6 months 
of last dose of Cycle 20, it is possible for subjects to have 2 EOT visits associated with this study. 
As of Amendment 5, this additional EOT visit associated with treatment extension should be 
conducted as specified in Attachment 4. 
As such, 2 EOT visit CRFs should be completed as applicable for subjects who continued to 
treatment extension (End of Treatment CRF and End of Treatment Extension CRF).  
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9.1.4.
Follow-up Phase
The Follow-up Phase will begin once subjects complete the planned number of cycles, and no 
treatment extension will be given as per investigator’s discretion. In case of treatment extension 
or treatment re-initiation, the same procedures are to be followed as outlined in Section 9.1.3 and 
Table 1 (as of Amendment 5, refer to Attachment 4). If included in the treatment extension, it is 
possible that subjects will have 2 Follow-up Phase portions of the study (1 after the planned 
20 cycles, and 1 after the last dose in the treatment extension). As of Amendment 5, these 
additional protocol-specified Follow-up assessments should be conducted as specified in 
Attachment 4.
Reasons for premature discontinuation of study treatment are listed in Section 10.3. Subjects who 
discontinue before disease progression must continue to have disease evaluations at Week 5, 
Week 9, and then every 8 weeks for the first year, thereafter every 16 weeks according to the 
Table 1 (as of Amendment 5, refer to Attachment 4) until confirmed PD, death, the start of a new 
anticancer therapy, withdrawal of consent, lost to follow-up, or the end of the study. If subjects 
have not progressed to symptomatic MM, no other treatment for SMM or MM is allowed during 
the study. After progressive disease, follow-up for subsequent multiple myeloma therapy 
(including the response to the first subsequent multiple myeloma therapy), second primary 
malignancies, and survival status will be obtained at least every 6 months.
If the information is obtained via telephone contact, written documentation of the communication 
must be available for review in the source documents. If the subject has died, the date and cause 
of death will be collected and documented in the eCRF. 
The end of the study will occur up to approximately 7 years after the last subject’s first dose, 
following a decision by the sponsor to end the study based on data from the smoldering multiple 
myeloma Phase 3 study (SMM3001), or for reasons outlined in Section 17.9.2, whichever occurs 
first. 
9.2.
Efficacy
As of Amendment 5, refer to Attachment 4 for a description of study procedures for subjects who 
continue in the Treatment Extension Phase or who have discontinued treatment but remain in 
Follow-up. Disease assessments will be performed at Week 5, Week 9, and then every 8 weeks in 
the first year, thereafter every 16 weeks (including treatment extension/re-initiation phase) until 
disease progression. A window of ±7 days before the scheduled assessment date is allowed. For 
subjects with treatment delays, disease assessments should be performed at the time of 
daratumumab administration, but do not need to be repeated if they were performed within 14 days 
before the actual treatment date. Disease progression, if based on laboratory results only, must be 
confirmed by a consecutive assessment.
Disease assessments will be performed by a central laboratory (unless otherwise specified) 
according to Table 1. Disease progression to symptomatic MM will be evaluated using the IMWG 
criteria (Rajkumar 2014)21. For subjects who discontinue study drug before disease progression,
disease assessments should continue to be performed as scheduled until disease progression, death, 
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withdrawal of consent for study participation, or the end of the study. Disease assessments 
scheduled for treatment days should be collected before study drug is administered.
9.2.1.
Evaluations
As of Amendment 5, refer to Attachment 4 for a description of study procedures for subjects who 
continue in the Treatment Extension Phase or who have discontinued treatment but remain in 
Follow-up. The text that follows in the subsections of 9.2.1 describes the evaluations required prior 
to Amendment 5.
9.2.1.1.
Assessment of Response
Disease evaluations must be performed as outlined in the Time and Events Schedules on the 
scheduled assessment day (±7 days). Disease evaluations scheduled for treatment days should be 
collected before study drug is administered. Disease evaluations will be performed by a central 
laboratory (unless otherwise specified).
This study will use the IMWG consensus recommendations for MM treatment response criteria 
(Durie 2007; Rajkumar 2011)4,22 presented in Table 4. For quantitative immunoglobulin at
baseline, M-protein, and immunofixation measurements in serum and 24-hour urine, the 
investigator will use results provided by the central laboratory.
Table 4:
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

<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%
Stable disease 
(SD)

Not meeting criteria for CR, VGPR, PR, or symptomatic MM
FLC = free light chain; PC = plasma cell
All response categories (CR, sCR, VGPR, PR) require 2 consecutive assessments made at any time before the institution of 
any new therapy and 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.
*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.
a Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio 
reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.
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9.2.1.2.
Assessment of Disease Progression to Multiple Myeloma
For data analysis and reporting, the sponsor will use a computer algorithm to objectively and 
consistently implement the IMWG diagnostic criteria for MM requiring systemic therapy. During 
the study, disease progression will be measured according to the published international uniform 
diagnostic criteria for MM requiring systemic therapy established by the IMWG 
(Rajkumar 2014)21 presented in Table 5.
Table 5:
Diagnostic Criteria for Multiple Myeloma Requiring Systemic Therapy
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytomaa PLUS 1 or more of the 
following:

Calcium elevation (>0.25 mmol/L [>1 mg/dL] higher than ULN or >2.75 mmol/L [>11 mg/dL])

Renal insufficiency (creatinine clearanceb <40mL/min or serum creatinine >177 µmol/L [>2 mg/dL])

Anemia (hemoglobin <10 g/dL [<6.5 mmol/L] or >2 g/dL [>1.25 mmol/L] lower than LLN

Bone disease (one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc)

Clonal bone marrow plasma cell percentagea ≥60%

Involved: uninvolved serum free light chain ratiod ≥100

>1 focal lesione on MRI studies
a.
Clonality should be established by showing /light-chain restriction on flow cytometry, immunohistochemistry, or 
immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; 
in case of a disparity between the aspirate and the core biopsy, the highest value should be used.
b.
Measured or estimated by validated equations.
c.
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.
These values are based on the serum Freelite assay (The Binding Site Group, Birmingham UK). The involved free light 
chain must be ≥100mg/L.
e.
Each focal lesion must be 5mm or more in size.
From Rajkumar 201421
Progressive disease must be documented consistently across clinical study sites using the same 
criteria. Disease progression based on 1 of the laboratory tests alone must be confirmed by at least 
1 repeat investigation. It is important that instances of progression be reported to the sponsor as 
soon as possible.
9.2.1.3.
Free Light Chain Ratio
In a subset of subjects, daratumumab disproportionally decreases the uninvolved light chain, thus 
artificially skewing the FLC ratio. The artificially elevated FLC ratios have led to ambiguous cases 
in interpretation of disease progression. In cases where the subject’s disease progresses solely 
based on FLC criteria, if the subject continues to benefit from the study treatment based on 
investigator assessment, the subject is allowed to continue the study treatment if agreed by the 
sponsor. The investigator or designee must consult with the subject and discuss the considerations 
for recommending continuation of study treatment. The agreement of the subject to continue 
treatment with daratumumab must be documented in the medical record. Disease evaluations must 
continue at a frequency of at least every 8 weeks.
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9.2.1.4.
CRAB Criteria-Related Laboratory Assessments
The following laboratory tests must be performed at every disease assessment, including during 
the follow-up period, whenever disease assessments are required:

Serum calcium corrected for albumin (central lab)

Creatinine clearance or serum creatinine (local lab)

