A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in Subjects With High-Risk Smoldering Multiple Myeloma
Phase: PHASE3
Conditions: Smoldering Multiple Myeloma
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Approved, Date: 23 September 2024
Janssen Research & Development*
Clinical Protocol
A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active
Monitoring in Subjects with High-risk Smoldering Multiple Myeloma
Protocol 54767414SMM3001; Phase 3
Amendment 6/EEA-1
JNJ-54767414 (daratumumab)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
This study will be conducted at sites in the United States (US) under US Food & Drug
Administration IND regulations (21 CFR Part 312) and at sites in the European Economic Area
(EEA) under Regulation EU No. 2023-507143-11.
EU TRIAL NUMBER: 2023-507143-11
Status: 
Approved
Date: 
23 September 2024
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-ERI-115748607, 12.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT03301220

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Approved, Date: 23 September 2024
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 6
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 7
SYNOPSIS.................................................................................................................................................... 9
TIME AND EVENTS SCHEDULE .............................................................................................................. 11
ABBREVIATIONS...................................................................................................................................... 20
1. 
INTRODUCTION................................................................................................................................ 22
1.1. 
Background.................................................................................................................................... 22
1.2. 
Overall Rationale for the Study...................................................................................................... 26
1.3. 
Benefit-Risk Assessment............................................................................................................... 27
1.3.1. 
Risks Associated with Daratumumab SC................................................................................... 27
1.3.2. 
Benefits for Study Participation .................................................................................................. 28
1.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 28
2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 28
2.1. 
Objectives and Endpoints .............................................................................................................. 28
2.1.1. 
Objectives ................................................................................................................................... 28
2.1.2. 
Endpoints.................................................................................................................................... 29
2.2. 
Hypothesis ..................................................................................................................................... 30
3. 
STUDY DESIGN AND RATIONALE................................................................................................. 30
3.1. 
Overview of Study Design.............................................................................................................. 30
3.2. 
Study Design Rationale.................................................................................................................. 33
4. 
SUBJECT POPULATION.................................................................................................................. 40
4.1. 
Inclusion Criteria ............................................................................................................................ 40
4.2. 
Exclusion Criteria ........................................................................................................................... 41
4.3. 
Prohibitions and Restrictions ......................................................................................................... 45
5. 
TREATMENT ALLOCATION ............................................................................................................ 46
6. 
DOSAGE AND ADMINISTRATION .................................................................................................. 47
6.1. 
Daratumumab ................................................................................................................................ 48
6.2. 
Treatment Schedule and Administration........................................................................................ 48
6.3. 
Guidelines for Prevention and Management of Infusion Reactions............................................... 48
6.3.1. 
Predose Medication.................................................................................................................... 48
6.3.2. 
Postdose Medication .................................................................................................................. 49
6.4. 
Management of Injection-site andInfusion-related Reactions....................................................... 49
6.4.1. 
Local Injection-site Reactions..................................................................................................... 49
6.4.2. 
Infusion-related Reactions.......................................................................................................... 49
6.5. 
Dose Delays and Dose Modification.............................................................................................. 50
6.5.1. 
Dose Modification ....................................................................................................................... 50
6.5.2. 
Toxicity Management.................................................................................................................. 51
6.5.3. 
Interruption or Missed Doses...................................................................................................... 52
7. 
TREATMENT COMPLIANCE............................................................................................................ 52
8. 
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 52
8.1. 
Recommended Therapies.............................................................................................................. 53

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Approved, Date: 23 September 2024
8.2. 
Permitted Therapies....................................................................................................................... 53
8.3. 
Prohibited Therapies...................................................................................................................... 53
8.4. 
Management of Hepatitis B Virus Reactivation ............................................................................. 54
9. 
STUDY EVALUATIONS.................................................................................................................... 54
9.1. 
Study Procedures........................................................................................................................... 54
9.1.1. 
Overview..................................................................................................................................... 54
9.1.2. 
Screening Phase ........................................................................................................................ 54
9.1.3. 
Active Monitoring Phase or Treatment Phase............................................................................ 55
9.1.4. 
Follow-Up Phase ........................................................................................................................ 56
9.2. 
Efficacy Evaluations....................................................................................................................... 56
9.2.1. 
Assessment of Response........................................................................................................... 57
9.2.2. 
Assessment of Disease Progression to Multiple Myeloma......................................................... 58
9.2.3. 
CRAB Criteria-related Laboratory Assessments ........................................................................ 60
9.2.4. 
Myeloma Protein Measurements in Serum and Urine................................................................ 61
9.2.5. 
2-microglobulin and Lactate Dehydrogenase........................................................................... 62
9.2.6. 
Bone Marrow Examination.......................................................................................................... 62
9.2.7. 
Assessment of Bone Disease..................................................................................................... 64
9.2.8. 
Best Response to First-line Multiple Myeloma Treatment.......................................................... 65
9.3. 
Pharmacokinetics and Immunogenicity......................................................................................... 65
Per protocol Amendment 6, no further Pharmacokinetics and Immunogenicity samples will be collected. ............. 65
9.3.1. 
Evaluations ................................................................................................................................. 65
9.3.2. 
Analytical Procedures................................................................................................................. 65
9.3.3. 
Pharmacokinetic Parameters ..................................................................................................... 66
9.3.4. 
Immunogenicity Assessments .................................................................................................... 66
9.4. 
Biomarkers..................................................................................................................................... 66
9.5. 
Patient-reported Outcomes............................................................................................................ 68
9.6. 
Medical Resource Utilization.......................................................................................................... 68
9.7. 
Safety Evaluations ......................................................................................................................... 69
9.8. 
Sample Collection and Handling.................................................................................................... 72
10. SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/ WITHDRAWAL
FROM THE STUDY........................................................................................................................... 73
10.1. 
Completion ..................................................................................................................................... 73
10.2. 
Discontinuation of Active Monitoring (Arm A) or Study Treatment (Arm B)................................... 73
10.3. 
Withdrawal from the Study (Arm A and Arm B) ............................................................................. 74
10.4. 
Withdrawal From the Use of Samples in Future Research............................................................ 74
11. STATISTICAL METHODS................................................................................................................. 75
11.1. 
Subject Information ........................................................................................................................ 75
11.2. 
Sample Size Determination ........................................................................................................... 75
11.3. 
Efficacy Analyses........................................................................................................................... 76
11.3.1. 
Primary Endpoint ........................................................................................................................ 76
11.3.2. 
Secondary Endpoints.................................................................................................................. 76
11.4. 
Pharmacokinetic Analyses............................................................................................................. 77
11.5. 
Immunogenicity Analyses .............................................................................................................. 77
11.6. 
Biomarker Analyses ....................................................................................................................... 78
11.7. 
Pharmacokinetic/Pharmacodynamic Analyses.............................................................................. 78
11.8. 
Patient-reported Outcomes............................................................................................................ 78
11.9. 
Medical Resource Utilization Analyses.......................................................................................... 78
11.10. Safety Analyses ............................................................................................................................. 78
11.11. Interim Analysis.............................................................................................................................. 79
11.12. Data Monitoring Committee ........................................................................................................... 79
12. ADVERSE EVENT REPORTING ...................................................................................................... 80
12.1. 
Definitions ...................................................................................................................................... 80
12.1.1. 
Adverse Event Definitions and Classifications ........................................................................... 80
12.1.2. 
Attribution Definitions.................................................................................................................. 81

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Approved, Date: 23 September 2024
12.1.3. 
Severity Criteria .......................................................................................................................... 82
12.2. 
Special Reporting Situations.......................................................................................................... 82
12.3. 
Procedures..................................................................................................................................... 82
12.3.1. 
All Adverse Events...................................................................................................................... 82
12.3.2. 
Serious Adverse Events ............................................................................................................. 84
12.3.3. 
Pregnancy................................................................................................................................... 85
12.4. 
Contacting Sponsor Regarding Safety........................................................................................... 85
13. PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 85
13.1. 
Procedures..................................................................................................................................... 85
13.2. 
Contacting Sponsor Regarding Product Quality............................................................................ 86
14. STUDY DRUG INFORMATION......................................................................................................... 86
14.1. 
Physical Description of Study Drug................................................................................................ 86
14.2. 
Packaging ...................................................................................................................................... 86
14.3. 
Labeling.......................................................................................................................................... 86
14.4. 
Preparation, Handling, and Storage............................................................................................... 86
14.5. 
Drug Accountability........................................................................................................................ 86
15. STUDY-SPECIFIC MATERIALS....................................................................................................... 87
16. ETHICAL ASPECTS......................................................................................................................... 87
16.1. 
Study-Specific Design Considerations........................................................................................... 87
16.2. 
Regulatory Ethics Compliance....................................................................................................... 88
16.2.1. 
Investigator Responsibilities ....................................................................................................... 88
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................... 89
16.2.3. 
Informed Consent ....................................................................................................................... 90
16.2.4. 
Privacy of Personal Data ............................................................................................................ 91
16.2.5. 
Long-Term Retention of Samples for Additional Future Research ............................................ 92
16.2.6. 
Country/Territory Selection......................................................................................................... 92
17. ADMINISTRATIVE REQUIREMENTS.............................................................................................. 92
17.1. 
Protocol Amendments.................................................................................................................... 92
17.2. 
Regulatory Documentation ............................................................................................................ 93
17.2.1. 
Regulatory Approval/Notification ................................................................................................ 93
17.2.2. 
Required Prestudy Documentation............................................................................................. 93
17.3. 
Subject Identification, Enrollment, andScreening Logs ................................................................ 94
17.4. 
Source Documentation................................................................................................................... 94
17.5. 
Case Report Form Completion ...................................................................................................... 95
17.6. 
Data Quality Assurance/Quality Control ........................................................................................ 95
17.7. 
Record Retention ........................................................................................................................... 96
17.8. 
Monitoring ...................................................................................................................................... 96
17.9. 
Study Completion/Termination....................................................................................................... 97
17.9.1. 
Study Completion/End of Study.................................................................................................. 97
17.9.2. 
Study Termination....................................................................................................................... 97
17.10. On-Site Audits................................................................................................................................ 97
17.11. Use of Information and Publication ................................................................................................ 98
18. COUNTRY/TERRITORY-SPECIFIC REQUIREMENTS................................................................. 100
18.1. 
Requirements for France ............................................................................................................. 100
19. PROTOCOL AMENDMENT HISTORY........................................................................................... 101
REFERENCES.......................................................................................................................................... 116
INVESTIGATOR AGREEMENT............................................................................................................... 134

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Approved, Date: 23 September 2024
LIST OF ATTACHMENTS
Attachment 1: 
ECOG Performance Status Scale............................................................................ 118
Attachment 2: 
Modified Diet in Renal Disease Formula.................................................................. 119
Attachment 3: 
Asthma Guidelines ................................................................................................... 120
Attachment 4: 
Antihistamine Medications........................................................................................ 122
Attachment 5: 
Conversion Table for Glucocorticosteroid Dose....................................................... 123
Attachment 6: 
Serum Calcium Corrected for Albumin..................................................................... 124
Attachment 7: 
Interpretation of the SEBIA Hydrashift 2/4 Daratumumab IFE Interference
test............................................................................................................................ 125
Attachment 8: 
EORTC QLQ-C30..................................................................................................... 126
Attachment 9: 
EORTC QLQ-MY20.................................................................................................. 128
Attachment 10: 
EQ-5D-5L.................................................................................................................. 130
Attachment 11: 
Women of Childbearing Potential............................................................................. 133

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Approved, Date: 23 September 2024
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Active Monitoring (Arm A) and Daratumumab (Arm B): Active Monitoring/Treatment
Phase, End-of-Active Monitoring/End-of-Treatment, Pre-PD Follow-up, and Post-PD
Follow-up .................................................................................................................................. 11
Table 2: 
Daratumumab Administration (Arm B Only) ............................................................................. 18
Table 3: 
Mitigation Strategies for Potential Risks Associated with Daratumumab................................. 28
Table 4: 
Summary of Key Efficacy Endpoints; Response-evaluable Analysis Set
(Study54767414SMM2001)..................................................................................................... 35
Table 5: 
Overview of Treatment-emergent Adverse Events; Safety Analysis Set
(Study54767414SMM2001)..................................................................................................... 36
Table 6: 
Designations of Medicinal Products Used in the Study............................................................ 46
Table 7: 
Daratumumab Administration Schedule for Within Cycle Doses ............................................. 51
Table 8: 
International Uniform Response Criteria Consensus Recommendations ................................ 58
Table 9: 
Diagnostic Criteria for Progression to Multiple Myelomaf......................................................... 59
Table 10: Bone Marrow Testing................................................................................................................ 63
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 33
Figure 2: Biochemical or Diagnostic Progression-free Survival; Intent-to-Treat Analysis Set
(Study54767414SMM2001)..................................................................................................... 35
Figure 3: Schematic Overview of Active Monitoring and Study Treatment Administration...................... 47