Hemoglobin (local lab)
Serum Calcium Corrected for Albumin
Development of hypercalcemia (according to CRAB criteria; corrected serum calcium >11 mg/dL 
or >2.75 mmol/L) indicates progression to symptomatic MM if it is not attributable to any other 
cause (see 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.
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])
Measurement of free ionized calcium is an acceptable alternative to corrected serum calcium for 
determining hypercalcemia. Free ionized calcium levels >1.5 mmol/L are considered to be 
hypercalcemic (according to CRAB criteria) for this study. Calcium and albumin will be analyzed 
centrally.
Creatinine Clearance
Development of renal insufficiency (according to CRAB criteria: measured or estimated creatinine 
clearance <40 mL/min using validated equations preferred; or creatinine >2 mg/dL or 
>177 μmol/L) indicates progression to symptomatic MM if it is not attributable to any other cause. 
Measured or estimated glomerular filtration rates (according to the modification of diet in renal 
disease [MDRD, Levey 2006]13 or chronic kidney disease epidemiology collaboration
[CKD-EPI, Levey 2009]14
formulae, as per local practice) are preferred over a 
fixed 
serum 
creatinine 
concentration. 
For 
online 
calculators, 
please 
go 
to
https://www.kidney.org/professionals/KDOQI/gfr_calculator. Creatinine clearance or serum 
creatinine will be analyzed locally as part of the safety laboratory evaluations during treatment. 
For subjects who discontinue treatment prior to PD, these measurements should continue to be 
analyzed locally every time disease assessments are performed.
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Hemoglobin
Development of anemia (according to CRAB criteria; hemoglobin <10 g/dL or >2 g/dL lower than 
LLN) indicates progression to symptomatic MM if it is not attributable to any other cause. Before 
PD is declared on the basis of anemia without other CRAB signs or symptoms, additional 
diagnostic tests should be carried out to determine that there is no other underlying cause of 
anemia. Hemoglobin will be analyzed locally as part of the safety laboratory evaluations during 
treatment. For subjects who discontinue treatment prior to PD, these measurements should 
continue to be analyzed locally every time disease assessments are performed.
9.2.1.5.
Myeloma Protein Measurements in Serum and Urine
Blood and 24-hour urine samples for M-protein measurements will be sent to and analyzed by a 
central laboratory. Only 1 serum and one 24-hour urine sample per time point are required by the 
central laboratory to perform the following tests.

Serum quantitative immunoglobulins (QIgs)

All subjects will be evaluated for IgG, IgA, IgM, IgE, and IgD at Screening. During 
treatment, subjects with IgD or IgE disease will be evaluated for IgG, IgA, IgM, IgE, and 
IgD and subjects with IgG, IgA, or IgM disease will be evaluated for IgG, IgA, and IgM.

Serum M-protein quantitation by electrophoresis (SPEP)

Serum immunofixation at Screening and thereafter when a CR is suspected or maintained. If 
daratumumab interference is suspected based on SPEP and IFE results, additional reflex IFE 
testing may be performed.

Serum free light chain assay

24-hour urine M-protein quantitation by electrophoresis (UPEP)

Urine immunofixation at Screening and thereafter when a CR is suspected or maintained.
Blood and 24-hour urine samples will be collected as specified in Table 1 until the development 
of confirmed disease progression. In subjects with baseline UPEP result below the level of 
quantification, UPEP analysis will be repeated only (1) at the time of disease progression and (2) to 
confirm a CR.  Serum/urine immunofixation assays will be performed at screening, and at other 
times if considered helpful in the interpretation of SPEP and UPEP results.
Daratumumab, as an immunoglobulin, may interfere with clinical SPE/IFE assessments. In cases 
where daratumumab interference is suspected, a reflex assay (DIRA: Daratumumab-specific 
Interference Reflex Assay) confirming the presence of daratumumab will be performed. In cases 
where CR or sCR is suspected and DIRA confirms that daratumumab is present on SPE/IFE, 
additional clinical assessments will be triggered to confirm the CR/sCR. A subject who meets all 
other clinical criteria for CR/sCR, and who has daratumumab interference confirmed by the reflex 
assay, will be considered a CR/sCR.
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9.2.1.6.
β2-microglobulin
Blood samples for β2 microglobulin analysis are to be collected at Screening and upon disease 
progression, and will be analyzed by the central laboratory.
9.2.1.7.
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
Disease characterization (morphology and 
either immunohistochemistry, 
immunofluorescence, or flow cytometry). 
Cytogenetics by conventional karyotype or 
FISH.
MRD and molecular subtyping: a portion of bone 
marrow aspirates collected at screening will be sent to a 
central laboratory.
If a fresh bone marrow aspirate will not be performed at 
screening because a sample is available within 56 days 
prior to randomization, then unstained, non-decalcified 
diagnostic tissue [bone marrow aspirate slides, touch 
prep from biopsy (rolled biopsy) slides, or clot specimen 
slides] must be collected for MRD assessment.
CR, sCR
For response confirmation, additional bone 
marrow aspirates or biopsies (or both) will 
be performed locally 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.
MRD: a portion of bone marrow aspirates collected 
during these timepoints will be sent to a central 
laboratory.
Maintained CR, 
sCR
Not applicable.
MRD: For subjects who maintain CR, an additional 
bone marrow aspirate will be obtained 12 and 18 months 
(+/-1 month) after first dose and sent to central 
laboratory.
Disease 
Progression
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; FFPE=formalin-fixed paraffin embedded; FISH=fluorescence in situ hybridization; MRD=minimal 
residual disease; sCR=stringent complete response
A portion of the bone marrow aspirate at baseline and at disease progression when feasible will be 
utilized for DNA/RNA sequencing to characterize subjects (t(4;14), del17p, t(14;16), UAMS70, 
etc) and to evaluate potential mechanisms of resistance (CD38 mutations, expression of CD38 and 
CD59).
9.2.1.8.
Assessment of Bone Lesions
The presence of bone lesions will be evaluated locally per local imaging practice (eg, complete 
skeletal survey including skull, entire vertebral column, pelvis, chest, humeri, femora, and any 
other bones for which the investigator suspects involvement by disease radiography). During the 
Treatment Phase and before disease progression is confirmed, imaging should be performed as 
indicated in the Time and Event Schedule, to document response or progression.
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Skeletal radiography or low-dose whole body CT 
Osteolytic lesions will be assessed by radiography, low-dose whole body CT scan, or PET-CT. 
Bone lesion assessments will be performed at Screening and regularly during the study as indicated 
in the Time and Events Schedule. The same methodology should be used throughout the study for 
comparison purposes. 
For subjects with (1) negative MRI results at baseline, (2) M-protein increase ≤25%, and (3) no 
other signs of clinical progression, only an MRI needs to be performed. For these subjects, 
low-dose whole body CT or skeletal survey does not need to be repeated unless focal lesions have 
been identified by MRI.
MRI
An MRI (spine and pelvis or whole body) will be performed to assess focal lesions at Screening, 
every 6 months for the first 3 years, and then yearly, and at biochemical progression (eg, increase 
of SPEP >25%) or at suspected PD. Whole body MRI should be performed per local practice or if 
clinically indicated. PET-CT can be used as an alternative imaging test to replace MRI.
Disease Progression
Sometimes subjects present with disease progression manifested by symptoms of pain or vertebral 
compression fractures due to bone changes. Therefore, disease progression may be documented, 
in these cases, by additional images such as CT or PET-CT to clarify if the changes are related to 
myeloma. One or more sites of osteolytic bone destruction (≥ 5 mm in size) seen on CT (including 
low-dose whole-body CT) or PET-CT does fulfil the criteria for bone lesion in MM and should be
regarded as meeting the CRAB requirement irrespective of whether they can be visualized on 
skeletal radiography or not. Increased uptake on PET-CT alone is not adequate for the diagnosis 
of osteolytic bone lesion; evidence of underlying osteolytic bone destruction is needed on the CT 
portion of the examination. However, PET-CT can be used as alternative imaging test to replace 
MRI for identification of focal lesions. If the diagnosis of disease progression is obvious by 
imaging investigations (skeletal radiography, low-dose whole-body CT, PET CT, or MRI), then 
no repeat confirmatory imaging is necessary. In instances where changes may be more subtle, 
repeat imaging may be performed in 1 to 3 months per investigator discretion.
9.2.1.9.
Best Response to First Subsequent Anti-myeloma Therapy
Best response to first subsequent anti-myeloma therapy will be assessed by physician report at 
6-month intervals. IMWG response criteria for MM will be used for these assessments. 
9.2.2.
Endpoints 
9.2.2.1.
Primary Endpoint
There are two co-primary endpoints:

Complete Response (CR) rate, defined as the proportion of subjects with a CR, as defined in 
Section 9.2.1.1
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
PD/Death rate, defined as the proportion of subjects that have progressed to MM or died per 
patient-year (number of events (PD or death)/total follow-up for all subjects).
9.2.2.2.
Major Secondary Endpoints

Minimal residual disease negative rate

Time to next treatment defined as, the time from the date of randomization to the date of the 
first subsequent MM treatment

Overall Response Rate defined as CR+PR rate

PFS, defined as the time from the date of randomization to the date of initial documented PD 
according to the CRAB criteria, myeloma defining events, or date of death, whichever occurs 
first. For subjects who are progression-free and are alive at the time of data cutoff for an 
analysis, PFS will be censored at their last disease assessments on or before initiation of 
subsequent anti-MM therapy, lost to follow-up, or withdrawal of consent if any of them 
occurred, or last disease assessments if none of them occurred. PFS will be censored at the 
date of randomization if there is no postbaseline disease evaluation recorded.

Incidence of symptomatic MM with adverse prognostic features, which include International 
Staging System (ISS) Stage III (based on β2-microglobulin and albumin) and adverse 
cytogenetic characteristics

Response to first subsequent MM treatment

Overall survival rate 
9.2.2.3.
Exploratory Endpoints
Exploratory endpoints include:

To explore biomarkers predictive of response to daratumumab

To evaluate the utility of CMMCs to predict SMM progression to MM
9.3.
Pharmacokinetics and Immunogenicity
As of Amendment 5, samples for the evaluation of PK and immunogenicity described below in 
the subsections of 9.3 will not be collected. Refer to Attachment 4 for a description of study 
procedures for subjects who continue in the Treatment Extension Phase or who have discontinued 
treatment but remain in Follow-up.
9.3.1.
Evaluations
Samples to assess both the serum concentration (PK) of daratumumab and the generation of 
antibodies to daratumumab (immunogenicity) will be obtained from all subjects according to 
Table 1. At specified timepoints, venous blood samples (5 mL per sample) will be collected to 
determine serum concentration of daratumumab and the serum will be divided into 3 aliquots 
(1 aliquot for PK analysis, 1 aliquot for antibodies to daratumumab analysis [when appropriate], 
and 1 aliquot as a backup). Samples collected for determining serum concentrations of 
daratumumab in this study may be retained to address questions about drug characteristics that 
may arise at a later time point. 
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The exact dates and times of blood sampling must be recorded. Refer to the Laboratory Manual or 
equivalent document for sample collection requirements. Collected samples must be stored under 
the specified and controlled conditions for the temperatures indicated in the laboratory manual.
9.3.2.
Analytical Procedures
Serum samples will be analyzed to determine concentrations of daratumumab or generation of 
antibodies to daratumumab using validated immunoassay methods by or under the supervision of 
the sponsor’s bioanalytical facility. 
For the 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.
9.3.3.
Pharmacokinetic Parameters
The PK parameters are defined as:
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
For daratumumab, the PK evaluations include Cmin and Cmax. If sufficient data are available, other 
PK parameters may be calculated. The Cmax will be determined based on visual inspection of the 
serum concentration profile. If there are sufficient data, population PK analysis of serum 
concentration-time data of daratumumab may be performed using nonlinear mixed-effects 
modeling and used to estimate the CL and V. If the population PK analysis is conducted it will 
include data from other clinical studies. Details will be provided in a population PK analysis plan 
and results of the analysis will be presented in a separate report.
9.3.4.
Immunogenicity Assessments
Serum from venous blood samples collected from all subjects will be assessed for the generation 
of antibodies to daratumumab (immunogenicity) according to Table 1. Daratumumab 
concentration is also evaluated at all immunogenicity time points to ensure appropriate 
interpretation of immunogenicity data. When both serum concentration and immunogenicity 
analyses are specified, they are performed on aliquots from the same blood draw and no additional 
sampling is required. Procedures for sample collection, preparation, identification, storage, and 
shipment will be provided in the Laboratory Manual or equivalent document.  
A blood sample should be drawn, if possible, for determination of antibodies to daratumumab any 
time an infusion reaction is observed or reported during the study. Daratumumab serum 
concentration will also be determined from the same infusion reaction sample for the purpose of 
interpreting immunogenicity data. These samples will be stored and evaluated if deemed 
necessary. If the infusion reaction results in treatment discontinuation, then subjects should 
undergo all scheduled safety and efficacy evaluations. Samples collected for the analysis of 
daratumumab immunogenicity/serum concentration may additionally be used to evaluate safety or 
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efficacy aspects that address concerns arising during or after the study period or for the evaluation 
of relevant biomarkers by the sponsor or sponsor’s designee.
9.4.
Biomarkers
As of Amendment 5, samples for the evaluation of biomarkers described below will not be 
collected. Refer to Attachment 4 for a description of study procedures for subjects who continue 
in the Treatment Extension Phase or who have discontinued treatment but remain in Follow-up.
Biomarker assessments will focus on 4 main objectives including evaluating the ability of 
daratumumab to reduce MRD in SMM subjects who achieve a complete response, to determine 
the clinical benefit (ORR, PFS, and OS) of daratumumab in subjects with genetic modifications, 
to evaluate the immunophenotype of SMM patients for potential immune cell contributions to 
daratumumab response, and to evaluate the contribution of CMMCs to progression of disease. All 
biomarker assessments will be performed centrally. 
Bone marrow aspirates will be collected at screening and following treatment as outlined in the 
Time and Events Schedule. Baseline bone marrow aspirates will be subjected to DNA sequencing 
in order to establish the myeloma clone for MRD monitoring. A fresh bone marrow aspirate at 
Screening is required if at all possible, for MRD assessment. If bone marrow aspirate is not 
available, unstained, non-decalcified diagnostic tissue [bone marrow aspirate slides, touch prep 
from biopsy (rolled biopsy) slides, or clot specimen slides] must be supplied for MRD assessment 
instead. For subjects who achieve a CR or sCR, additional bone marrow aspirate will be utilized 
for assessment of MRD by next-generation sequencing (NGS) of immunoglobulin heavy and light 
chains (Vij 2014)24. For subjects who maintain a CR, MRD will also be assessed at 12 and
18 months after first dose in bone marrow aspirate. If this methodology is unavailable, or 
determined to be scientifically inferior, then alternative methods for MRD assessment may be 
utilized. In cases where daratumumab is suspected of interfering with serum IFE and preventing 
clinical CR response calls, subjects with VGPR may also be evaluated for MRD by NGS. 
In addition to MRD evaluations, bone marrow aspirates will be utilized for whole exome 
DNA/RNA sequencing in subjects with genetic modifications (t(4;14), t(14;16), del17p, 
UAMS-70, etc) and to monitor for potential predictive biomarkers of response and/or resistance, 
including changes in CD38 and CD59 expression. In addition, changes in expression patterns of 
genes associated with ADCC, CDC, or other mechanisms of action of daratumumab may be 
evaluated. 
A whole blood sample will be drawn at time points indicated in the Time and Events Table 1 to 
evaluate immune cell populations by flow cytometry and/or CyTOF, and to reserve plasma for 
potential proteomic evaluations. These samples may be used to evaluate specific subsets of 
immune cells such as cytotoxic T cells, regulatory T cells, MDSCs, B cells, and NK cells. Cells 
may also be used for additional phenotypic and functional profiling. Proteomic analysis may also 
be used to evaluate changes in cytokines, complement proteins, soluble CD38, IFNγ, granzyme, 
perforin, and other proteins associated with ADCC/CDC/ADCP and to evaluate potential 
biomarkers of response and resistance.  
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Additional whole blood samples will be drawn to evaluate patients for CMMCs when feasible. 
Use of the CellSearch® or other adequate CTC discovery platforms may be used to enumerate 
circulating cells and subsequently conduct phenotypic and/or genotypic analysis. As of 
Amendment 4, these samples will no longer be collected.
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and may 
be deferred or not performed if during or at the end of the study it becomes clear that the analysis 
will have no scientific value, or if there are not enough samples or not enough responders to allow 
for adequate biomarker evaluation. In the event the study is terminated early or shows poor clinical 
efficacy, completion of biomarker assessments is based on justification and intended utility of the 
data. Samples for biomarker evaluations will be collected as specified in the Time and Events 
Schedule.
9.5.
Safety Evaluations
9.5.1.
Electrocardiogram (ECG) 
For subjects not participating in the QTc evaluation substudy, a 12-lead ECG will be performed at 
screening, Cycle 1 dose 8, and at End-of-Treatment.
QTc Evaluation Substudy
For subjects participating in the QTc evaluation substudy, the QTc endpoint will be the change in 
QTc interval (at each measured timepoint) from time matched baseline, where baseline is the QTc 
measurement before any administration of daratumumab.
For the first 30 subjects eligible for the QTc substudy at sites participating in the QTc evaluation 
substudy, 12-lead ECGs will be obtained at the following timepoints (see Time and Events 
Schedule for allowable windows):