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Approved, Date: 23 September 2024
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Country/Territory Affected  
Date
Amendment 6/EEA-1 
All 
9 September 2024
Amendment 5/EEA-1 
All 
14 August 2023
Amendment 5/FRA-2 
France 
14 January 2021
Amendment 5 
All 
14 January 2021
Amendment 4/FRA-2 
France 
22 June 2020
Amendment 4 
All 
22 June 2020
Amendment 3/FRA-2 
France 
12 June 2019
Amendment 3/FRA-1 
France 
31 January 2019
Amendment 3 
All 
25 January 2019
Amendment 2/FRA-1 
France 
14 November 2018
Amendment 2 
All 
19 September 2018
Amendment 1 
All 
30 January 2018
Original Protocol 
All 
19 July 2017
In the description of change column, modified text is presented as follows: text in strikethrough has been
deleted, text in bold has been added.
Amendment 6/EEA-1: the primary analysis concluded when the planned number of PFS events were
achieved andthe study was subsequently unblinded. The overall reason for this amendment is to discontinue
the use of central laboratory assessments and IRC evaluation of progressive disease. Disease evaluations
and confirmation of disease progression will continue, according to the Time and Events Schedule, by local
assessment only.
The changes made to the clinical protocol as part of Protocol Amendment 6 are listed below, including the
rationale of each change and a list of all applicable sections. Changes made in previous protocol
amendments are listed in Section 19: Protocol Amendment History.
Section Number
and Name
Description of Change 
Brief Rationale
Table 1: Time and
Events Schedule
3.1 Overview of Study
Design
9.2 Efficacy Evaluations
9.2.1 Assessment of
Response
Evaluation of disease progression by IRC and validated 
computerized algorithm will be discontinued. Disease 
evaluations will be conducted locally, according to the 
Time and Events Schedule, and disease progression will 
be assessed according to IMWG criteria and reported
when confirmed.
The 
primary 
analysis
concluded when the planned
number of PFS events were
achieved, hence evaluation
of disease progression by
IRC criteria and validated
computerized algorithm is no
longer required.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Approved, Date: 23 September 2024
Table 1: Time and Events 
Schedule
9.2 Efficacy Evaluations 
9.2.3 CRAB Criteria- 
related Laboratory 
Assessments 
9.2.4 Myeloma Protein 
Measurements in Serum 
and Urine 
9.2.5 2-microglobulin 
and Lactate
Dehydrogenase
9.2.6 Bone Marrow
Examination
Assessment of Bone
Disease
9.7 Safety Evaluations
9.5 Patient-reported 
outcomes 
9.6 Medical Resource 
Utilization
Central laboratory testing will be discontinued.
Pre-PD follow up and PD assessments:
Disease evaluations should continue according to
Time & Events Schedule, by local assessment
Only disease progression by investigator via local
assessment will be reported to the Sponsor.
Assessment of response for disease evaluations and
local laboratory and imaging results will not be
reported to the Sponsor.
Post-PD follow-up:
PRO and MRU collection at Months 12 and 18 in the have
been discontinued.
Post primary analysis,
central 
laboratory
testing 
and 
central
imaging are no longer
required.
Post primary analysis,
PRO 
and 
MRU
collection at Months 3
and 6 are considered
sufficient.
Table 1: Time and Events 
Schedule 
9.4 Biomarkers
Table 10
Central Laboratory Biomarker assessments will be
discontinued.
Post primary analysis,
biomarker analyses are
no longer required.
9.3 Pharmacokinetics and 
Immunogenicity  
Immunogenicity and PK assessments will no longer be
collected.
SYNOPSIS
Table 1: Time and 
Events Schedule 
Table 2: Daratumumab
Administration (Arm B
Only)
9.1.1 Overview
9.2 Efficacy Evaluations
9.3.2 Analytical
Procedures
9.4 Biomarkers
9.5 Patient-reported
Outcomes
9.6 Medical Resource
Utilization
Home health care visits have been removed throughout the
protocol.
Home health care visits
are no longer available.
NOTE: 
Tele 
health
visits (conducted via
phone 
or 
video
conference) 
may
continue as deemed
necessary.
11.12 Data Monitoring 
Committee 
The IDMC will be discontinued once the primary analysis
endpoint has been achieved.
IDMC will no longer
be required.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were
made.
Minor errors were
noted.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Approved, Date: 23 September 2024
SYNOPSIS
A Phase 3 Randomized, Multicenter Study of Subcutaneous Daratumumab Versus Active Monitoring in
Subjects with High-risk Smoldering Multiple Myeloma
EU TRIAL NUMBER: 2023-507143-11
BENEFIT-RISK ASSESSMENT
Currently, the standard of care for patients with high-risk smoldering multiple myeloma (SMM) is active
monitoring, and most patients with SMM are not treated until end organ damage and evolution to an
incurable disease occur. Preliminary data show that daratumumab has single agent activity in intermediate-
and high-risk SMM.
Based on the results of nonclinical studies, the mechanism of action, the route of administration, and results
from participants treated in daratumumab studies, the potential safety risks for daratumumab are systemic
administration-related reactions, cytopenia, and infections. Considering the measures taken to minimize
risk to participants of this study, the potential risks associated with daratumumab are justified by the
anticipated benefits that may be afforded to participants with SMM.
OBJECTIVES AND HYPOTHESIS
Primary Objective
To determine whether treatment with daratumumab administered subcutaneously (SC) prolongs
progression-free survival (PFS) compared to active monitoring in subjects with high-risk smoldering
multiple myeloma (SMM)
Secondary Objectives
To demonstrate additional clinical benefit (overall response rate, duration of response, overall survival,
etc) for subjects with high-risk SMM treated with daratumumab compared with active monitoring
To assess the safety profile of daratumumab in subjects with high-risk SMM
To assess the clinical characteristics of symptomatic multiple myeloma (MM) following progression
of disease after therapy with daratumumab
To evaluate the pharmacokinetics and immunogenicity of daratumumab administered SC in subjects
with high-risk SMM
To evaluate the immunogenicity of recombinant human hyaluronidase (rHuPH20) when administered
in combination with daratumumab SC in subjects with high-risk SMM
To evaluate the effect of treatment with daratumumab on health-related quality of life
Exploratory Objectives
To investigate clinical efficacy of daratumumab in high-risk subjects with genetic modifications
(del17p, t(4:14), 1q gain, or other high-risk molecular subtypes)
To explore biomarkers of response or resistance to daratumumab, including immunophenotypes and
expression of MM markers (ie, CD38)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Approved, Date: 23 September 2024
Hypothesis: Daratumumab administered as monotherapy will prolong PFS compared with active
monitoring in subjects with high-risk SMM.
OVERVIEW OF STUDY DESIGN: This is a Phase 3, randomized, open-label, 2-arm, multicenter study
to evaluate the efficacy and safety of daratumumab SC administration versus active monitoring in subjects
with high-risk SMM. Approximately 360 subjects will be assigned randomly to active monitoring (Arm A)
or daratumumab (Arm B) in a 1:1 ratio. Key inclusion criteria include the following: subjects who are ≥18
years of age, have a confirmed diagnosis of high-risk SMM, and an Eastern Cooperative Oncology Group
performance status score of 0 or 1.
For subjects in both study arms for whom there are no safety concerns, tele-health (conducted via phone or
video conference) visits are permitted per the clinical judgement of the investigator, and where feasible and
permissible by local policy and regulations. All assessments should be followed with in person examination,
if clinically indicated. Refer to the Time and Events Schedule (Tables 1 and 2) for guidance.
DOSAGE AND ADMINISTRATION
Subjects randomized to active monitoring will receive no study medication but will undergo the same
disease evaluations and at the same frequency as subjects randomized to daratumumab. Subjects
randomized to daratumumab will receive daratumumab SC (daratumumab 1800 mg + rHuPH20
[2000 U/mL]) once weekly in Cycle 1 and 2, then every 2 weeks for Cycle 3 to Cycle 6, and thereafter
every 4 weeks for up to 39 cycles or 36 months, whichever occurs first. Each cycle will be 28 days. All
doses should be administered at outpatient visits.
EFFICACY EVALUATIONS
Assessment of disease will be conducted in accordance with the International Myeloma Working Group
(IMWG) response criteria. Disease evaluations will include the following: measurements of myeloma
proteins; bone marrow examinations; other imaging studies; and measurements of β2-microglobulin, lactate
dehydrogenase, albumin, hemoglobin, creatinine clearance, and serum calcium corrected for albumin.
OTHER EVALUATIONS
In the daratumumab group, blood samples will be drawn from subjects to characterize the pharmacokinetics
of daratumumab and to assess for the generation of antibodies to daratumumab; additional blood samples
will be assessed for the generation of antibodies to rHuPH20. Blood, bone marrow aspirate, and stool
samples will be used to better understand the mechanism of action of daratumumab and to obtain
information about potential markers of clinical response and resistance.
Safety will be measured by adverse events, physical examination findings, electrocardiogram monitoring,
SC injection site evaluation, clinical laboratory test results (hematology and chemistry), and assessment of
Eastern Cooperative Oncology Group performance status.
STATISTICAL METHODS
Assuming a median PFS for Arm A (active monitoring) of 30 months and that daratumumab treatment will
reduce the risk of the disease progression or death by 37.5% (ie, a hazard ratio of 0.625; median PFS of 48
months for daratumumab), 165 PFS events are needed to achieve a power of 85% to detect this hazard ratio
with a log-rank test (one sided alpha=0.025). With a 24-month accrual period and an additional 24 months
of follow-up, the sample size needed for the study is approximately 360 (180 in active monitoring, 180 in
daratumumab) subjects. There will be one interim analysis for futility. This analysis will occur when
approximately 60% of the PFS events (99) have occurred. This is expected to occur approximately 8 months
after the last subject has been randomized. The purpose of this interim analysis is to evaluate cumulative
interim safety and efficacy data. The non-binding futility boundary at this interim analysis will be
determined using the Kim-Demets power spending function with parameter p=4.0. The beta spent at this
futility analysis will be 0.0194.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Approved, Date: 23 September 2024
Abbreviations to the Time and Events Schedule:
Anti-HBc= antibodies to hepatitis B core antigen; Anti-HBs=antibodies to hepatitis B surface antigen; C=cycle; CR=complete response; CT=computed tomography;
D=day; DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; EORTC=European Organization for Research and Treatment of Cancer;
EQ-5D-5L=European Quality of Life Five Dimensions Questionnaire; FEV1=forced expiratory volume in 1 second; FFPE= formalin-fixed paraffin-embedded;
FISH=fluorescence in situ hybridization; FLC=free light chain; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; ICF=informed consent form;
IFE=immunofixation electrophoresis; LDCT=low-dose whole-body computed tomography; MM=multiple myeloma; PET=positron emission tomography;
PFS2=progression-free survival on first-line treatment for MM; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PD=disease progression;
PRO=patient-reported outcomes; QLQ=quality of life questionnaire; Q12W= every 12 weeks; SIFE=serum immunofixation electrophoresis; SPEP=serum M-protein
quantification by electrophoresis; UIFE=urine immunofixation electrophoresis; UPEP=urine M-protein quantitation by electrophoresis

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
20
Approved, Date: 23 September 2024
ABBREVIATIONS
ADCC  
antibody-dependent cell-mediated cytotoxicity
ALT  
alanine aminotransferase
Anti-HBc 
antibodies to hepatitis B core antigen
Anti-HBs 
antibodies to hepatitis B surface antigen
AST  
aspartate aminotransferase
BMPCs 
bone marrow plasma cells
BOD 
biochemical or diagnostic
CDC  
complement-dependent cytotoxicity
CI 
confidence interval
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration
Cmax  
maximum observed serum concentration
Cmin  
minimum observed serum concentration
COPD  
chronic obstructive pulmonary disease
CR  
complete response
CRAB  
calcium, renal insufficiency, anemia, or bone lesions
CT  
computed tomography
Ctrough
maximum trough concentration
Dara-CF  
daratumumab and recombinant human hyaluronidase for subcutaneous injection:
co-formulated (Dara-SC)
Dara-MD  
daratumumab and recombinant human hyaluronidase for subcutaneous injection: mix and
deliver
DNA  
deoxyribonucleic acid
DTT  
dithiothreitol
ECG  
electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EORTC  
European Organization for Research and Treatment of Cancer
EQ-5D-5L 
European Quality of Life Five Dimensions Questionnaire
FEV1 
forced expiratory volume in 1 second
FFPE 
formalin-fixed paraffin-embedded
FISH  
fluorescence in situ hybridization
FLC  
free light chain
FSH  
follicle stimulating hormone
GCP  
Good Clinical Practice
HBsAg 
hepatitis B surface antigen
HBV  
hepatitis B virus
HR  
hazard ratio
HRQoL 
health-related quality of life
IAT  
indirect antiglobulin test (also known as indirect Coombs test)
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICMJE 
International Committee of Medical Journal Editors
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IgG1ĸ 
immunoglobulin G1 kappa
IMiD  
immunomodulatory agent
IMWG  
International Myeloma Working Group
IPPI 
Investigational Product Preparation Instructions
IRB  
Institutional Review Board
IRC  
Independent Review Committee
IRR  
infusion/injection-related reactions
IV  
intravenous(ly)
IWRS  
interactive web response system
LDCT  
low-dose whole body computed tomography

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
21
Approved, Date: 23 September 2024
mAb 
monoclonal antibody
MDE 
Myeloma Defining Event
MDRD  
Modification of Diet in Renal Disease
MDSC  
myeloid derived suppressor cells
MGUS  
monoclonal gammopathy of undetermined significance
MM  
multiple myeloma
MRD  
minimal residual disease
MRI 
magnetic resonance imaging
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
PCR  
polymerase chain reaction
PD 
progressive disease
PET  
positron-emission tomography
PET-CT  
positron-emission tomography-computed tomography
PFS  
progression-free survival
PFS2 
progression-free survival on first-line treatment for MM
PI 
proteasome inhibitor
PK 
pharmacokinetics
PO 
per os (by mouth; orally)
PQC  
Product Quality Complaint
PR 
partial response
PRO  
patient-reported outcome
QIg 
quantitative immunoglobulin
QLQ  
quality of life questionnaire
RBC  
red blood cell
rHuPH20 
recombinant human hyaluronidase
Rd 
lenalidomide and dexamethasone
RNA  
ribonucleic acid
SAE 
serious adverse event
SAR  
systemic administration-related
SC 
subcutaneous(ly)
sCR  
stringent complete response
SD 
standard deviation
SIFE 
serum immunofixation electrophoresis
SLiM-CRAB  
≥60% bone marrow plasma cells, free light chain involved/uninvolved ratio ≥100, >1 focal
bone lesions on MRI, calcium elevation, renal insufficiency by creatinine clearance, anemia,
or bone disease due to lytic bone lesions
SMM  
smoldering multiple myeloma
SPEP  
serum M-protein quantification by electrophoresis
SUSAR  
suspected unexpected serious adverse reactions
TEAE  
treatment-emergent adverse event
Tmax  
time to maximum serum concentration
UIFE 
urine immunofixation electrophoresis
ULN  
upper limit of normal
UPEP  
urine M-protein quantitation by electrophoresis
US  
United States
VGPR  
very good partial response

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Approved, Date: 23 September 2024
1. 
INTRODUCTION
Daratumumab is a human immunoglobulin G1 kappa (IgG1ĸ) monoclonal antibody (mAb) that
binds CD38 expressing malignant cells with high affinity. In the United States, intravenously (IV)
administered daratumumab is indicated for use as follows: (1) in combination with lenalidomide
and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple
myeloma who have received at least one prior therapy; (2) in combination with pomalidomide and
dexamethasone for the treatment of patients with multiple myeloma who have received at least
two prior therapies including lenalidomide and a proteasome inhibitor (PI); (3) as monotherapy,
for the treatment of patients with multiple myeloma who have received at least 3 prior lines of
therapy including a PI and an immunomodulatory agent (IMiD), or whose disease is refractory to
both a PI and an IMiD. In the European Union, IV administered daratumumab is indicated for use
as follows: (1) as monotherapy for the treatment of adult patients with relapsed and refractory
multiple myeloma, whose prior therapy included a PI and an IMiD and who have demonstrated
disease progression on the last therapy; (2) in combination with lenalidomide and dexamethasone,
or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who
have received at least one prior therapy. For other countries/territories, refer to the daratumumab
label for the approved indication in that country.
For the most comprehensive nonclinical and clinical information regarding daratumumab, refer to
the latest version of the Investigator's Brochure daratumumab. The term "sponsor" used throughout
this document refers to the entities listed in the Contact Information page(s), which will be
provided as a separate document.
1.1. 
Background
Disease Background
Multiple myeloma (MM) is thought to evolve from premalignant, asymptomatic plasma cell
disorders such as (non-immunoglobulin [Ig]M) monoclonal gammopathy of undetermined
significance (MGUS) or smoldering multiple myeloma (SMM), which are characterized by
monoclonal plasma cell proliferation in the bone marrow without end-organ damage (Kyle 200916,
Kyle 201015, Landgren 200917, Weiss 200936). Smoldering multiple myeloma accounts for
approximately 15% of all myeloma patients (Rios-Tamayo 201433). Several models for high-risk
SMM have been proposed (Mateos 201624, Rajkumar 201330). According to these risk models,
subjects with high-risk SMM have an approximate 50% risk of progression to MM within the first
2 years. This is in contrast to the lower risk of progression in the broader SMM population where
it is estimated that 50% of patients will progress to MM within the first 5 years, equivalent to 10%
per year (Rajkumar 201532). These models were developed prior to the update of the International
Myeloma Working Group (IMWG) criteria for the diagnosis of SMM, ie, they included a
population of ultra-high risk SMM patients, who are now considered to have MM. It is estimated
that approximately 40% of all patients with SMM are at high-risk of progression to MM (Mateos
201323). Overall, approximately 50% of all patients with SMM are at high-risk of progression to
MM, and 10% to 15% of those have been reclassified as MM under the 2014 SLiM criteria
(Rajkumar 201532).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
23
Approved, Date: 23 September 2024
There is no approved treatment for patients with SMM. Outside of clinical studies, clinical
management involves monitoring patients for the development of symptomatic disease
(Landgren 201318). Some early studies that investigated treatment for SMM with various
chemotherapy regimens (melphalan-prednisone, thalidomide) or bisphosphonates did not show
consistent clinical benefit (Dispenzieri 20136, Landgren 201318). A recent study (QuiRedex) of
patients with high-risk SMM compared treatment with lenalidomide and dexamethasone (Rd,
n=57) with observation (n=62). Rd treatment was associated with a significant delay in the
progression to symptomatic MM (Mateos 201624). Median time to progression was not reached
with Rd compared with 23 months for observation (hazard ratio [HR] 0.24, p<0.0001). Rd
significantly improved overall survival (OS) (median not reached vs 117.6 months; HR 0.43,
p=0.027) (Mateos 201624). In summary, these data have provided proof of concept that treatment
of patients with SMM may prolong progression-free survival (PFS) and OS.
However, critiques have been put forward. In the QuiRedex study, mandatory evaluation for bone
lesions was not required at baseline. The majority of progression events were related to bone
disease, which raises the question of whether a portion of the subjects met criteria of symptomatic
MM at the time of enrollment. Furthermore, the QuiRedex study was conducted prior to the 2014
update of the IMWG criteria for the diagnosis of MM. The new SLiM criteria include a bone
marrow plasma cell content >60% or a serum (involved:uninvolved) free light chain (FLC) ratio
>100 as well as >1 focal lesion on magnetic resonance imaging (MRI) imaging. This raises concern
about whether data from the QuiRedex study are applicable to a population of patients who meet
the current definition of SMM (Rajkumar 2014).29 Rd is not without toxicities, and is not currently
approved for the treatment of patients with SMM. In summary, a number of limitations of the
QuiRedex study leave room to establish a less toxic treatment regimen for this asymptomatic
patient population.
Nonclinical Studies
Pharmacology
Daratumumab is a human IgG1ĸ mAb that binds with high affinity to a unique epitope on CD38,
a transmembrane glycoprotein. It is a targeted immunotherapy that attacks tumor cells that
overexpress CD38, a transmembrane glycoprotein, in a variety of hematological malignancies
including MM. Daratumumab induces lysis of CD38-expressing tumor cells, including MM tumor
cells that were freshly isolated from patients, by a wide spectrum of mechanisms including
complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity
(ADCC), antibody-dependent cellular phagocytosis, through activation of complement proteins,
natural killer (NK) cells, and macrophages, respectively (de Weers 20115, Overdijk 201528).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Approved, Date: 23 September 2024
Clinical Studies
Daratumumab IV Monotherapy
Efficacy/Safety Studies
Daratumumab monotherapy induces deep and durable responses in subjects with heavily
pretreated MM. Phase 2 Study 54767414MMY2002 (hereafter referred to as MMY2002) and
Phase 1/2 Study GEN501 Part 2 (Part 1 was the dose-escalation phase of this first-in-human study)
are ongoing single-arm, open-label studies in which subjects with relapsed and refractory MM are
administered daratumumab IV as monotherapy weekly for 8 weeks, every 2 weeks for an
additional 16 weeks, and every 4 weeks thereafter until disease progression or unacceptable
toxicity. One hundred forty-eight (148) subjects treated with daratumumab 16 mg/kg administered
IV were included in a combined analysis of efficacy in Study GEN501 and Study MMY2002. The
overall response rate (ORR) for the combined data set was 31.1% (95% confidence interval [CI],
23.7%-39.2%). Responses included 3 subjects with stringent complete response (sCR; 2.0%), 4
subjects with complete response (CR; 2.7%), 13 subjects with very good partial response (VGPR;
8.8%), and 26 subjects with partial response (PR; 17.6%). Within the individual studies, the ORR
was 35.7% (95%CI, 21.6%-52.0%) in Study GEN501 and 29.2% (95% CI, 20.8%-38.9%) in Study
MMY2002. After a median duration offollow-up of 20.7 months, the Kaplan-Meier based median
OS was 20.1 months (Usmani 201634).
Among 156 subjects treated with daratumumab 16 mg/kg IV in Studies GEN501, MMY2002, and
54767414MMY1002 (hereafter referred to as MMY1002) (a single-arm, open-label Phase 1 study
of pharmacokinetics (PK) and safety conducted in Japanese subjects), 6 subjects (4%)
discontinued daratumumab treatment due to a treatment-emergent adverse event (TEAEs). Three
subjects (2%) died due to TEAEs. The most frequently reported TEAEs were fatigue (40%),
nausea and anemia (28% each), back pain (26%), cough (24%), neutropenia (23%), pyrexia (22%),
upper respiratory tract infection (22%), and thrombocytopenia (21%). Serious adverse events were
reported in 33% of subjects; the most frequently reported serious adverse events were pneumonia
(6%), pyrexia, hypercalcemia, and general physical health deterioration (3% each).
In the ongoing Phase 2 study 54767414SMM2001 (hereafter referred to as SMM2001), which
evaluates daratumumab in SMM, single-agent activity in this population has been established in
interim analysis 1 (March 2017). The safety profile of daratumumab in SMM2001 was consistent
with what was observed in Studies GEN501, MMY2002, and MMY1002. For additional details
regarding Study SMM2001, see Section 3.2.
Human Pharmacokinetics and Immunogenicity
Over the dose range from 1 to 24 mg/kg as daratumumab monotherapy or in combination with
other treatments, increases in area-under-the-concentration-time curve were more than
dose-proportional. Clearance decreased with increasing dose and repeated dosing, indicating
target-mediated clearance. The mean (SD) estimated terminal half-life associated with linear
clearance was approximately 18 (±9) days.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Approved, Date: 23 September 2024
Of the 199 subjects in Studies GEN501 and MMY2002 who were evaluable for immunogenicity,
none were positive for anti-daratumumab antibodies; 2 (0.7%) of the 298 daratumumab
combination therapy subjects analyzed were positive for anti-daratumumab antibodies.
For further details and the most up-to-date information about single-agent studies, please refer to
the Investigator's Brochure (IB Daratumumab 2017 11).
Daratumumab SC Monotherapy
Study 54767414MMY1004 (hereafter referred to as MMY1004) is an ongoing, open-label,
dose-escalation, Phase 1b study to assess the safety and PK of subcutaneous (SC) delivery of
daratumumab. In Part 1 of this study, a mix and-deliver SC presentation (Dara-MD) of the
currently approved daratumumab IV formulation was used: recombinant human hyaluronidase
(rHuPH20) and daratumumab were mixed just prior to delivery. Up to 90 mL of Dara-MD was
administered SC weekly for 8 weeks, every 2 weeks for 16 weeks, and then every 4 weeks
thereafter. Preliminary data from this study show that SC administration results in acceptable PK,
is efficacious, and has a substantially shortened administration time compared with standard IV
administration. Part 2 of this study uses a new co-formulated preparation of daratumumab for SC
administration (Dara-CF). Hereafter, Dara-CF will be referred to as Dara-SC. Updated information
regarding daratumumab SC can be found in the Investigator's Brochure (IB Daratumumab 2017
11).
Efficacy
Fifty-three subjects (8 subjects in the 1200 mg cohort and 45 subjects in the 1800 mg cohort) were
evaluable for efficacy. In the Dara-MD 1200-mg cohort, the ORR was 25% (95% CI: 3%-65%),
both PRs; 1 was achieved at 8 weeks and the other at 20 weeks. In the Dara-MD 1800-mg cohort,
17 responses were observed for an ORR of 38% (95% CI: 24%-54%). One subject (2%) had a
sCR, 3 subjects (7%) had VGPR, and 13 subjects (29%) had PRs. The median time to first
response was 4 weeks (range, 4 to 8 weeks). In relapse or refractory MM, the antitumor activity of
daratumumab 1800 mg SC (ORR 38%) was consistent with daratumumab 16 mg/kg IV (Usmani
201634).
Pharmacokinetics
-time curves following administration indicate
a later time to maximum serum concentration (Tmax) of approximately 72 hours post-dose,
compared with IV administration when Tmax  occurs at or near the end of infusion. The 1800-mg
SC dose achieved similar or higher maximum trough concentrations (Ctrough) (the predose
concentration on Cycle 3 Day 1) as 16 mg/kg IV and had similar variability. Preliminary analyses
indicate that the bioavailability of Dara-MD is approximately 77% when administered SC.
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
26
Approved, Date: 23 September 2024
Safety
Treatment-emergent adverse events for daratumumab administered SC appeared to be similar to
those reported in single-agent studies of daratumumab administered IV, but with a lower incidence
of infusion/injection-related reactions (IRRs) (Lokhorst 201520, Lonial 201621). The incidence of
all-grade IRRs was 13% and 24% in the Dara-MD 1200 mg and 1800 mg cohorts, respectively.
By comparison, among subjects treated in single-agent or combination studies with IV
daratumumab, IRRs were reported in 47% of subjects.
Administration of daratumumab in the abdominal SC tissue was associated with injection site
erythema in 34% of subjects (1200 mg: 63%; 1800 mg: 29%) and induration 26% of subjects (1200
mg; 50%; 1800 mg: 22%).
1.2. 
Overall Rationale for the Study
The standard of care for premalignant stages of disease in the MM continuum, ie, MGUS and
SMM, has been active monitoring. Published data show that specific criteria can identify patients
with SMM who are at particularly high risk for progression (see Section 1.1). The general interest
in the field in developing effective therapies for high-risk SMM is illustrated by the initiation of
several studies. The regimens evaluated in these studies vary considerably from relatively low-
intensity monotherapy to multi-agent therapy incorporating autologous stem cell transplantation.
One shortcoming noted is that most studies are single-arm studies that will not allow a definitive
evaluation of survival endpoints.
Daratumumab is a
 candidate for use in high-risk SMM. Compelling clinical activity has
been demonstrated with daratumumab treatment in subjects with pretreated MM, as monotherapy
and in combination with bortezomib/dexamethasone, lenalidomide/dexamethasone or
pomalidomide/dexamethasone. Importantly, daratumumab is well-tolerated as demonstrated by a
low rate of treatment discontinuation across clinical studies. This favorable safety profile is
especially important in the treatment of patients with an asymptomatic condition. A Phase 2 study
designed to evaluate whether daratumumab IV given as a single agent is effective in delaying the
transition from a high-risk SMM to MM and to find the optimal dosing is currently ongoing.
Preliminary data are presented in Section 3.1.
Plasma cells from subjects with SMM and MM express high levels of CD38. In addition to direct
targeting of CD38+ tumor cells, daratumumab can deplete CD38+ immune suppressive
subpopulations, such as myeloid derived suppressor cells (MDSC) and regulatory T cells that
express high levels of CD38. Reduction of these immune suppressive populations may promote
expansion of cytotoxic CD8+ T cells that could have additional antitumor effects in these
pre-symptomatic subjects with presumably higher immune competent system versus those with
MM.
Subjects with high-risk SMM as defined in this study have approximately 50% risk of progression
to MM within 30 months. This study is designed to evaluate whether daratumumab will be
effective in delaying the transition from a high-risk premalignant condition (SMM) to MM in a
safe manner. Given the potential advantages of SC administration of daratumumab (eg, small
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
27
Approved, Date: 23 September 2024
volume; fewer IRRs), this study will use a new, co-formulated drug product administered SC. The
co-formulated drug product will reduce the time for drug preparation, reduce the infusion volume
to approximately 15 mL, and can be administered in approximately 5 minutes by manual SC push.
1.3. 
Benefit-Risk Assessment
1.3.1. 
Risks Associated with DaratumumabSC
Study participants with SMM will receive treatment with daratumumab.
The primary acute toxicities for daratumumab SC are systemic administration-related reactions
that occur mainly within 6 hours after the first administration. Although the majority ofthese are
predominantly Grade 1 and Grade 2, severe injection-site reactions which could be considered
potential aggravating risk factors for cardiac events have occurred. Details regarding the
management of injection-site reactions are presented in Section 6.4.1.
Daratumumab may increase neutropenia and thrombocytopenia induced by background therapy.
Neutropenia and hypogammaglobulinemia associated with daratumumab may contribute to the
risk of infection. Higher incidence of Grade 3 or 4 neutropenia has been observed in participants
with lower body weight who receive daratumumab SC. Increased incidence of serious infections,
most notably pneumonia, in association with daratumumab have been reported.
Daratumumab binds to CD38 found at low levels on red blood cells (RBCs); it may interfere with
blood typing and result in a positive Indirect Antiglobulin Test (IAT) (see Section 9.7).
The potential risks for daratumumab detailed in Table 3 are based on: 1) results of nonclinical
studies; 2) mechanism of action; 3) route of administration; and 4) results from participants treated
in daratumumab studies (see Sections 1.1 and 3.2). See discussions in Section 9.2.4 and 9.7
regarding the potential for daratumumab to interfere with disease evaluations.
Please refer to the current label/IB of daratumumab for additional information.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
29
Approved, Date: 23 September 2024
To assess the clinical characteristics of symptomatic MM following progression of disease
after therapy with daratumumab
To evaluate the PK and immunogenicity of daratumumab administered SC in subjects with
high-risk SMM
To evaluate the immunogenicity of rHuPH20 when administered in combination with
daratumumab SC in subjects with high-risk SMM
To evaluate the effect of treatment with daratumumab on health-related quality of life
(HRQoL)
Exploratory Objectives
To investigate clinical efficacy of daratumumab in high-risk subjects with genetic
modifications (del17p, t(4:14), 1q gain, or other high-risk molecular subtypes)
To explore biomarkers of response or resistance to daratumumab, including
immunophenotypes and expression of MM markers (ie, CD38)
2.1.2. 
Endpoints
Primary Endpoint
The primary endpoint of this study is PFS (defined as the time from the date of randomization to
the date of initial documented progression to MM according to the IMWG diagnostic criteria for
MM or the date of death, whichever occurs first).
Secondary Endpoints
To demonstrate additional clinical benefit, the following secondary endpoints will be evaluated:
Time to biochemical or diagnostic (SLiM-CRAB) progression defined as the earlier of time
to the earlier of biochemical progression or diagnostic (SLiM-CRAB) progression (see
Section 9.2.2)
Overall response rate (ORR), defined as, the proportion of subjects with a PR or better as
defined by the IMWG response criteria
Complete response (CR) rate, defined as, the proportion of subjects with a CR (or better) as
defined by the IMWG response criteria
Time to first-line treatment for MM, defined as, the time from the date of randomization to
the date of the first-line treatment for MM
Progression-free survival on first-line treatment for MM (PFS2), defined as, the time from the
date of randomization to the date of documented progressive disease (PD) on the first-line
treatment for MM or death, whichever comes first
Overall survival (OS), defined as, the time from the date of randomization to the date of death
Incidence of MM with adverse prognostic features, which include International Staging
System Stage III (based on β2-microglobulin and albumin) and adverse cytogenetic
characteristics