Screening (one day from the range Day -14 to Day -1):  1:00 PM, 2:00 PM, 3:00 PM, 4:00 PM, 
5:00 PM

Cycle 1, Dose 1:  pre-dose and after the end of infusion

Cycle 1, Dose 8:  pre-dose, after the end of infusion, and 1 hour after the end of infusion
ECGs must be performed with the subject in the same comfortable supine resting position for at 
least 10 minutes before the ECG tracings. Pre-dose ECGs will be obtained in the time period 
following administration of preinfusion medications but before the daratumumab infusion. The 
12 lead ECGs will be done in triplicate (three 10 second digital ECGs within 5 minutes). It is 
important to note that the actual test time should be consistent with a timepoint for both the 
screening and on-study ECGs, to minimize variability in the results obtained. Similarly, for 
subjects participating in ECG data collection, daratumumab infusions should be administered 
beginning at approximately the same time of day for Doses 1 and 8 in Cycle 1. 
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Vital signs, ECGs, and PK samples must be collected according to the timepoints and windows 
specified in Table 2. On days when triplicate ECGs are scheduled, pre-dose assessments should 
be performed in the following order:
1.
Administer preinfusion medications.
2.
Measure vital signs.
3.
Obtain triplicate ECGs.
4.
Draw blood samples for PK.
5.
Administer daratumumab infusion.
Twelve-lead ECGs will be recorded at a paper speed of 25 mm per second until 4 regular 
consecutive complexes are available. Computer-generated interpretations of ECGs should be 
reviewed for data integrity and reasonableness by the treating physician. All digital ECG tracings 
will be sent to a third-party central ECG laboratory for measurement of intervals, diagnostics of 
abnormalities and review of ECG waveform morphology. For the triplicate ECGs collected at each 
time point, the mean of 3 measurements for each ECG parameter will be considered for all listing 
and statistical analyses. Refer to the ECG Manual for details.
9.5.2.
Other Safety Evaluations
Safety will be measured by adverse events, laboratory test results, ECGs, vital sign measurements, 
physical examination findings, and assessment of ECOG performance status score. All toxicities 
will be graded according to the NCI-CTCAE Version 4. 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. A QTc substudy 
will be conducted in a subpopulation of subjects at selected sites.
Based on the previous human experience with daratumumab, in vitro studies, and animal 
toxicological findings, IRRs/allergic reactions, infection, hemolysis, and thrombocytopenia will 
be closely monitored. As a biologic agent, immunogenicity also will be monitored. Any of the 
safety monitoring assessments may be performed more frequently, and AEs should be evaluated 
by the investigator according to the standard practice, if clinically indicated.
Adverse Events
Adverse events (with the exception of progression of MM) will be reported by the subject (or, 
when appropriate, by a caregiver, surrogate, or the subject's legally acceptable representative) for 
the duration of the study. Adverse events will be followed by the investigator as specified in 
Section 12, Adverse Event Reporting.
Clinical Laboratory Tests 
As of Amendment 5, refer to Attachment 4 for a description of study procedures for subjects who 
continue in the Treatment Extension Phase or who have discontinued treatment but remain in 
Follow-up. 
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Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF. The laboratory reports must be filed 
with the source documents.
The tests below will be performed by the local laboratory unless otherwise noted.

Hematology Panel
-hemoglobin
-white blood cell (WBC) count with absolute 
neutrophils and lymphocytes
-platelet count