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
30
Approved, Date: 23 September 2024
Serum daratumumab PK concentrations and parameters including minimum observed
concentration (Cmin) and maximum observed concentration (Cmax)
Incidence of anti-daratumumab antibodies and anti-rHuPH20 antibodies
Change from baseline in global health status and emotional functioning scales of the European
Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire
(QLQ)-C30, future perspective scale of the EORTC QLQ-MY20, and utility and visual analog
scale of the European Quality of Life Five Dimensions Questionnaire (EQ-5D-5L)
Duration of response, defined as date of onset of first response until date of disease
progression or death
Time to response, defined as the time from randomization until onset of first response
Exploratory Endpoints
Identification of novel biomarkers in relation to PFS/OS
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypothesis
Daratumumab SC administered as monotherapy will prolong PFS compared with active
monitoring in subjects with high-risk SMM.
3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a Phase 3, randomized, open-label, 2-arm, multicenter study of active monitoring and
daratumumab in subjects with high-risk SMM (see inclusion criteria, Section 4.1). Approximately
360 subjects will be stratified and then randomized in a 1:1 ratio to receive active monitoring (Arm
A) or daratumumab (Arm B). Randomization will be stratified based on the number of factors
associated with progression to MM (<3 vs ≥3). The factors are (1) involved:uninvolved FLC ratio
≥8 (yes vs no), (2) serum M-protein ≥30 g/L (yes vs no), (3) IgA SMM (yes vs no),
(4) immunoparesis (reduction of 2 uninvolved immunoglobulins vs other), and (5) bone marrow
plasma cells (BMPCs) (>50% to <60% vs ≤50%).
Subject participation will include a Screening Phase, an Active Monitoring Phase (Arm A) or a
Treatment Phase (Arm B), and a Follow-up Phase. The Screening Phase will be within 35 days
before randomization. The Active Monitoring Phase (Arm A) and Treatment Phase (Arm B) will
be 36 months in duration, to balance efficacy with subject convenience and expected side effects.
Cycles are 4 weeks in length. For all subjects, disease evaluations will be performed every
12 weeks until confirmed PD. Confirmation of eligibility will be based on central disease,
hematology, and chemistry laboratory assessments and will also include assessment of ECG,
ECOG, medical history, concomitant medications, adverse events, and screening images. Bone
lesions assessment at screening will be done by an independent reviewer after subject eligibility is
confirmed by the site (no lytic lesions and/or ≤ 1 focal lesion with diameter ≥5 mm present unless
proven benign/post-traumatic origin) (refer to Section 9.2.7). This central review of screening

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
31
Approved, Date: 23 September 2024
images will be used to determine the subject’s eligibility. For optimal assessment of the screening
images by the independent reviewers, additional clinical data, including benign/post-traumatic
pre-existing bone lesions, data of recent bone marrow procedures, and general medical history,
will be included in the independent review.
For subjects randomized to active monitoring (Arm A), no disease-specific treatment will be given
and subjects are to be evaluated every 12 weeks. For subjects randomized to daratumumab (Arm
B), daratumumab SC (daratumumab 1800 mg + rHuPH20 [2000 U/mL]) will be administered
weekly in Cycles 1 and 2, then every 2 weeks for Cycle 3 to Cycle 6, and every 4 weeks thereafter
until 39 cycles or up to 36 months or confirmed PD (or other reasons as outlined in Section 10),
whichever occurs first. All subjects in the daratumumab group will be observed for at least 6 hours
after the end of the SC injection during Cycle 1 Day 1 and, if deemed necessary by the investigator,
after subsequent injections. Based on the data available as of October 2017 from Study MMY1004,
no subject has had an IRR with an onset >6 hours after daratumumab SC injection (IB
Daratumumab 2017 11). Measures to prevent IRRs include predose medication with
methylprednisolone, paracetamol, and an antihistamine. Montelukast may also be added as a
predose medication at the investigator’s discretion. Methylprednisolone also will be administered
after daratumumab administration with the intention of preventing delayed IRRs.
The Follow-up Phase will begin once a subject completes 39 cycles or 36 months (whichever
occurs first) or discontinues active monitoring (Arm A) or daratumumab treatment (Arm B) and
completes the End-of-Active Monitoring Visit (Arm A) or End-of-Treatment Visit (Arm B). In
both groups, disease evaluation will continue every 12 weeks thereafter until disease progression,
as indicated in the Time and Events Schedule (Table 1). The Follow-up Phase for each subject will
continue until death, lost to follow up, consent withdrawal, or study end, whichever occurs first.
Assessment of disease response will be conducted in accordance with the IMWG response criteria
(Table 8) using a validated computer algorithm. Disease progression will be assessed using the
IMWG diagnostic criteria for MM using a computer algorithm. Cases for which progression is
based on FLC criteria only, progression will be determined based on modified FLC criteria
combining IMWG progression criteria with IMWG FLC ratio criteria (Section 9.2.2). Progression
evaluations for the primary endpoint/final analysis will be based on IRC review, in a blinded
fashion, to objectively and consistently implement the IMWG diagnostic criteria for MM
(Section 9.2.2). Evaluation of disease progression by IRC and validated computerized algorithm
will be discontinued once the number of planned PFS events for the primary analysis is achieved.
Per protocol Amendment 6, following the primary analysis, disease evaluations will be conducted
locally and disease progression will be assessed by the study investigator according to IMWG
criteria.
Safety evaluations will include adverse event monitoring, physical examinations, SC injection site
evaluations, clinical laboratory parameters (hematology and chemistry), and Eastern Cooperative
Oncology Group (ECOG) performance status. Blood samples will be drawn for assessment of PK
and biomarker parameters. All study evaluations will be conducted according to the Time and

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
32
Approved, Date: 23 September 2024
Events Schedules (Table 1 and Table 2). An Independent Data Monitoring Committee (IDMC)
will review safety data at regular intervals during the study.
Three data cutoff time points are planned:
The first is for an interim analysis for futility when approximately 60% of the planned PFS
events (99) have occurred. This is expected to occur approximately 8 months after the last
subject has been randomized. All available data at the time of this data cutoff will be included
in the interim analysis.
The second is for the primary analysis and will occur when approximately 165 PFS events
have occurred. This analysis is expected to occur approximately 2 years after the last subject
is randomized. All available data at the time of this data cutoff will be included in the Clinical
Study Report.
A third will occur at the end ofthe study. The data collected will be reported as an addendum
to the Clinical Study Report.
Additionally, the IDMC will meet after the first 60 subjects have been randomized and treated
or observed for 8 weeks to assess safety, 6 months later, and thereafter every 12 months until
the primary analysis.
The end of the study will occur approximately 8 years after the first subject is randomized, or when
the sponsor decides to stop the study. At this time, approximately 107 OS events are expected in
both arms (64 at the time of the primary analysis of PFS). This will provide approximately 65%
probability to show that the upper 95% CI of the HR is below 1.25, assuming the true HR is 0.80
(median OS: 100 vs. 125 months). Note, that in the hierarchical testing procedure, only superiority
will be tested for this endpoint. Furthermore, approximately 134 PFS2 events are expected in both
arms (81 at the time of the primary analysis of PFS). This will provide approximately 80%
probability to show that the upper 95% CI of the HR is below 1.25, assuming the true HR is 0.75
(median PFS2: 72 vs. 96 months). Note that in the hierarchical testing procedure, only superiority
will be tested for this endpoint.
A diagram of the study design is provided in Figure 1.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
34
Approved, Date: 23 September 2024
Preliminary data from an ongoing Phase 2 study in subjects with SMM (SMM2001) suggest that
long and intense treatment with daratumumab IV (as used in MM) yields better results than less
intense administration. The approved dose regimen used in MM is being used in the current study
in SMM.
Study SMM2001 is an ongoing, randomized, open-label, 3-arm, multicenter study of daratumumab
IV in subjects at least 18 years old with intermediate- or high-risk SMM. The study is designed to
evaluate whether daratumumab as a single agent is effective in delaying the transition from a high-
risk premalignant condition (SMM) to MM, and to find the optimal schedule of treatment
administration. Approximately 120 subjects were planned to be enrolled in this study, 40 subjects
per treatment arm. It was originally hypothesized that in a pre-symptomatic patient population, a
less intensive dosing schedule may be preferred by patients and healthcare providers. Therefore, 3
dose schedules are being evaluated in the Phase 2 study. Subjects were assigned randomly to
treatment in a 1:1:1 ratio to 1 of the following 3 treatment arms:
Arm A (long intense): daratumumab IV is administered weekly in Cycle 1, every other week
in Cycle 2 and Cycle 3, every 4 weeks in Cycle 4 to Cycle 7, and every 8 weeks from Cycle 8
to Cycle 20.
Arm B (intermediate): daratumumab IV is administered weekly in Cycle 1 and then every
8 weeks from Cycle 2 to Cycle 20.
Arm C (short intense): daratumumab is administered weekly for 8 weeks in Cycle 1.
Each cycle is 8 weeks. Disease progression to MM is evaluated using the IMWG criteria
(Rajkumar 201429).The key efficacy data from the interim analysis (6 months after the last subject
was randomized) and the Kaplan-Meier (biochemical or diagnostic [BOD] PFS) curves are
displayed in Table 4 and Figure 2, respectively. The long-intense arm had numerically better
VGPR-or-better rate and ORR. The only deep response (sCR) observed in this study to date was
also observed in the long-intense arm. The PD/death rate was also numerically lower in the
long-intense arm compared with the intermediate- and short-intense arms. Furthermore, the
12-month BOD PFS rate was higher in the long-intense arm (97.5%) compared with the
intermediate-intense arm (76.8%) and short-intense arm (71.1%). These data suggest that the
long-intense arm demonstrates better efficacy than the other 2 treatment arms.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
35
Approved, Date: 23 September 2024
Table 4: 
Summary of Key Efficacy Endpoints; Response-evaluable Analysis Set
(Study 54767414SMM2001)
Long Intense 
Intermediate 
Short Intense
Complete response (sCR+CR) rate 
1 (2.4%) 
0 
0
90% confidence intervala 
(0.1%, 11.1%)
VGPR or better (sCR+CR+VGPR) rate 
9 (22.0%) 
7 (17.1%) 
6 (15.0%)
90% confidence intervala 
(12.0%, 35.2%) 
(8.3%, 29.7%) 
(6.7%, 27.5%)
Overall response (sCR+CR+VGPR+PR) rate 
23 (56.1%) 
21 (51.2%) 
15 (37.5%)
90% confidence intervala 
(42.1%, 69.4%) 
(37.4%, 64.9%) 
(24.7%, 51.7%)
PD/Death rateb 
80% confidence intervalc 
0.028 
(-0.0078,0.0629) 
0.093 
(0.0241,0.1611) 
0.159
(0.0680,0.2505)
BOD PFS
12-month BOD PFS rate % (90% CI) 
97.5 (87.7, 99.5) 
76.8 (61.1, 86.8) 
71.1 (56.8, 81.3)
BOD=biochemical or diagnostic; CI=confidence interval; CR=complete response; PD=progressive disease;
PFS=progression-free survival; PR=partial response; sCR=stringent complete response; VGPR=very good
partial response
a 
Exact 90% CI.
b 
PD/Death rate is the ratio of the patients who progressed or died divided by the total progression-free survival
for all subjects.
c 
Normal approximation.
Figure 2: 
Biochemical or Diagnostic Progression-free Survival; Intent-to-Treat Analysis Set
(Study 54767414SMM2001)
BOD=biochemical or diagnostic

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
36
Approved, Date: 23 September 2024
Safety analyses are consistent with previous experience using daratumumab for the treatment of
MM. No new safety signals were identified in the SMM population (Table 5). No subjects died
due to a TEAE). Although the percentages of Grade 3 or 4 TEAEs and SAEs were higher in the
long-intense treatment arm, the percentages of daratumumab discontinuations due to TEAEs were
low (5% or less in each arm) and similar in the 3 treatment arms.
Table 5: 
Overview of Treatment-emergent Adverse Events; Safety Analysis Set
(Study 54767414SMM2001)
Long Intense 
Intermediate 
Short Intense
Analysis set: safety  
41 
41 
40
Any treatment-emergent adverse event 
39 (95.1%) 
40 (97.6%) 
37 (92.5%)
At least one reasonably related to daratumumab 
33 (80.5%) 
30 (73.2%) 
28 (70.0%)
Maximum toxicity grade
Grade 1 
7 (17.1%) 
8 (19.5%) 
9 (22.5%)
Grade 2 
18 (43.9%) 
28 (68.3%) 
22 (55.0%)
Grade 3 
11 (26.8%) 
4 (9.8%) 
4 (10.0%)
Grade 4 
3 (7.3%) 
0 
2 (5.0%)
Grade 5 
0 
0 
0
Any serious treatment-emergent adverse event 
10 (24.4%) 
1 (2.4%) 
4 (10.0%)
Treatment-emergent adverse events leading to dose
delay  
4 (9.8%) 
0 
1 (2.5%)
Treatment-emergent adverse events leading to
discontinuation of daratumumab 
2 (4.9%) 
1 (2.4%) 
2 (5.0%)
Note: Adverse events are reported using Medical Dictionary for Regulatory Activities, version 19.0.
Note: Percentages are calculated with the number of subjects in each group as denominator.
Preliminary PK data from Study SMM2001 were analyzed. In this study, which used a dose of 16
mg/kg IV, the data indicate that the long-intense schedule maintains trough concentrations above
the 99% CD38 target saturation concentration (defined in MM subjects) throughout dosing.
However, for subjects treated on the intermediate-intense schedule, trough concentrations fall
below the target saturation concentration by Cycle 3 Day 1 (the end of the first cycle of every-8-
week dosing), and for subjects treated in the short-intense schedule, concentrations fall below the
target saturation concentration by 8 weeks after the last dose. Data are not available after every-8-
week dosing starts in the long-intense schedule; however, it is expected that as the dosing
frequency decreases to every 8 weeks, the trough concentrations will begin to fall below the target
saturation concentration. In addition, an increase in BOD progression events was observed in
intermediate and short-intense schedules after weekly dosing ended (Table 4), indicating that
daratumumab treatment needs to continue longer than 8 weeks of weekly dosing, but continuing
to dose daratumumab only every 8 weeks may not be sufficient to maintain response.
In summary, these data suggest that more intense treatment with daratumumab may be required
for optimal efficacy in high-risk SMM. Therefore, the long-intense schedule will be used in
SMM3001 with the modification that dosing every 4 weeks will continue until treatment
discontinuation.
Treatment with daratumumab IV in SMM has led to a low number of subjects who discontinued
treatment due to a TEAE and there were no deaths due to a TEAE. The most common side effect

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
37
Approved, Date: 23 September 2024
associated with daratumumab is infusion-related reactions, which were experienced by
approximately half of the subjects receiving daratumumab. The vast majority (>90% of
infusion-related reactions) occurred during the first infusion. Due to the risk of infusion-related
reactions, the IV infusion requires a large volume (500 mL to 1000 mL), and the median infusion
time for the first infusion is 7 hours; subsequent infusions are approximately 3 to 4 hours.
A new SC formulation of daratumumab co-formulation with rHuPH20 (Dara-SC) offers several
key benefits, such as:
Potential to reduce IRRs (compared with IV administration), due to slower absorption of
daratumumab into systemic circulation
Shorter preparation and administration time
Reduced administration volume (SC administration of approximately 15 mL instead of
500 mL to 1000 mL IV infusion), which may be clinically meaningful for elderly patients
with comorbid cardiac or renal insufficiency
An ongoing Phase 1b study of SC daratumumab (MMY1004) has provided preliminary evidence
of local tolerance for SC administration of daratumumab (Section 1.1). The study aims to identify
a dose which can be safely administered SC and achieves a maximum Ctrough  at Cycle 3 Day 1
similar to or higher than that achieved following 16 mg/kg IV administration. The maximum Ctrough
has been shown in population PK and exposure-response analyses to be related to ORR in MM.
Preliminary PK data from the 1800-mg SC cohort indicate that the serum maximum trough
concentrations at Cycle 3 Day 1 were similar to or higher than those achieved with 16 mg/kg of
IV daratumumab. Furthermore, to date, the rate of IRRs reported with SC administration of
daratumumab has been substantially lower than the rate reported with IV administration of
daratumumab. Preliminary efficacy data suggest that, in this patient population, SC administration
of 1800 mg daratumumab may enable comparable response rates compared with IV daratumumab.
Based on these preliminary PK, safety, and efficacy data, the 1800-mg SC dose is selected for this
study. For further details and the most up-to-date information about single-agent studies, please
refer to the Investigator's Brochure (IB Daratumumab 2017 11).
Rationale for Pharmacokinetics and Immunogenicity Assessments
Preliminary PK data from a planned interim analysis in Study SMM2001 indicate PK in
SMM subjects using IV daratumumab appears similar to MM subjects based on similar predose
and end-of-infusion concentrations. To obtain additional data for daratumumab in SMM,
especially regarding PK of daratumumab following SC administration of the co-formulated
product, samples will be obtained from all subjects for assessment of Cmin and Cmax. Data may also
be used for a population-PK analysis to estimate additional PK parameters and provide information
about the determinants of intersubject variability in this population. Pharmacokinetic data may
also be used in an exposure-response analysis incorporating safety, efficacy or other endpoints.
Immunogenicity to daratumumab or rHuPH20 is possible. The incidence of anti-drug antibody
generation in subjects with SMM may be different from previously studied. Therefore, the

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
38
Approved, Date: 23 September 2024
presence of antibodies to daratumumab and antibodies to rHuPH20 (immunogenicity) will be
determined from serum samples collected from subjects who receive daratumumab.
Rationale for Biomarker Evaluations
The biomarker hypotheses are that administration of daratumumab will result in better responses
in high-risk subjects and greater anti-tumor immune modulation versus active monitoring.
Biomarker samples will be collected to evaluate factors that may contribute to daratumumab
response including but not limited to CD38 expression, resistance markers, immune repertoire
changes, and depth of response by minimal residual disease (MRD).
Certain high-risk cytogenetic modifications are known to be present in the plasma cells of the
premalignant phases of MM (Rajkumar 201330). Progression to MM has been associated with
several cytogenetic modifications, such as deletion 17p, amp(1q21), t(4;14), and t(14;16) that
confer different levels of risk or poor prognosis. Though there has been debate about their
frequencies and effect on plasma cells (Agarwal 20121), significantly shorter time to progression
and OS was observed in t(4;14) SMM patients (28 months, time to progression; 105 months, OS)
compared to t(11;14) SMM patients (55 months, 147 months OS) (Rajkumar 201330). These data
suggest there maybe value in understanding the contribution these abnormalities have on disease
progression. Therefore, response rates in specific molecular subgroups may be determined by
deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) sequencing of myeloma cells. Additionally,
plasma from subjects will be collected to explore a less invasive technique for identification of
prognostic biomarkers.
In previous daratumumab studies of subjects with MM, NK cell counts were reduced significantly
following the first dose of daratumumab and maintained at low levels on therapy while other
immune cell populations were not susceptible to decreases. Furthermore, it is hypothesized that
SMM patients have a higher level of immune competency than MM patients, and this may allow
for other daratumumab mechanism of actions to contribute to response (Krejcik 201613). Recent
data have demonstrated a potential role of the gut microbiome in influencing clinical outcomes by
modulating inflammatory regulators (Goodman 20189, Meisel 201826). Therefore, immune cell
populations and gut immune microenvironment may be examined to determine whether similar
changes play a role in daratumumab response for this premalignant condition.
Minimal residual disease assessment allows evaluation of the depth of clinical response beyond
the standard IMWG CR/sCR response category. Several studies have demonstrated that MRD
status is correlated with PFS and OS in MM (Martinez-Lopez 201422) and achievable in SMM
(Korde 201512). In the present study, standardized methodology will be used for MRD in bone
marrow aspirate when samples are obtained at screening, at confirmation of CR, and 12 months
after the date of the initial CR for those subjects who maintain CR.
Rationale for Patient-Reported Outcomes
Patient-reported outcome (PRO) data complement data collected by other methods to support the
clinical data and cost-effectiveness modeling as well as contributing to enhanced communication
of value to patients, clinicians, regulators, and payers. Based on the clinical presentation of patients

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
39
Approved, Date: 23 September 2024
with SMM and prior PRO research in myeloma clinical trials, the PRO endpoints of interest
include scales from the EORTC QLQ-C30 (global health status, emotional functioning), EORTC
QLQ-MY20 (future perspective), and the EQ-5D-5L (utility value and visual analog scale). These
PRO measures will be administered to support the hypothesis that treatment with daratumumab
maintains HRQoL by delaying the onset of disease symptoms. PRO data will be collected as
outlined in the Time and Events Schedule to understand how the endpoints change over time, with
treatment, and with the clinical state of the subject.
Summary of Benefits and Risks
The primary objective of study SMM3001 is to determine whether treatment with
daratumumab SC prolongs PFS compared with active monitoring in subjects with high risk SMM.
Subjects with SMM have clonal plasma cell which express high levels of CD38, making
daratumumab a candidate therapeutic. Preliminary data from study SMM2001 show that
daratumumab has efficacy in a high-risk SMM population.
The preliminary safety and PK data from Study MMY1004 supports the 1800 mg
daratumumab SC dose selection for the proposed Phase 3 study. The PK data indicate that an
1800 mg dose of daratumumab administered subcutaneously would be anticipated to result in a
similar or greater Cycle 3 Day 1 trough concentration (C3D1 Ctrough) compared to 16 mg/kg IV
administration. Study MMY1004 also showed that daratumumab SC can be administered
subcutaneously by manual injection with a median of 5 minutes (ranging from 2 to 11 minutes)
and it is associated with a relatively low incidence of IRRs. The overall safety profile for the
daratumumab SC cohort is similar to prior experience with daratumumab IV administration and
subcutaneous administration with Dara-MD. There are no new safety signals with the
daratumumab SC administration. The potential risks will be mitigated by comprehensive and
careful medical monitoring during the conduct of the study, as described in the protocol and
summarized in this section. All subjects should comply with the described inclusion and exclusion
criteria and will be closely monitored for possible toxicity. This includes adverse event monitoring,
physical examinations, SC injection-site evaluations, electrocardiogram (ECG) monitoring,
clinical laboratory parameter (hematology and chemistry) monitoring, pulmonary function testing,
and ECOG performance status score evaluation. An ongoing review of the safety data will be
performed by the Study Responsible Physician and Scientist to identify any safety signal.
Furthermore, an IDMC will also review the safety and efficacy in preplanned analyses, per
Section 11.12, of the protocol. In addition, a Steering Committee, including 3 independent expert
physicians together with the Company Clinical Team Leader and Study Responsible Physician,
will meet regularly (at least yearly) or as needed (if a safety signal is identified). Lastly, a review
of cumulative safety data from all daratumumab studies will be performed by an internal safety
management team at regular intervals. Therefore, the Company believes the benefit/risk profile is
favorable to support further evaluation of efficacy, safety, and PK of daratumumab SC in Phase 3
of Study SMM3001.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
40
Approved, Date: 23 September 2024
4. 
SUBJECT POPULATION
Screening of subjects will be performed within 35 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, then the investigator must
consult with the appropriate sponsor representative and resolve any issues before enrolling a
subject in the study. Waivers are not allowed. For the purpose of this study, a subject that is
randomized is considered enrolled.
4.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. 
At least 18 years of age or at least the legal age of consent in the jurisdiction in which the
study is taking place, whichever is the older age.
2. 
Criterion amended per Amendment 1:
2.1 
Diagnosis of SMM (per IMWG criteria) for ≤5 years with measurable disease at the time
of randomization, defined as serum M protein ≥10 g/L or urine M protein
≥200 mg/24 hours or involved serum FLC ≥100 mg/L and abnormal serum FLC ratio.
3. 
Criterion amended per Amendment 1:
3.1 
Clonal BMPCs ≥10%; and
At least 1 of the following risk factors;
a. 
Serum M protein ≥30 g/L,
b. 
IgA SMM,
c. 
Immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes (only
IgA, IgM, and IgG should be considered in determination for immunoparesis; IgD
and IgE are not considered in this assessment),
d. 
Serum involved: uninvolved FLC ratio ≥8 and <100, or
e. 
Clonal BMPCs >50% to <60% with measurable disease.
4. 
ECOG performance status score of 0 or 1 (Attachment 1).
5. 
Pretreatment clinical laboratory values meet the following criteria during the Screening
Phase:
a. 
Absolute neutrophil count ≥1.0 x 109/L (ie, ≥1000/µL)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
41
Approved, Date: 23 September 2024
b. 
Platelet count ≥50 x 109/L (not permissible to transfuse a subject within 2 weeks
prior to the Screening platelet count 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 ≤2.0 x ULN, except in subjects with congenital bilirubinemia, such
as Gilbert syndrome (in which case direct bilirubin ≤2.0 x ULN is required)
6. 
Must sign an informed consent form (ICF) or their legally designated representative must
sign indicating that he or she understands the purpose of, and procedures required for, the
study and is willing to participate in the study.
7. 
Criterion amended per Amendment 1:
7.1 
Contraceptive use by men or women should be consistent with local regulations regarding
the use of contraceptive methods for subjects participating in clinical studies.
Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse or to use 1 method highly effective form of contraception
(tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal
patches, vaginal rings or implants], or partner's vasectomy). Contraception must begin 4
weeks prior to dosing. Highly effective contraception is indicated even where there has
been a history of infertility, unless due to hysterectomy. See Attachment 11 for definitions
of Women of Childbearing Potential
8. 
A woman of childbearing potential must have a negative serum or urine pregnancy test at
screening within 14 days prior to randomization. For requirements during the Treatment
Phase, see Section 4.3
9. 
During the study and for 3 months after receiving the last dose of daratumumab, a woman
must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
10. 
Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
Criterion amended per Amendment 2:
1.1 
Multiple myeloma, requiring treatment, defined by any of the following:

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
42
Approved, Date: 23 September 2024
a. 
Bone lesions (one or more osteolytic lesions on low-dose whole body computed
tomography [LDCT], positron-emission tomography with computed tomography
[PET-CT] or CT). Subjects who have benign/post-traumatic bone lesions visible
on screening images as well as previous imaging, may be considered for
inclusion. Details (diagnosis, location, duration) on benign/post-traumatic pre-
existing bone lesions that can be seen on the screening images (eg, old fractures)
and were also present on previous imaging are to be reported in the CRF (see
Section 9.1.2 and Section 9.2.7).
b. 
Hypercalcemia (serum calcium >0.25 mmol/L [>1 mg/dL] higher than ULN or
>2.75 mmol/L [>11 mg/dL]). Subjects who have clinically stable hypercalcemia
attributable to a disease other than multiple myeloma (eg, hyperparathyroidism)
may be considered for inclusion after a case by case review by the medical
monitor (see Section 9.2.3).
c. 
Renal insufficiency, preferably determined by creatinine clearance <40 mL/min
measured or estimated using the MDRD (Attachment 2), or serum creatinine
>177 µmol/L. Subjects who have clinically stable renal insufficiency attributable
to a disease other than multiple myeloma (eg, glomerulonephritis) may be
considered for inclusion after a case by case review by the medical monitor (see
Section 9.2.3).
d. 
Anemia, defined as hemoglobin <10 g/dL or >2 g/dL below lower limit of normal
or both; transfusion support or concurrent treatment with erythropoietin
stimulating agents is not permitted. Subjects who have clinically stable anemia
attributable to a disease other than multiple myeloma (eg, thalassemia, vitamin
B12 deficiency, iron  deficiency) may be considered for inclusion  after a case
by case review by  the medical monitor (see Section 9.2.3). (Refer to
Appendix 18.1 for specific requirements for France.)
e. 
Clonal BMPC percentage ≥60%
f. 
Serum FLC ratio (involved:uninvolved) ≥100 (The involved FLC must be
≥100 mg/L)
g. 
More than 1 focal lesion ≥5 mm in diameter by MRI
2. 
Primary systemic AL (immunoglobulin light chain) amyloidosis.
3. 
Criterion amended per Amendment 2:
3.1 
Exposure to any of the following
a. 
Prior exposure to daratumumab or prior exposure to other anti-CD38 therapies