Serum Chemistry Panel
-uric acid
-aspartate aminotransferase (AST)
-total bilirubin a
-alanine aminotransferase (ALT)
-creatinine b
-alkaline phosphatase
-blood urea nitrogen (BUN)
-lactate dehydrogenase (LDH)
At Screening and during Cycle 1 only, before the second through eighth infusions of 
daratumumab 
-potassium
-calcium
-sodium
-magnesium
a.
direct bilirubin if Gilbert’s disease
b. calculate creatinine clearance; please refer to Section 9.2.1.4.
HBV serology
For subjects who enter extension treatment period, HBV serology (HBsAg, anti-HBs, and 
anti-HBc) testing is to be performed locally prior to re-initiation. HBV serology is not required at 
re-initiation if this was performed as part of standard of care within 3 months prior to the 
re-initiation or the start of extension treatment is within 3 months of last daratumumab dose. For 
subjects with evidence of positive HBV serology, monitor for clinical and laboratory signs of HBV 
reactivation during treatment (Q12W), and for at least 6 months (Q12W) following the end of 
study treatment.
HBV DNA test
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by 
PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the 
only serologic marker) and a known history of prior HBV vaccination do not need to be tested for 
HBV DNA by PCR. During and following study treatment, subjects who have history of HBV 
infection will be closely monitored for clinical and laboratory signs of reactivation of HBV as 
specified in the Time and Events Schedule (Table 1). Where required by local law, the results of 
HBV testing may be reported to the local health authorities.
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Serum or urine pregnancy testing
For women of childbearing potential only, serum or urine pregnancy test at screening and as 
clinically indicated.
Calcium and albumin adjusted calcium:
These parameters will be part of the efficacy evaluations as specified in Section 9.2.1.4 and will 
be analyzed by the central laboratory. Measurement of calcium and albumin should follow the 
schedule for disease assessments.
Hemoglobin and creatinine
These parameters will be part of the efficacy evaluations as specified in Section 9.2.1.4 and will 
be analyzed by the local laboratory. At screening and during treatment, these parameters are part 
of the safety laboratory assessments. After end of treatment, subjects who stopped before PD will 
continue to have these parameters evaluated locally with each disease assessment.
β-2 microglobulin
β-2 microglobulin will be assessed at screening and upon disease progression, as part of efficacy 
evaluations. Sample will be analyzed by the central laboratory.
Daratumumab Interference with Indirect Antiglobulin Test (IAT) results 
Daratumumab interferes with the Indirect Antiglobulin Test (IAT), which is a routine 
pre-transfusion test performed to identify a patient’s antibodies to minor antigens so that suitable 
donor blood can be given for transfusion. Daratumumab does not interfere with ABO/RhD typing. 
CD38 is expressed at very low levels on erythrocytes. Daratumumab binds to the CD38 on 
erythrocytes, which results in a positive IAT (Indirect Coombs Test). This positive result masks 
the detection of antibodies to minor antigens and may prevent or delay blood banks from issuing 
donor blood for transfusion. This effect occurs during daratumumab treatment and for up to 
6 months after treatment ends. Subjects will receive a patient identification wallet card for the 
study that includes the blood profile (ABO, Rh, and IAT) determined before the first infusion of 
daratumumab along with information on the IAT interference for healthcare providers/blood 
banks. Subjects are to carry this card throughout the treatment period and for at least 6 months 
after treatment ends. Blood banks can eliminate the daratumumab IAT interference by treating 
reagent RBCs with dithiothreitol (DTT) [Chapuy 2015]1.
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
a)
Providing ABO/RhD compatible, phenotypically or genotypically matched units
b)
Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using 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 IB.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test during screening. Refer to 
Section 6.4.2 for details on subjects with higher risk of respiratory complications
Vital Signs 
Vital signs (pulse, temperature, and blood pressure) will be performed as specified in Table 3. It 
is recommended that blood pressure (sitting) and pulse measurements be preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones). Only vital 
signs associated with an AE will be entered in the eCRF; all measurements will be recorded in the 
source documents.
Physical Examination and ECOG Performance Status
A complete physical examination (including neurological examination) should be performed 
during the Screening Phase. Thereafter, only a symptom and disease directed physical examination 
is required. Height will be measured at screening only; weight will be measured regularly as 
specified in Table 3. Abnormalities will be recorded in the appropriate sections of the eCRF. 
ECOG Performance Status (Attachment 1) will be used to evaluate the impact of the disease status 
on the activities of daily living. When scheduled, ECOG assessments should be obtained prior to 
any other study procedures planned for the same day.
9.6.
Sample Collection and Handling
If blood samples are collected via an indwelling cannula, an appropriate amount (1 mL) of 
serosanguineous fluid slightly greater than the dead space volume of the lock will be removed 
from the cannula and discarded before each blood sample is taken. After blood sample collection, 
the cannula will be flushed with 0.9% sodium chloride, United States Pharmacopeia 
(or equivalent)/sodium heparin of 10 U/mL and charged with a volume equal to the dead space 
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected. 
Refer to the Table 1 for the timing and frequency of all sample collections.
For samples collected from the central laboratory, sample dates and times must be recorded on the 
laboratory requisition form. Further instructions for the collection, handling, storage, and shipment 
of samples are found in the laboratory manual that will be provided. Collection, handling, storage, 
and shipment of samples must be under the specified, and where applicable, controlled temperature 
conditions as indicated in the laboratory manual.
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10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion of Treatment
A subject will be considered to have completed study treatment if he or she has finished all planned 
doses of daratumumab in the treatment arm to which they were randomized. 
For subjects in Arm A (long intense) and Arm B (intermediate), there is a possibility to extend 
treatment with IV daratumumab (Q8W) after the end of Cycle 20 if, as per investigator discretion, 
there is a positive benefit/risk ratio, absence of Grade ≥3 treatment related toxicity, and at least 
stable disease has been achieved. In the case of subjects who already completed EOT and end of 
Cycle 20 occurred <6 months, these subjects can also continue receiving IV daratumumab 
administrations every 8 weeks.
For subjects who are treated in the Treatment Extension Phase as of Amendment 5, daratumumab 
16 mg/kg IV may be switched to daratumumab 1800 mg SC at the discretion of the investigator at 
the same dosing (Q8W) schedule. Subjects with a known allergy/intolerance to sorbitol will not 
be eligible to switch to daratumumab SC.
10.2.
Completion of Study
A subject will be considered to have completed the study if he or she has finished all protocol-
specified procedures before the end of the study, has not been lost to follow up, and has not 
withdrawn consent for study participation before the end of the study.
10.3.
Premature Discontinuation of Study Treatment
If a subject's study treatment must be discontinued before the end of the planned number of cycles 
or during treatment extension/re-initiation, this will not result in automatic withdrawal of the 
subject from the study. After treatment discontinuation, the subject will move into the Follow-
up Phase. The End-of-Treatment Visit should be performed, and Follow-up visit assessments 
should continue as specified in Table 1 (as of Amendment 5, refer to Attachment 4). If study 
treatment is discontinued for a reason other than disease progression, then disease evaluations will 
continue to be performed as specified in Table 1 (as of Amendment 5, refer to Attachment 4).
A subject's study treatment must be discontinued if:

The investigator believes that for safety reasons (eg, AE) it is in the best interest of the subject 
to discontinue study treatment

The subject becomes pregnant 

The subject (or the subject’s legally acceptable representative) withdraws consent for 
administration of study treatment

The subject experiences unacceptable toxicity, including IRRs described in Section 6.4.3

The subject missed more than 2 consecutive planned doses due to daratumumab-related AEs 
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
The subject experiences disease progression (please see below). 
A subject who experiences a second primary malignancy that cannot be treated by surgery alone 
must be withdrawn from the study. However, a subject who develops a malignancy that can be 
cured surgically may continue to receive the assigned study treatment and should continue to be 
followed for subsequent progression of MM.  
Before subjects discontinue study treatment due to disease progression, sites will document 
disease progression (for example by completing a disease progression form or by contacting the 
IWRS) as soon as possible and within 48 hours. The medical monitor will confirm that treatment 
should be discontinued. After confirmation from the sponsor, study treatment will be discontinued 
and the subject entered into Follow-up.
The primary reason for discontinuation of study treatment is to be recorded in the eCRF.
10.4.
Withdrawal from the Study
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent for study participation

Death

The study investigator or Sponsor, for any reason, stops the study or stops the subject’s 
participation in the study
Before a subject is considered lost to follow-up, every reasonable effort must be made by the study 
site personnel to contact the subject and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study treatment assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. If a 
subject withdraws from the study before the end of the Treatment Phase, assessments outlined in 
the End-of-Treatment Visit should be obtained.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for future research (refer to Section 16.2.5). 
In such a case, samples will be destroyed after they are no longer needed for the clinical study. 
Details of the sample retention for research are presented in the main ICF.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the Sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan. 
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11.1.
Subject Information
The main analysis populations are:

ITT population, defined as randomized subjects

Safety population, defined as randomized subjects who received at least 1 dose of study agent
The ITT population will be used to summarize the study population and characteristics and 
efficacy; and the safety population will be used to summarize the safety data.
11.2.
Sample Size Determination
Two hypotheses will be tested:
1.
H0: CR rate ≤ 15% 
Ha: CR rate ≥ 35%
2.
H0: PD/death rate ≥ 0.346/patient-year (median PFS < 24 months)
Ha: PD/death rate ≤ 0.185/patient-year (median PFS > 45 months)
This study will enroll 120 subjects (40/arm) in total. With 40 subjects per arm, each arm will have:

90% power to show that the true CR rate is 35% at a one-sided level of 0.05

80% power to show that the true PD/death rate is 0.185/patient year at a one-sided level of 0.1
If two or more treatment schedules are deemed to be effective, with 40 subjects per arm this study 
would have:

85% probability of identifying the arm with the higher CR

80% probability of identifying the arm with the lower PD/death rate
For the QTc substudy, assuming that the intrasubject standard deviation for change from baseline 
in QTc (ΔQTc) is 20 milliseconds and that the true difference in means is 5 milliseconds, a sample 
size of 25 evaluable subjects (completers) will have 80% power to show that the upper limit of the 
two-sided 90% confidence interval (1 sided upper 95% confidence interval) for the difference in 
mean QTc (ΔQTc) at each timepoint and baseline will be less than 20 milliseconds. To ensure 
25 subjects are evaluable, the QTc substudy will enroll approximately 30 subjects.
11.3.
Efficacy Analyses
The first primary efficacy analysis of CR rate will occur 6 months after the last subject has been 
randomized and will be considered as an interim analysis. The purpose of this analysis is to select 
an appropriate dose and schedule and enable the sponsor’s decision to proceed to Phase 3.
The second primary efficacy analysis of PD/death rate will occur 12 months after the last subject 
has been randomized. The purpose of this analysis is to make a decision to either proceed to 
Phase 3 if at the interim analysis there was not enough evidence to do so or to confirm the decision 
made after the interim analysis to proceed to Phase 3.
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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.
11.3.1.
Primary Efficacy Endpoint
The primary efficacy endpoints are:
1.
CR rate: The number and proportion of subjects who achieve a CR in each arm will be 
summarized. An exact 90% confidence interval and an exact p-value for rejecting the null 
hypothesis that the CR rate is 15% will be calculated.
2.
PD/death rate: The ratio of subjects with an event (PD or death) to the total follow-up for all 
subjects will be summarized. A 90% confidence interval and a p-value for rejecting the null 
hypothesis that the PD/death rate is 0.346 will be calculated.
11.3.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:
1.
Minimal residual disease (MRD) rate: The number and proportion of subjects who have a 
negative MRD will be summarized for each treatment arm. An exact 90% confidence interval 
will also be calculated
2.
Time to next treatment: The median TNT in each treatment arm will be estimated using the 
Kaplan-Meier method. A 90% confidence interval will also be calculated 
3.
Overall Response Rate defined as CR+PR rate: The number and proportion of subjects who 
achieve a CR or PR in each arm will be summarized. An exact 90% confidence interval will 
also be calculated.
4.
PFS: The median PFS in each treatment arm will be estimated using the Kaplan-Meier 
method. A 90% confidence interval will also be calculated
5.
Incidence of symptomatic MM with adverse prognostic features, which include International 
Staging System (ISS) Stage III (based on β2-microglobulin and albumin) and adverse 
cytogenetic characteristics: The number and proportion of subjects with an incidence of 
symptomatic MM with adverse prognostic features will be summarized for each treatment 
arm. An exact 90% confidence interval will also be calculated
6.
Response to first subsequent MM treatment will be summarized descriptively.
7.
Overall survival rate 
11.4.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the PK-evaluable population, defined as subjects 
who have received 1 dose of daratumumab and provided at least one postinfusion sample.
All serum concentrations below the lowest quantifiable concentration in a sample or missing data 
will be labeled as such in the concentration data listings. Concentrations below the lowest 
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quantifiable concentration in a sample 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 timepoint and PK parameters of daratumumab: Cmin and Cmax. Other PK parameters, 
when available, will also be summarized.
If sufficient data are available, population PK analysis of serum concentration-time data of 
daratumumab may be performed and the analysis may include data from other studies. If the 
population PK analysis is conducted, details will be specified in a population PK analysis plan and 
the results of the analysis will be presented in a separate report.
11.5.
Immunogenicity Analyses
The incidence of antibodies to daratumumab will be summarized for all subjects who receive a 
dose of daratumumab and have appropriate samples for detection of antibodies to daratumumab.
11.6.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamic modeling of the relationship between serum concentrations of 
daratumumab and change from baseline in QTc interval will be performed.  If sufficient data are 
available, PK/pharmacodynamic modeling will be performed, including exploring the relationship 
between serum concentrations of daratumumab and endpoints of clinical efficacy and safety. 
Details and results of the analysis will be presented in a separate report.
11.7.
Biomarker Analyses
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
daratumumab. 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 [ANOVA], 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 dose schedule or clinical response. As this is an open-label study without a 
control treatment, statistical analyses will be done to aid in the understanding of the results. 
Results of biomarker and pharmacodynamic analyses may be presented in a separate report. 
Planned analyses are based on the availability of clinically valid assays and may be deferred if 
emerging study data show no likelihood of providing useful scientific information.
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11.8.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). The severity assessment for an AE or 
SAE should be completed using the NCI-CTCAE Version 4. All reported AEs with onset during 
the treatment phase (ie, treatment-emergent AEs, and AEs that have worsened since baseline) will 
be included in the analysis. For each AE, the percentage of subjects who experience at least 
1 occurrence of the given event will be summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those 
subjects who die, who discontinue treatment due to an AE, or who experience a severe or a serious 
AE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and 
for observed values and changes from baseline at each scheduled time point. Changes from 
baseline results will be presented in pre- versus post treatment cross-tabulations (with classes for
below, within, and above normal ranges). Frequency tabulations of the abnormalities will be made. 
A listing of subjects with any laboratory results outside the reference ranges will be provided. A 
listing of subjects with any markedly abnormal laboratory results will also be provided.
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst toxicity grade experienced by the subject during the study will be provided 
as shift tables. Worst toxicity grade during treatment will be presented, according to NCI-CTCAE 
(version 4). Clinically relevant changes (ie, causing a treatment intervention and/or need for 
concomitant therapy) will be also recorded on the AE eCRF. All other lab abnormalities need not 
be recorded as AEs.
Vital Signs
Descriptive statistics of temperature and blood pressure (systolic and diastolic) values and changes 
from baseline will be summarized. The percentage of subjects with values beyond clinically 
important limits will be summarized.
ECG Analysis
QT interval corrected for heart rate using Fridericia’s (QTcF) and Bazett’s (QTcB) formulae will 
be calculated. Descriptive statistics of QTc intervals and changes from baseline will be 
summarized at each scheduled timepoint.  A mixed effects analysis of variance (ANOVA) model 
will be fit with QTc as the dependent variable, scheduled timepoint of measurement as the fixed 
effect, and subject as a random effect.  Using the means and intrasubject variance obtained from 
this model, 2 sided 90% confidence intervals will be calculated for the difference in the mean QTc 
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from baseline at each scheduled timepoint.  An effect on QTc will be ruled out if the upper bound 
of the 90% confidence interval for the difference in means between the postbaseline QTc (at each 
timepoint) and baseline QTc is less than 20 milliseconds.
The proportion of subjects with a post-dose QTc interval >450 milliseconds and >480 milliseconds 
will be summarized, as will the proportion of subjects with QTc interval increases from baseline 
>30 milliseconds or >60 milliseconds. A listing of subjects with a QTc interval >500 milliseconds 
will also be provided.
The proportion of subjects with post-dose PR interval >200 milliseconds, QRS >110 milliseconds, 
and heart rate >100 bpm and <50 bpm will be reported. The proportion of subjects with ST segment 
and T and U wave abnormalities will be reported.
All important abnormalities in ECG waveform that are changes from the baseline readings will be 
reported (eg, changes in T-wave morphology or the occurrence of U waves.
11.9.
Interim Analysis
There will be one interim analysis for efficacy. This analysis will occur 6 months after the last 
subject has been randomized. The purpose of this analysis is to make a decision to go forward into 
Phase 3 based on the analysis of the primary endpoint of CR.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Council on Harmonisation [ICH])
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This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. These should usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal 
relationship between the study treatment and the event (eg, death from anaphylaxis), the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a component 
of the study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For daratumumab, the expectedness of an adverse event will 
be determined by whether or not it is listed within the Reference Safety Information included in 
the Investigator's Brochure. 
Adverse Event Associated with the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
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12.1.2.
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity assessment for an adverse event or serious adverse event should be completed using 
the NCI-CTCAE Version 4.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug. No MTD has been reached for daratumumab. However, if 
the dose for IV subjects exceeds the maximum tested dose of 24 mg/kg, then it will be 
considered as overdose in this study.