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
43
Approved, Date: 23 September 2024
b. 
Prior exposure to approved or investigational treatments for SMM or MM
(including but not limited to conventional chemotherapies, IMiDs, or PIs). Stable
standard dosing of bisphosphonate and denosumab as indicated for osteoporosis
is acceptable.
c. 
Exposure to investigational drug (including investigational vaccines) or invasive
investigational medical device for any indication within 4 weeks or 5 half-lives,
whichever is longer, before Cycle 1, Day 1
d. 
Ongoing treatment with corticosteroids with a dose >10 mg prednisone or
equivalent per day at the time of randomization; or >280 mg cumulative
prednisone dose or equivalent for any 4-week period in the year prior to
randomization
e. 
Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab),
immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine) or
other treatments that are likely to interfere with the study procedures or results
4. 
Received treatment (chemotherapy, surgery, etc) for a malignancy (other than SMM)
within 3 years before the date of randomization (exceptions are squamous and basal cell
carcinomas of the skin, carcinoma in situ of the cervix or breast, or other non-invasive
lesion), which is considered cured with minimal risk of recurrence within 3 years.
5. 
Either of the following:
a. 
Known or suspected chronic obstructive pulmonary disease (COPD) with a
forced expiratory volume in 1 second (FEV1) <50% of predicted normal
b. 
Moderate or severe persistent asthma within the past 2 years (see Attachment 3),
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).
The LDCT/PET-CT/CT performed for screening should be taken into consideration to
determine if additional pulmonary workup is required.
6. 
Criterion amended per Amendment 1:
6.1 
6.2 
Criterion modified per Amendment 3:
Any of the following:
a. 
Known to be seropositive for human immunodeficiency virus (HIV)
b. 
Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Local testing and results of hepatitis B serology (Includes

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
44
Approved, Date: 23 September 2024
HBsAg, anti-HBs, and anti-HBc) is required for all patients prior to randomization
when this amendment 3 is implemented. Subjects with resolved infection
(ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B
core antigen [Anti-HBc] and/or antibodies to hepatitis B surface antigen
[Anti-HBs]) must be screened using real-time polymerase chain reaction (PCR)
measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR
positive will be excluded. EXCEPTION: Subjects with serologic findings
suggestive of HBV vaccination (Anti-HBs positivity as the only serologic
marker) AND a known history of prior HBV vaccination, do not need to be tested
for HBV DNA by PCR
c. 
Known to be seropositive for hepatitis C (except in the setting of a sustained
virologic response [SVR], defined as aviremia at least 12 weeks after completion
of antiviral therapy)
7. 
Medical or psychiatric condition or disease (eg, active systemic disease [including
presence of auto-antibodies], uncontrolled diabetes) 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. 
Clinically significant cardiac disease, including:
a. 
myocardial infarction within 6 months with left ventricular dysfunction or
uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or
uncontrolled disease/condition related to or affecting cardiac function
(eg, unstable angina, congestive heart failure, New York Heart Association
Class III-IV)
b. 
Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer
Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE]
Version 4.03) or clinically significant ECG abnormalities
c. 
Screening 12-lead ECG showing a baseline QT interval as corrected QT interval
corrected for heart rate >470 msec.
The LDCT/PET-CT/CT performed for screening should be taken into consideration to
determine if additional cardiac workup is required.
9. 
Criterion amended per Amendment 1:
9.1 
Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
antibodies, hyaluronidase, or other human proteins, or their excipients (refer to
Daratumumab Investigator Brochure11), or known sensitivity to mammalian-derived
products (including dairy allergy).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
45
Approved, Date: 23 September 2024
10. 
Vaccination with live attenuated vaccines within 4 weeks of first study agent
administration
11. 
Pregnant, breast-feeding, or planning to become pregnant while receiving study
treatment or within 3 months after the last dose of daratumumab
12. 
Plans to father a child while receiving study treatment or within 3 months after the last
dose of daratumumab
13. 
Major surgery (requiring general anesthesia or presence of other factors that determines
surgery to be considered major) within 2 weeks before randomization or who have not
fully recovered from surgery, or has surgery planned during the time the subject is
expected to participate in the study or within 2 weeks after the last dose of
daratumumab. Note: subjects with planned surgical procedures to be conducted under
local anesthesia may participate. If there is a question whether a procedure is considered
a major surgery, then the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a subject in the study.
14. 
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.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a subject's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the start of the Active Monitoring Phase
(Arm A) or the first dose of daratumumab (Arm B) is given, such that he or she no longer meets
all eligibility criteria, then the subject should be excluded from participation in the study.
Section 17.4, Source Documentation, describes the required documentation to support meeting the
enrollment criteria. Subjects who fail to meet the inclusion and exclusion criteria (ie, screen
failures) may be rescreened if their condition changes. Rescreening must be discussed with and
approved by the sponsor on a case-by-case basis. Subjects who are determined to be eligible for
the study after rescreening must sign a new ICF and then will be assigned a new Subject number.
4.3. 
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and restrictions
during the course of the study to be eligible for participation. For subjects randomized to the
daratumumab arm, the prohibitions and restrictions listed below will apply. For restrictions related
to concomitant medications, please refer to Section 8.3.
1. 
For women of childbearing potential, adequate contraception as specified in Section 4.1
must continue during the Treatment Phase, during any dose interruptions, and for

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
47
Approved, Date: 23 September 2024
6. 
DOSAGE AND ADMINISTRATION
Subjects randomized to active monitoring will receive no study medication but will undergo the
same disease evaluations and at the same frequency as subjects randomized to daratumumab.
Daratumumab SC (daratumumab 1800 mg + rHuPH20 [2000 U/mL]) will be administered as
described in the Time and Events Schedule (Table 2). Each cycle is 28 days. All doses should be
administered at outpatient visits. The first visit of a cycle should be 4 weeks after the start of the
previous cycle. The start of Cycles 2 to 39 may occur ±3 days of the scheduled day in order to
accommodate the schedule of the site or subject, only if a minimal interval of 4 days between
daratumumab doses is maintained. All subsequent days within that cycle and Day 1 of subsequent
cycles should be adjusted accordingly to maintain the 28-day cycle duration. In case of dose delays
affecting days other than Day 1, because of reasons other than toxicity, administration should occur
within the prespecified window (Table 7). If an administration does not commence within the
prespecified window of the scheduled administration date, then the dose will be considered a
missed dose. Administration may resume at the next planned dosing date. A missed dose will not
be made up. Every effort should be made to avoid dose delays because of reasons other than
toxicity (refer to Section 6.5.3, for details on interrupted or missed doses). Changes to within-cycle
daratumumab dosing should not affect Day 1 of the next cycle. Subjects will continue to receive
daratumumab according to the Time and Events Schedule until disease progression, unacceptable
toxicity, or other reasons as listed in Section 10.1.
A schematic of study treatment administration is provided in Figure 3.
Figure 3: 
Schematic Overview of Active Monitoring and Study Treatment Administration
Arm B
Cycle 1-2
(4-week cycle)
Cycle 3-6  
Cycle 7-39 
Daratumumab
Follow-up
Active Monitoring
Arm A  
D1D8
D22 
D15
D1  D15 
D1

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
48
Approved, Date: 23 September 2024
6.1. 
Daratumumab
Detailed description for preparation and administration of daratumumab will be supplied in the
Investigational Product Preparation Instructions (IPPI).
6.2. 
Treatment Schedule and Administration
Daratumumab SC (daratumumab 1800 mg + rHuPH20 [2000 U/mL]) will be administered by SC
injection through a syringe by a manual push over approximately 5 minutes. For subjects
randomized to daratumumab, daratumumab will be administered weekly in Cycle 1 and 2, then
every 2 weeks for Cycle 3 to Cycle 6, and thereafter every 4 weeks until 39 cycles or up to
36 months or until confirmed PD, or one of the reasons outlined in Section 10, whichever occurs
first. Doses will be administered at alternating locations on the abdomen. Subjects will receive
predose and postdose medications as detailed in Section 8. All subjects in the daratumumab arm
will be observed for at least 6 hours after the end of the SC injection during Cycle 1 Day 1 and, if
deemed necessary by the investigator, after subsequent injections.
If a subject experiences a significant medical event, then the investigator should assess whether
the subject should be hospitalized overnight for observation.
6.3. 
Guidelines for Prevention and Management of Infusion Reactions
For the purpose of this protocol, infusion-related reactions are defined as systemic reactions related
to the SC administration of daratumumab.
6.3.1. 
Predose Medication
In an effort to prevent IRRs, subjects in the daratumumab arm will receive all of the following
medications 1 to 3 hours prior to each daratumumab administration (1 hour prior to daratumumab
administration is preferred):
An antipyretic: paracetamol (acetaminophen) 650-1000 mg orally (PO) or IV
An antihistamine: diphenhydramine 25-50 mg PO or IV, or equivalent. Avoid the use of IV
promethazine. After Cycle 6, if a subject has not developed an IRR and is intolerant to
antihistamines, then modifications are acceptable as per investigator discretion.
(See Attachment 4 for a list of antihistamines that may be used)
A corticosteroid: methylprednisolone 100 mg PO or IV or equivalent for the first 2 doses and
60 mg for all subsequent doses. This reduction in steroid dose can only be done in the absence
of IRR adverse events in both of the first 2 doses. Substitutions for methylprednisolone are
allowed, but conversion rules have to be taken into account (refer to Attachment 5).
Predose administration of a leukotriene inhibitor (montelukast 10 mg PO, or equivalent) is
recommended on Cycle 1 Day 1. If necessary, all PO predose medications may be administered
outside of the clinic on the day of daratumumab administration, provided they are taken within
1 to 3 hours prior to the administration.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
49
Approved, Date: 23 September 2024
6.3.2. 
Postdose Medication
In an effort to prevent delayed IRRs, subjects in the daratumumab arm will receive a long- or
intermediate-acting corticosteroid (20 mg methylprednisolone PO or equivalent [refer to
Attachment 5 for conversion rules], in accordance with local standards) on the 2 days following
each daratumumab administration (beginning the day after daratumumab administration). Only
when no IRR adverse events occurred during the first 3 doses, postdose corticosteroids should be
administered per investigator discretion.
For subjects with higher risk of respiratory complications (eg, subjects with COPD who have a
FEV1 <80% and subjects with asthma), the following postdose medications should be considered,
as per investigator discretion:
antihistamine (diphenhydramine or equivalent) on the first and second days after each dose,
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol, and
Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or
salmeterol ± inhaled corticosteroids for subjects with COPD).
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after
daratumumab administration. If subjects are hospitalized, then an improvement in FEV1 should
be documented prior to discharge. If these subjects are not hospitalized, then a follow-up telephone
call should be made to monitor their condition within 48 hours. Investigators may prescribe
bronchodilators, antihistamines, and corticosteroids that are deemed necessary to provide adequate
supportive care in the event a bronchospasm occurs after subjects are released from the
hospital/clinic. If an at-risk subject experiences no major IRRs, then these postdose medications
may be waived after 4 doses at the investigator’s discretion.
6.4. 
Management of Injection-site and Infusion-related Reactions
6.4.1. 
Local Injection-site Reactions
In Study MMY1004, SC administration of daratumumab in abdominal SC tissue was associated
with local injection-site reactions such as induration and erythema in some subjects. The reactions
usually resolved within 60 minutes. Local injection-site reactions should be managed per
institutional standards.
6.4.2. 
Infusion-related Reactions
Subjects should be observed carefully during study drug administrations. Trained study staff at the
clinic should be prepared to intervene in case of any IRRs, and resources necessary for
resuscitation (eg, agents such as epinephrine and aerosolized bronchodilator, also medical
equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator) must be available
at the bedside.
If an IRR develops, then daratumumab administration should be temporarily interrupted. Please
see the IPPI for further details. Subjects who experience adverse events during daratumumab