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject exposure to the sponsor 
study drug, eg, name confusion)
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Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the adverse event page of the 
eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until 30 days after the last dose of study treatment, 
unless the subject withdraws consent for study participation, or starts subsequent anticancer 
therapy. For subjects who have received subsequent treatment with therapeutic intent for MM 
during the adverse event reporting period, only adverse events that are considered to be possibly, 
probably, or definitely related to daratumumab need to be reported. Serious adverse events, 
including those spontaneously reported to the investigator within 30 days after the last dose of 
study treatment, must be reported using the Adverse Event Form. The sponsor will evaluate any 
safety information that is spontaneously reported by an investigator beyond the time frame 
specified in the protocol.
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition (refer to Section 12.1.1). 
Death should not be recorded as an adverse event or serious adverse event, but as the outcome of 
an adverse event. The adverse event that resulted in the death should be reported as a serious 
adverse event. All events that meet the definition of a serious adverse event will be reported as 
serious adverse events, regardless of whether they are protocol-specific assessments.
All adverse events, regardless of seriousness, severity, or presumed relationship to study treatment, 
must be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to study therapy. All measures required for adverse event 
management must be recorded in the source document and reported according to sponsor 
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB. 
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Subjects (or their designees, if appropriate) will be provided with a "wallet (study) card" and 
instructed to carry this card with them for the duration of the study 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 9.5.2)
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, and 
transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious adverse 
event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not resolved 
upon discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious 
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject's participation in a study must be reported as a serious adverse event, 
except hospitalizations for the following:

If the subject has not experienced a significant medical event but is hospitalized overnight 
only for observation following administration of daratumumab, then the hospitalization 
should not be reported as a serious adverse event.
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
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such 
as pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the study-site personnel within
24 hours of their knowledge of the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital anomaly) are 
considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any subject who becomes pregnant during the study must promptly discontinue further study 
treatment.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from studies are crucial for the protection of subjects, investigators, 
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting 
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
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If the defect is combined with a serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
Daratumumab IV
The daratumumab supplied for IV infusion is a colorless to yellow liquid and sterile concentrate 
of 20 mg/mL in a 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. Refer to the current Investigator's Brochure for a 
list of excipients.
Daratumumab SC
The daratumumab supplied for SC injection is a colorless to yellow liquid and sterile concentrate 
of 120 mg/mL daratumumab + 2000 U/mL rHuPH20 in a 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 current Investigator's Brochure for a list of excipients.
14.2.
Packaging
Daratumumab IV
Daratumumab IV is supplied in glass vials containing daratumumab at a concentration of 20 mg/mL. 
It will be supplied to the site/pharmacy as open-label supply.
Daratumumab SC
Daratumumab 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 µg/mL). It will be supplied to the 
site/pharmacy as open-label supply.
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.
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14.4.
Preparation, Handling, and Storage
Daratumumab IV
Vials 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. Daratumumab IV must not be utilized after 
the expiry date printed on the label. The product must be protected from light and must not be 
frozen. Daratumumab IV does not contain preservatives; therefore, any unused portion remaining 
in the vial must be discarded.
Daratumumab will be diluted in a sterile, pyrogen-free physiological saline solution (0.9% NaCl) 
prior to IV administration. Refer to the IPPI and SIPPM for details regarding dose preparation, 
storage, and handling of diluted solutions.
Daratumumab SC
Daratumumab 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. Daratumumab SC must not be 
utilized after the expiry date printed on the label. Daratumumab 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 and SIPPM for additional guidance on 
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The study drug administered to the subject must be 
documented on the drug accountability form. All study drug will be stored and disposed of 
according to the sponsor's instructions. Study-site personnel must not combine contents of the 
study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug must be available for verification by the sponsor's 
study site monitor during on-site monitoring visits. The return to the sponsor of unused study drug, 
or used returned study drug for destruction, will be documented on the drug return form. When the 
study site is an authorized destruction unit and study drug supplies are destroyed on-site, this must 
also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for drug accountability purposes. 
Study drug should be dispensed under the supervision of the investigator or a qualified member of 
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Study drug may not be relabeled or reassigned for use by other 
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subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site 
other than the study sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure for daratumumab

Site Investigational Product Procedures Manual

Laboratory manual

eCRF completion guidelines

Sample ICF

Subject wallet card indicating blood type and IAT

Other manuals and guidance documents as needed
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
The primary safety profile of daratumumab is consistent with IRRs; see Section 6.4 for prevention 
details. Based on the mode of action of daratumumab, a potential risk could be infection; therefore, 
the protocol requires the review of hematological laboratory results prior to daratumumab 
administration. CD38 is distributed in erythrocytes and platelets. A significant reduction of platelets 
was reported in an animal study. In a human clinical study (Study GEN501), thrombocytopenia was 
also reported. However, safety laboratory monitoring did not show a clinically meaningful reduction 
of platelets. Anemia was also reported in Study GEN501. Free hemoglobin was mildly elevated, but 
other parameters did not support hemolysis. No bleeding events were observed. Routine safety 
laboratory measurement of RBCs and platelets will be closely monitored in this study.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The maximum blood volume for the study is estimated at approximately 25 mL during screening 
and 340 mL during the first year. In the Follow-up Phase, subjects 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.
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16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB 
with current and complete copies of the following documents (as required by local regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries 

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol, 
amendments (if any, excluding the ones that are purely administrative, with no consequences for 
subjects, data or study conduct), the ICF, applicable recruiting materials, and subject compensation 
programs, and the sponsor has received a copy of this approval. This approval letter must be dated 
and must clearly identify the IEC/IRB and the documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct)

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
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
Revisions to compensation for study-related injuries 