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
50
Approved, Date: 23 September 2024
administration must be treated for their symptoms. Subjects should be treated with acetaminophen,
antihistamine, or corticosteroids, as needed. Intravenous saline may be indicated. For
bronchospasm, urticaria, or dyspnea, subjects may require antihistamines, oxygen, corticosteroids,
or bronchodilators. For hypotension, subjects may require vasopressors. In the event of a life-
threatening IRR (which may include pulmonary or cardiac events) or anaphylactic reaction,
daratumumab should be discontinued and no additional daratumumab should be administered to
the subject.
Infusion-related Reactions of Grade 1 or Grade 2
If the investigator assesses a Grade 1-2 IRR adverse event to be related to administration of study
drug, then the daratumumab administration should be paused. When the subject's condition is
stable, daratumumab administration may be restarted at the investigator's discretion.
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher
event of bronchospasm that does not respond to systemic therapy and does not resolve within
6 hours from onset, then the subject must be withdrawn from daratumumab treatment.
Infusion-related Reactions of Grade 3 or Higher
For IRR adverse events (other than laryngeal edema or bronchospasm) that are Grade 3, the
daratumumab administration must be stopped and the subject must be observed carefully until
resolution of the adverse event or until the intensity of the event decreases to Grade 1, at which
point the daratumumab administration may be restarted at the investigator’s discretion. If the
intensity of the adverse event returns to Grade 3 after restart of the daratumumab administration,
then the subject must be withdrawn from daratumumab treatment.
For IRR adverse events that are Grade 4, the daratumumab administration must be stopped and the
subject withdrawn from daratumumab treatment.
Recurrent Infusion-related Reactions
If a Grade 3 IRR (or Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher event of
bronchospasm) recurs during or within 24 hours after a subsequent daratumumab administration,
the daratumumab treatment must be discontinued.
6.5. 
Dose Delays and Dose Modification
6.5.1. 
Dose Modification
Dose modification of daratumumab (increase or decrease) is not permitted. Dose delay is the
primary method for managing daratumumab-related toxicities. On the first day of each new
treatment cycle and before each dose of daratumumab, the subject will be evaluated by the treating
physician for possible toxicities that may have occurred after the previous dose(s). Toxicities are
to be assessed according to NCI-CTCAE, Version 4.03. Cycle delays will be based on the toxicity
experienced during the previous cycle of therapy or newly encountered on Day 1 of a cycle.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
51
Approved, Date: 23 September 2024
6.5.2. 
Toxicity Management
Daratumumab must be held if any of the following criteria are met, to allow for recovery from
toxicity, regardless of relationship to study drug:
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
Grade 3 or higher thrombocytopenia
Febrile neutropenia
Neutropenia with infection, of any grade
Grade 3 or higher non-hematologic toxicities with the following exceptions:
Grade 3 nausea that responds to antiemetic treatment within 7 days
Grade 3 vomiting that responds to antiemetic treatment within 7 days
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
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
Daratumumab administration should be resumed when the toxicity has resolved to Grade
Dose delays affecting Day 1: If Day 1 of a cycle is delayed, the entire cycle will be delayed until
either the dose can be given or daratumumab is to be discontinued (see below). If the start of a
cycle is delayed, the starting day of subsequent cycles is adjusted accordingly.
Dose delays affecting days other than Day 1: If an administration does not commence within
the prespecified window (Table 7) of the scheduled administration date, then the dose will be
considered a missed dose. Administration may resume at the next planned dosing date. A missed
dose will not be made up.
Table 7: 
Daratumumab Administration Schedule for Within Cycle Doses
Cycles 
Frequency  
Dose Held  
Dosing Restart
1 and 2 
Weekly  
>3 days 
Next planned weekly dosing date
3 to 6 
Every 2 weeks 
>1 week  
Next planned biweekly dosing date
Any adverse event deemed to be related to daratumumab that requires a dose hold of >28 days due
will result in permanent discontinuation of daratumumab. If a dose delay occurs, then PK and
pharmacodynamic assessments should be performed on the actual day of study drug
administration, not on the original scheduled administration day.
In case the dose is to be delayed because of reasons other than toxicity, the aforementioned rules
should be applied as well (refer to Section 6). However, every effort should be made to avoid dose

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
52
Approved, Date: 23 September 2024
delays because of reasons other than toxicity (refer to Section 6.5.3 for details on interrupted or
missed doses).
6.5.3. 
Interruption or Missed Doses
A daratumumab dose held for more than 3 days from the per-protocol administration date for any
reason other than toxicities suspected to be related to daratumumab should be brought to the
attention of the sponsor at the earliest possible time. Subjects missing ≥3 consecutive planned
doses of daratumumab for reasons other than daratumumab-related toxicity should be withdrawn
from treatment, unless, upon consultation with the sponsor and the review of safety and efficacy,
continuation is agreed upon.
7. 
TREATMENT COMPLIANCE
Daratumumab will be administered by qualified study-site personnel, and the details of each
administration will be recorded in the electronic case report form (eCRF). Subjects will be
provided with a treatment diary which will be used to assess the use of predose and postdose
medications at home. Additional details are provided in the Site Investigational Product Procedures
Manual.
8. 
PRESTUDY AND CONCOMITANT THERAPY
Throughout the study, investigators may prescribe any concomitant medications or treatments
deemed necessary to provide adequate supportive care except for those listed in Section 8.3.
Routine systemic use of the following concomitant medications will be collected in the eCRF and
recorded in the source documents as specified in the Time and Events Schedule (Table 1):
Growth factors
Transfusions
Anti-infectives (antibacterials, antivirals, and antimycotics)
Corticosteroids
Anti-arrhythmics and other cardiac supportive therapy
Anti-epileptics
Centrally acting psychiatric medication
Antihistamines, and other medications targeting postdose systemic reactions
Bisphosphonates, denosumab
Any anticancer therapy (including radiation)
The use of concomitant medications used to treat adverse events will be collected as specified in
the Time and Events Schedule (Table 1).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
53
Approved, Date: 23 September 2024
8.1. 
Recommended Therapies
Prophylaxis for herpes zoster reactivation, as per institutional guidelines, is recommended during
the Treatment Phase for subjects in the daratumumab arm (Arm B). Prophylaxis for pneumocystis
carini/jirovecci pneumonia, according to institutional guidelines, should be considered for subjects
in Arm B (daratumumab).
8.2. 
Permitted Therapies
Subjects are to receive full supportive care during the study. The following medications and
supportive therapies are examples of support therapies that may be used during the study:
Constipation prophylaxis (eg, adequate hydration, high-fiber diet, and stool softeners, if
needed)
Prophylactic antiemetics, with the exception of corticosteroids, in subjects with history of
nausea or vomiting
Stable standard dosing of a bisphosphonate or denosumab as indicated for osteoporosis
unrelated to MM is allowed.
Other symptoms may be managed according to institutional guidelines provided prohibited
therapies are not administered (see Section 8.3).
8.3. 
Prohibited Therapies
Use of the treatments listed below is prohibited during the study:
Other agents that target CD38
Medications used for other indications that have anti-myeloma properties (eg, interferon and
clarithromycin; Ghosh 20138)
Administration of approved or investigational treatments for SMM or MM or both (including
but not limited to conventional chemotherapies, IMiDs, or PIs)
Therapeutic use of systemic corticosteroids for MM (>280 mg cumulative dose of prednisone
or equivalent for 4 weeks) (other than those given for IRRs as described in Section 6.3)
Ongoing treatment with other monoclonal antibodies (eg, infliximab, rituximab),
immunomodulators (eg, abatacept, methotrexate, azathioprine, cyclosporine), or other
treatments that are likely to interfere with the study procedures or results
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
54
Approved, Date: 23 September 2024
8.4. 
Management of Hepatitis B Virus Reactivation
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, HBV DNA
testing by PCR is mandatory for subjects at risk for HBV reactivation (see Section 9.7).
For subjects 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 Schedules (Table 1 and Table 2) summarize the frequency and timing of
efficacy, PK, immunogenicity, pharmacodynamics, biomarker, PRO, and safety measurements
applicable to this study. Every effort should be made to keep subjects on the planned study
schedule. For subjects in both study arms for whom there are no safety concerns, tele-health
(conducted via phone or video conference) visits are permitted per the clinical judgement of the
investigator, and where feasible and permissible by local policy and regulations. All assessments
should be followed with in person examination, if clinically indicated. Refer to the Time and
Events Schedule (Table 1 and Table 2) for guidance.
Patient reported outcome assessments should be completed after informed consent forms are
signed, but before any tests, procedures, or other consultations that may influence subject
perception scheduled for the same day as the PRO assessments are collected. If the subject is
unable to complete the PRO assessments, the reason for not completing the questionnaires will be
documented (ie, too ill, subject refused, etc). Refer to Section 9.5 for details.
The maximum blood volume for the study is estimated at approximately 55 mL during screening,
115 mL during the first year for Arm A (active monitoring), and 302 mL for Arm B
(daratumumab). In the Follow-up Phase, subjects prior to PD will continue to have approximately
20 mL blood drawn every 3 months for disease evaluations. The maximum total blood volume for
a subject completing the projected study duration of approximately 8 years is estimated at 546 mL
for Arm A (active monitoring) and 895 mL for Arm B (daratumumab). 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 ICF is signed. During the Screening Phase, eligibility criteria
will be reviewed and a complete clinical evaluation will be performed as specified in the Time and
Events Schedule. Screening procedures will be performed within 35 days before randomization;

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
55
Approved, Date: 23 September 2024
however, 12-lead ECGs, imaging (LDCT, PET-CT, 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. Imaging from routine standard of care assessments can be used only
if these meet the minimum requirements as set by the current version of the Image Acquisition
Guidelines.
Eligibility of the subject disease status is based on central screening laboratory results and on an
independent review of screening images after confirmation of eligibility by the site. For optimal
assessment of the screening images by the independent reviewers, additional clinical data,
including benign/post-traumatic pre-existing bone lesions, data of recent bone marrow procedures,
and general medical history, will be included in the independent review.  Details (diagnosis,
location, duration) on benign/post-traumatic pre-existing bone lesions that can be seen on the
screening images (eg, old fractures) and were also present on previous imaging are to be reported
in the CRF (see Section 9.2.7).
If a subject does not meet all inclusion and exclusion criteria (is a screen failure) but at some point
in the future is expected to meet the subject eligibility criteria, then the subject may be rescreened.
Subjects who are rescreened will be assigned a new subject number, undergo the informed consent
process, and then restart a new Screening Phase.
9.1.3. 
Active Monitoring Phase or Treatment Phase
Details of the procedures performed during the Active Monitoring Phase (Arm A) and the
Treatment Phase (Arm B) are outlined in the Time and Events Schedule (Table 1). Subjects in the
daratumumab arm (Arm B) should start study treatment within 5 days after randomization. Active
monitoring of subjects in Arm A will start immediately after randomization. All subjects will be
closely monitored for adverse events, laboratory abnormalities, and clinical response. Clinical
evaluations and laboratory studies may be repeated more frequently, if clinically indicated. If
disease progression is confirmed in a subject during the Active Monitoring Phase, then the subject
will discontinue active monitoring, complete the End-of-Active Monitoring Visit, and enter the
Follow-up Phase. For subjects in the Active Monitoring (Arm A), the End-of- Active-Monitoring
visit is to be performed within 30 days (±3 days) of confirmation of disease progression by
investigator. If disease progression is confirmed in a subject in the daratumumab arm, then the
subject will discontinue study treatment, complete the End-of-Treatment Visit (30 days ±3 days
after the last dose of daratumumab, or before starting subsequent therapy, if earlier), and enter the
Follow-up Phase. Biochemical progression without meeting diagnostic criteria for MM (Table 9)
does not constitute a reason to discontinue study treatment.
End-of-Active Monitoring Visit (Arm A)/End-of-Treatment Visit (Arm B)
Unless a subject withdraws consent for study participation or is lost to follow-up, an End-of-Active
Monitoring Visit (Arm A)/End-of-Treatment (Arm B) Visit is to occur. For subjects in Arm A, the
End-of Active Monitoring Visit is to occur after 36 months (±3 days) (from the date of
randomization) of active monitoring if disease progression was not yet confirmed earlier, or if the
subject did not meet other criteria for discontinuation prior to 36 months (refer to Section 10.2).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
56
Approved, Date: 23 September 2024
In case of discontinuation because of reasons other than disease progression, the End-of-Active
Monitoring/End-of-Treatment Visit is to be performed within 30 days (±3 days) after notification
that the subject will discontinue Active monitoring/treatment. For subjects in the Arm B, the End-
of-Treatment Visit is to occur 30 (±3) days after the last dose of daratumumab. Every effort should
be made to conduct the End-of-Active Monitoring Visit (Arm A)/ End-of-Treatment Visit (Arm B)
before the subject starts subsequent therapy. If a subject is unable to return to the site for the End-
of-Active Monitoring (Arm A)/End-of-Treatment Visit (Arm B), then the subject should be
contacted to collect information on adverse events and concomitant medications used to treat
adverse events as specified in Section 12.3.1. If the End-of-Treatment Visit (Arm B) occurs earlier
than 30 days after the last dose of daratumumab SC, then the subject should be contacted after 30
days have passed from the last dose of daratumumab SC, so that all adverse events that occurred
within the 30-day period from the last dose of daratumumab SC are recorded. Additional
information on reporting of adverse events is presented in Section 12.
9.1.4. 
Follow-Up Phase
The Follow-up Phase will begin once the subject completes 39 cycles or 36 months (whichever
occurs first) of active monitoring (Arm A) or daratumumab treatment (Arm B). Reasons for
premature discontinuation of active monitoring or daratumumab treatment are listed in
Section 10.2. Subjects who discontinue before PD must continue to have disease evaluations as
described in Section 9.2, until study completion or confirmed PD (or other reasons as outlined in
Section 10). If subjects have not progressed to MM, then no other treatment for SMM or MM is
allowed during the study. Follow-up for first-line MM treatment (including the response to first-
line MM treatment), secondprimary malignancies, and survival status will be obtained as specified
in the Time and Events Schedule (Table 1). Survival will be followed until the end of the study
and at a frequency of at least every 12 weeks until PD. After PD, survival is to be followed at least
every 6 months, until the end of the study.
If PRO or survival information is obtained via telephone contact, then written documentation of
the communication must be available for review in the source documents. If the subject has died,
then the date and cause of death will be collected and documented in the eCRF.
9.2. 
Efficacy Evaluations
Disease assessments will be performed every 12 weeks until PD. A window of ±7 days around the
scheduled assessment date is allowed. For subjects with treatment delays, disease assessments
should be performed at the scheduled disease assessment dates. They do not need to be repeated
at the time of delayed daratumumab administration. Disease progression, if based on laboratory
results only, must be confirmed by a consecutive assessment. A repeated investigation for
confirmation of disease progression does not need to occur within a specified timeframe and could
potentially occur on the same date (at a later timepoint). However, the original value meeting
disease progression and the confirmation value must be consecutive (ie, no intermediate values
that do not meet the definition of disease progression). It is not a requirement to have a repeat
investigation if disease progression is based on at least 2 of the laboratory tests of Hb, calcium,