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the study 
drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of the 
change(s).
Furthermore, where required, progress reports/written summaries of the trial status will be 
submitted to the IRB/IEC annually, or more frequently if requested.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (if applicable, the notification will be submitted through the head of 
investigational institution). 
16.2.3.
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local 
requirements after the nature of the study has been fully explained. The ICF(s) must be signed 
before performance of any study-related activity. The ICF(s) that is/are used must be approved by 
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and 
understand. The informed consent should be in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and 
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects or their legally acceptable representatives the aims, 
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort 
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 
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disease. Subjects will be told that alternative treatments are available if they refuse to take part and 
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator 
will maintain a subject identification register for the purposes of long-term follow up if needed 
and that their records may be accessed by health authorities and authorized sponsor personnel 
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s) 
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing 
such access, including permission to obtain information about his or her survival status, and agrees 
to allow his or her study physician to recontact the subject for the purpose of obtaining consent for 
additional safety evaluations, if needed, and subsequent disease-related treatments, or to obtain 
information about his or her survival status.
The subject or legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of either the subject's or his or her legally acceptable 
representative's personally dated signature. After having obtained the consent, a copy of the ICF 
must be given to the subject.
If the subject or legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject or legally acceptable representative is obtained.
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.
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Exploratory biomarker/PK/immunogenicity research is not conducted under standards appropriate 
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand daratumumab, to understand MM, 
to understand differential drug responders, and to develop tests/assays related to daratumumab and 
MM. 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 10.4, Withdrawal from the Study (Withdrawal from the Use 
of Samples in Future Research).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by 
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the 
change(s) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor representative 
(see Contact Information page(s) provided separately). Except in emergency situations, this 
contact should be made before implementing any departure from the protocol. In all cases, contact 
with the sponsor must be made as soon as possible to discuss the situation and agree on an 
appropriate course of action. The data recorded in the eCRF and source documents will reflect any 
departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it.
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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. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data collected 
in the eCRF: subject identification, eligibility, and study identification; study discussion and date 
of signed informed consent; dates of visits; results of safety and efficacy parameters as required 
by the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study treatment administration information; 
and date of study completion and reason for early discontinuation of study treatment or withdrawal 
from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 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.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
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Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure manner 
to the sponsor within the timeframe agreed upon between the sponsor and the study site. The 
electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. Data must be entered into 
eCRFs in English. Study site personnel must complete the eCRF as soon as possible after a subject 
visit, and the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be completed 
by the same individual who made the initial baseline determinations whenever possible. The 
investigator must verify that all data entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized
study-site personnel. If necessary, queries will be generated in the eDC tool. The investigator or 
study-site personnel must adjust the eCRF (if applicable) and complete the query.
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor's 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 eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the study database they 
will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
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investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and study-site 
personnel and are accessible for verification by the sponsor study-site contact. If electronic records 
are maintained at the study site, the method of verification must be discussed with the study-site 
personnel. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be provided 
for review of study-related documents. The monitor will meet with the investigator on a regular 
basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed up to approximately 7 years after the last subject’s first dose, 
following a decision by the sponsor to end the study based on data from the smoldering multiple 
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myeloma Phase 3 study (SMM3001), or for reasons outlined in Section 17.9.2, whichever occurs 
first. The final data from the study site will be sent to the sponsor (or designee) after completion 
of the final subject at that study site in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not 
limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the eCRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible for 
being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 
of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as a 
result of this study, are considered confidential and remain the sole property of the sponsor. The 
investigator agrees to maintain this information in confidence and use this information only to 
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accomplish this study, and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of daratumumab, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any publication 
by the investigator as provided for below) shall be the property of the sponsor as author and owner 
of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data and 
information without approval from the investigator. The investigator has the right to publish study 
site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow for 
filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will 
not mandate modifications to scientific content and does not have the right to suppress information. 
For multicenter study designs and substudy approaches, secondary results generally should not be 
published before the primary endpoints of a study have been published. Similarly, investigators 
will recognize the integrity of a multicenter study by not submitting for publication data derived 
from the individual study site until the combined results from the completed study have been 
submitted for publication, within 12 months of the availability of the final data (tables, listings, 
graphs), or the sponsor confirms there will be no multicenter study publication. Authorship of 
publications resulting from this study will be based on the guidelines on authorship, such as those 
described in the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, which 
state that the named authors must have made a significant contribution to the design of the study 
or analysis and interpretation of the data, provided critical review of the paper, and given final 
approval of the final version.
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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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Attachment 1: ECOG Performance Status Scale
Grade 
ECOG Performance Status 
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% 
of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
Reference:  Oken 198219
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
110
Status: Approved,  Date: 29 March 2021
Attachment 2: Asthma Guidelines
Components of Severity
ClassificationofAsthma 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
onany day
Daily
Several time per day
Interference 
with normal 
activity
None
Minor limitation
Some limitation
Extremely limited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1 
between 
exacerbations
> 80%
> 85%
Normal FEV1 
between 
exacerbations
> 80%
Normal
N/A
> 80%
> 80%
> 80% Normal
N/A
60-80%
75-80%
60-80% 
Reduced
5%
N/A
< 60%
< 75%
< 60% 
Reduced 5%
Risk
Exacerbations 
requiring oral 
systemic 
corticosteroids
0-1/year
≥2 
exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 
year lasting
>1 day and
risk factors
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative annual
risk may be 
related to FEV1.
≥ 2 
exacerbations 
in 6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 
year lasting 
>1 day and
risk factors
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2 
exacerbations
in
6 months 
requiring oral 
steroids or >4 
wheezing 
episodes/1 
year lasting 
>1 day and 
risk factors 
for persistent 
asthma
≥ 2/year
Relative 
annual risk 
may be 
related to 
FEV1.
≥ 2/year
Relative 
annual risk
may be
related
to FEV1.
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category.
Recommended Step for
Initiating Treatment
Step 1
Step 2
Step 3 and 
consider
short course 
of oral 
steroids
Step 3: 
medium
dose ICS
and 
consider
short 
course of
oral 
steroids
Step 3 and 
consider 
short 
course of
oral 
steroids
Step 3 and 
consider 
short course 
of oral 
steroids
Step 3: 
medium
dose ICS
OR Step 4 
and consider 
short course
of oral
steroids
Step 4 or 5 
and consider 
short course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy. 5-11 and 12+ years: adjust therapy
accordingly.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
111
Status: Approved,  Date: 29 March 2021
Components of 
Control
Classification of Asthma Control
Well Controlled
Not Well Controlled
Very Poorly Controlled
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
0-4 yrs
5-11 yrs
12 + yrs
Symptoms
≤ 2 days/week but not more
than once on each day
≤ 2 days/
week
> 2 days/week or multiple times 
on ≤2 days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime awakenings
≤ 1x/month
≤ 2x/month
> 1x/month
≥ 2x/month
1-3x/week
> 1x/week
≥ 2x/week
≥ 4x/week
Interference with normal activity
None
Some limitation
Extremely limited
SABA use for symptom control 
(not prevention of EIB)
≤2 days/week
> 2 days/week
Several times per day
Lung function
FEV1 or peak flow
FEV1/FVC
N/A
> 80%
> 80%
> 80%
N/A
60-80%
75-80%
60-80%
N/A
< 60%
< 75%
< 60%
Validated questionnaires
ATAQ
ACQ
ACT
0
≤ 0.75
≥ 20
1-2
≥ 1.5
16-19
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral 
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung function
Evaluation requires long-term follow-up
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 weeks
• For side 
effects, 
consider 
alternative 
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.
NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
112
Status: Approved,  Date: 29 March 2021
Attachment 3: 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
NCT02316106

NCT02316106

JNJ-54767414  Daratumumab
Clinical Protocol 54767414SMM2001 Amendment 6
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
114
Status: Approved,  Date: 29 March 2021
Attachment 4: Dosing Administration and Required Study Evaluations as of Protocol Amendment 5 for Subjects Remaining in Treatment Extension
or Follow Up (Continued).
Notes
Treatment Extension Phase 
EOT
Follow-up
Other Study Procedures
Hematology
To be performed by local lab and 
reported in the CRF
Prior to every dose of daratumumab: hemoglobin, white blood cell count with absolute
neutrophils and lymphocytes, platelet count.  
X
After completion of study 
treatment, obtain with 
disease assessments until 
PD.
Clinical
Chemistry
Day 1 of each cycle of daratumumab administration: uric acid, total bilirubin,
creatinine, blood urea nitrogen, AST, ALT, ALP, LDH
X
Creatinine only:  
After completion of study 
treatment, obtain with 
disease assessments until 
PD.
Weight
If a subject’s weight changes by
more than 10% from baseline, the
dose of study drug will be re-
calculated for subjects receiving 
daratumumab IV
Day 1 of each cycle of daratumumab IV administration
Vital Signs
Vital signs (blood pressure, 
temperature) measured in sitting
position for subjects receiving 
daratumumab IV
Day 1 of each cycle of daratumumab IV administration immediately before
administration start and at end of each daratumumab administration
The start of each cycle may occur ±5 days of the scheduled day in order to accommodate the schedule of the site or subject. After EOT, subjects in all treatment arms prior to PD will continue 
to return for local disease evaluations per Standard of Care. After PD is documented, subjects will be followed only for survival; subsequent anticancer therapy, and occurrence of other 
malignancies every 6 months.
NCT02316106

NCT02316106

NCT02316106

NCT02316106