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
57
Approved, Date: 23 September 2024
renal function and FLC at the same assessment date (eg, when Hb <10 g/dL and creatinine
clearance <40 mL/min are present on the same day).
Disease assessments will be performed according to the Time and Events Schedule (Table 1).
Disease evaluations scheduled for treatment days should be collected before study drug is
administered. Disease progression to MM will be evaluated using the IMWG diagnostic criteria
for MM (Table 9) (Rajkumar 201429). For subjects who discontinue active monitoring (Arm A) or
daratumumab (Arm B) before PD, disease assessments should be performed according the Time
and Events Schedule (Table 1) until study completion or confirmed PD (or other reasons as
outlined in Section 10).
Per protocol Amendment 6, disease assessments will only be performed locally and locally
diagnosed disease progression will be reported based upon study investigator review per IMWG
criteria.
9.2.1. 
Assessment of Response
Per protocol Amendment 6, assessment of response will no longer be collected.
This study will use the IMWG consensus recommendations for MM treatment response criteria
(Durie 20077, Rajkumar 201131, Kumar 201614) presented in Table 8. For quantitative
immunoglobulin (QIg) at baseline, M-protein, and immunofixation measurements in serum and
24-hour urine, the investigator will use results provided by the central laboratory.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
58
Approved, Date: 23 September 2024
Table 8: 
International Uniform Response Criteria Consensus Recommendations
Responsea 
Response Criteria
Stringent complete 
Response (sCR) 
CR as defined below, plus
Normal FLC ratio, and
Absence of clonal PCs by immunohistochemistry, immunofluorescenceb or 2- to 4-
color flow cytometry.
Complete response 
(CR)c 
Negative immunofixation on the serum and urine, and
<5% PCs in bone marrow.
Very good partial 
Response (VGPR)c 
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, then 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, then a ≥50% reduction in bone marrow PCs is required in place of
M-protein, provided baseline bone marrow PC percentage was ≥30%.
Stable disease 
Not meeting criteria for CR, VGPR, PR, or symptomatic MM.
IMWG=International Myeloma Working Group; FLC=free light chain; MM=multiple myeloma; 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.
a 
Subjects will continue in the last confirmed response category until there is confirmation of progression or
improvement to a higher response status; subjects cannot move to a lower response category.
b 
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.
c 
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.
9.2.2. 
Assessment of Disease Progression to Multiple Myeloma
Assessment of Progression to Multiple Myeloma (diagnostic progression)
During the study, disease progression will be measured according to the published international
uniform diagnostic criteria for MM established by the IMWG (Rajkumar 201429) presented in
Table 9. Progression evaluations for the primary endpoint/final analysis will be based on IRC
review, in a blinded fashion, to objectively and consistently implement the IMWG diagnostic
criteria for MM. The IRC responsibilities and procedures will be documented in a separate IRC
charter.
Per protocol Amendment 6, disease progression will be evaluated locally by the study investigator
using the IMWG criteria in Table 9. Disease progression will no longer be centrally evaluated by
IRC. Local determination of disease progression should be reported in the eCRF.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
59
Approved, Date: 23 September 2024
Table 9: 
Diagnostic Criteria for Progression to Multiple Myelomaf
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 <40 mL/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 the lower limit of
normal
Bone disease (one or more osteolytic lesions on LDCT, PET-CT, or CT)c
Clonal bone marrow plasma cell percentagea ≥60%
Involved: uninvolved serum free light chain ratiod ≥100
>1 focal lesionse on MRI studies.
CT=computed tomography; LDCT=low-dose whole body computed tomography; MRI=magnetic resonance
imaging; PET-CT=positron-emission tomography with computed tomography; ULN=upper limit of normal.
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 (per IMWG criteria; however, bone marrow aspirate only is
acceptable for this study); 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, then 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 ≥100 mg/L. To avoid overcalling progression based on FLC ratio, the
progression will be determined based on modified FLC criteria combining IMWG progression criteria with
IMWG FLC ratio criteria, as described below.
e. Each focal lesion must be 5 mm or more in size.
f. . Per protocol Amendment 6, progressive disease identification is based on local assessment only.
From Rajkumar 2014.29
Free light chain criteria are designed for de novo diagnosis rather than for progression of SMM to
MM. Prior experience suggests that therapy, especially with daratumumab, can in some instances
preferentially reduce the uninvolved light chain, therefore suggesting progression despite actual
therapeutic response/absolute reduction of the involved light chain. To avoid overcalling
progression based on FLC ratio, the progression will be determined based on modified FLC criteria
combining IMWG progression criteria with IMWG FLC ratio criteria:
Serum FLC (involved/uninvolved) light chain ratio ≥100
Involved light chain ≥100 mg/L
Difference of involved –uninvolved light chain shows confirmed increase ≥25% from lowest
value (nadir)
Assessment of Biochemical Progression
Biochemical progression is defined as an increase of 25% from nadir value in any one of the
following:
Serum M-component (absolute increase must be ≥5 g/L)
Urine M-component (absolute increase must be ≥200 mg/24 hours).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
60
Approved, Date: 23 September 2024
If the lowest M component was ≥50 g/L, then a serum M-protein increase ≥10 g/L is sufficient for
biochemical progression.
In subjects without measurable serum and urine M-protein levels: the difference between involved
and uninvolved FLC levels (ie, absolute difference) must be increased by 25% from nadir and the
absolute increase must be >100 mg/L.
Biochemical progression is to be considered as an important risk factor to evolve to diagnostic
progression and those subjects should be monitored closely. However, biochemical progression
alone does not constitute a reason for discontinuing therapy.
9.2.3. 
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.
Per protocol Amendment 6, CRAB Criteria-related laboratory tests should be performed locally.
Serum calcium corrected for albumin
Creatinine clearance or serum creatinine
Hemoglobin
Serum Calcium Corrected for Albumin
According to CRAB criteria, corrected serum calcium >11 mg/dL or >2.75 mmol/L indicates
progression to MM, if it is not attributable to any other cause (see Table 9). Measurement of free
ionized calcium is the preferred test for determining hypercalcemia. Free ionized calcium levels
>1.5 mmol/L are considered to be hypercalcemic (according to CRAB criteria) for this study.
As an alternative, the serum calcium level must be adjusted for abnormal albumin levels
(“corrected serum calcium”). The formula for adjustment is presented in Attachment 6.
The elevation in calcium should not be due to another reason, such as hyperparathyroidism. An
appropriate workup should be performed, including, at a minimum, laboratory determination of
parathyroid hormone.
Subjects who, at screening, have clinically stable hypercalcemia that has existed for several years
and did not show any deterioration during the prior year, can be considered for eligibility as long
as the causality of hypercalcemia is proven to be attributed to a disease other than multiple
myeloma (eg, hyperparathyroidism). Prior to screening, a case-by-case discussion with the medical
monitor may occur with the inclusion of prior laboratory results.
Creatinine Clearance
According to CRAB criteria, measured or estimated creatinine clearance <40 mL/min using
validated equations (preferred), creatinine >2 mg/dL or >177 μmol/L indicates progression to MM
if it is not attributable to any other cause. Decrease in glomerular filtration rates should not be due

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
61
Approved, Date: 23 September 2024
to non-myeloma-related etiology; an appropriate workup should be performed. A kidney biopsy
should be strongly considered when there is no increase in FLC or increase in urine Bence-Jones
proteins. Measured or estimated glomerular filtration rates (according to the Modification of Diet
in Renal Disease (MDRD) [Levey 200619] formula; Attachment 2), as per local practice, are
preferred over a fixed serum creatinine concentration. For subjects who discontinue treatment prior
to PD, these measurements should continue to be analyzed every time disease assessments are
performed.
Subjects who, at screening, have clinically stable renal insufficiency that has existed for several
years and did not show any deterioration during the prior year, can be considered for eligibility as
long as the causality of renal insufficiency is proven to be attributed to a disease other than multiple
myeloma (eg, glomerulonephritis). Prior to screening, a case-by-case discussion with the medical
monitor may occur with the inclusion ofprior laboratory and biopsy results.
Hemoglobin
According to CRAB criteria, hemoglobin <10 g/dL or >2 g/dL lower than the lower limit of normal
indicates progression to 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 (at a
minimum, iron, ferritin, transferrin, manual smear review, Coombs testing, lactate dehydrogenase,
vitamin B12, and folate) should be carried out to determine that there is no other underlying cause
of anemia. Positive tests thought to at least partially explain the anemia should continue to be
analyzed every time disease assessments are performed. In questionable cases, especially when
there is anemia with no concomitant increase in measurable disease, a bone marrow examination
must be performed to clarify the diagnosis of anemia before progression to MM can be diagnosed.
Subjects who, at screening, have anemia that has existed for several years and did not show any
decline during the prior year, can be considered for eligibility as long as the anemia’s causality is
proven to be attributed to a disease other than multiple myeloma (eg, iron deficiency, Vitamin
B12 deficiency, thalassemia). Prior to screening, a case-by-case discussion  with  the medical
monitor may occur with the inclusion of prior laboratory results. (Refer to Appendix 18.1 for
specific requirements for France.)
9.2.4. 
Myeloma Protein Measurements in Serum and Urine
Per protocol Amendment 6, M-protein measurements will no longer be analyzed by the central
laboratory and will only be analyzed locally.
The following tests will be performed.
Serum quantitative immunoglobulins (QIgs): All subjects will be evaluated for IgG, IgA, IgM,
IgE, and IgD at Screening. During the study, subjects with IgD or IgE disease will be evaluated
for IgG, IgA, IgM, IgE, and IgD and subjects with IgG, IgA, or IgM disease will be evaluated
for IgG, IgA, and IgM.
Serum M-protein quantification by electrophoresis (SPEP)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
62
Approved, Date: 23 September 2024
24-hour urine M-protein quantitation by electrophoresis (UPEP)
Serum immunofixation electrophoresis (SIFE)/urine immunofixation electrophoresis
Serum FLC assay
Blood and 24-hour urine samples for disease assessments will be collected during screening and
as specified in the Time and Events Schedule (Table 1) until the development of PD. If blood and
24-hour urine disease assessment samples collected at screening were taken within 14 days before
Cycle 1 Day 1, then it is not mandatory to collect these samples again at the Cycle 1 Day 1 visit.
Repeat laboratory studies in cases where screening values were obtained >14 days from Cycle 1
Day 1 only need to be obtained for Arm B subjects.
In subjects with a baseline UPEP result below the level of measurable disease (<200 mg/24 hours),
UPEP analysis will be repeated only at the time of suspected 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. In subjects without measurable disease in the urine at diagnosis who
show rising involved serum FLC (or raise other clinical concerns), UPEP may be performed at the
investigator's discretion to assess for excretion of light chains. Baseline value is defined as the last
value prior to initiating treatment (Arm B) or prior to randomization for active-monitoring subjects
(Arm A).
Daratumumab is an immunoglobulin that may interfere with clinical SPEP/SIFE assessments. In
cases in which daratumumab interference is suspected, a reflex assay confirming the presence of
daratumumab will be performed (Attachment 7). In cases where CR or sCR is suspected and the
reflex assay confirms that daratumumab is present on SPEP/SIFE, 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.
9.2.5. 
2-microglobulin and Lactate Dehydrogenase
As per protocol Amendment 6, 2-microglobulin and lactate dehydrogenase at time of disease
progression will no longer be analyzed by the central laboratory and will only be analyzed locally.
9.2.6. 
Bone Marrow Examination
Per protocol Amendment 6, central lab MRD testing will be discontinued. Bone marrow aspirate
should be performed locally for morphology and cytogenetics by FISH at PD per the Time and
Events Schedule in Table 10.
Bone marrow aspiration will be performed for disease assessments for all subjects as specified in
the Time and Events Schedule. For details of bone marrow analysis, see Table 10. The volume
required for these tests will be based on laboratory standard practices. Details for performing FISH
are provided in the Laboratory Manual. A portion of any bone marrow aspirates may be sent to a
laboratory for MRD clone identification or molecular subtyping.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
63
Approved, Date: 23 September 2024
Cytogenetic FISH testing will include the specified probes [del(17p13), amp(1q21), t(4;14) and
t(14;16). If the subject had a routine bone marrow aspirate performed prior to screening, and no
additional aspirate is performed, (formalin-fixed paraffin-embedded (FFPE) samples are the only
available sample for FISH), these samples can be analyzed by the local site laboratory where every
effort should be made to obtain FISH using the specified probes [del(17p13), amp(1q21), t(4;14)
and t(14;16)]. NOTE: An additional bone marrow aspirate, if feasible, should be performed within
2 months after the first date of the diagnosis of PD.
Table 10: 
Bone Marrow Testing
Local Testing 
Central Testing
Per protocol Amendment 6, all central lab
testing detailed below will be discontinued.
Screening 
Disease characterization (morphology and
either 
immunohistochemistry,
immunofluorescence, or flow cytometry).
Cytogenetics by FISH (centrally or locally
[for China only in case only FFPE is
available]). FISH must include probes for
del(17p13), 
amp(1q21), 
t(4;14) 
and
t(14;16) [for China only in case only FFPE
is available].
Cytogenetics by FISH (centrally or locally [for
China only in case only FFPE is available]). If a
fresh bone marrow aspirate is collected at
Screening, then a portion may be sent to a central
laboratory for MRD clone identification or
molecular subtyping. If a fresh bone marrow
aspirate will not be performed at Screening
because a sample is available within 56 days
prior to randomization, then non-decalcified
diagnostic tissue (bone marrow aspirate slides,
touch-prep from biopsy [rolled biopsy] slides, or
clot specimen slides) should be collected for
MRD assessment.
On Study (every 2 years until 
PD or yearly if a follow-up is 
BMPC ≥40%. If BMPC 
≥40% at screening, then 
obtain every 12 months) 
Disease characterization (morphology and
either 
immunohistochemistry,
immunofluorescence, or flow cytometry)
to determine extent of plasma cell
infiltration (plasma cell infiltration)
CR, sCR  
Per protocol Amendment 6, 
central lab testing will be 
discontinued 
For response confirmation, additional bone
marrow aspirates or biopsies (or both) will 
be 
performed 
locally 
(Disease 
characterization [morphology and either
immunohistochemistry, 
immuno-
fluorescence, or flow cytometry]) to
confirm sCR or CR.
For 
sCR: 
immunohistochemistry,
immunofluorescence 
(requires 
kappa/
lambda ratio from analysis of ≥100 cells)
or 2- to 4-color flow cytometry.
A portion may be sent to a central laboratory
for potential MRD evaluation.
Maintained CR, sCR  
Per protocol Amendment 6, 
central lab testing will be 
discontinued 
Not applicable. 
If feasible for subjects who maintain CR or
sCR, a bone marrow aspirate sample will be
obtained 12 months after the date of the initial
CR.
Disease Progression 
Per protocol Amendment 6, 
central lab testing will be 
discontinued 
Bone marrow aspirate for 
cytogenetics by FISH should 
be performed locally. 
When suspected: Disease characterization: 
morphology 
and 
either 
immunohistochemistry, 
immunofluorescence, or flow cytometry. 
Cytogenetics by FISH1 (local testing) [for 
China only in case only FFPE is 
available]). FISH at suspected PD must
include probes for del(17p13), amp(1q21),
t(4;14) and t(14;16) [for China only in case
only FFPE is available]).
If feasible, a bone marrow aspirate may be
collected from subjects at disease progression
to evaluate mechanism of daratumumab
resistance. Cytogenetics by FISH (centrally or
locally [for China only in case only FFPE is
available]).
BMPC=bone marrow plasma cell; CR=complete response; FFPE=formalin-fixed paraffin-embedded; FISH=fluorescence in
situ hybridization; MRD=minimal residual disease; PD=progressive disease; sCR=stringent complete response.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
64
Approved, Date: 23 September 2024
9.2.7. 
Assessment of Bone Disease
Per protocol Amendment 6, central review of imaging studies will be discontinued. Imaging
studies and review should be performed locally according to the Time and Events schedule.
The presence of bone lesions will be evaluated locally. The site will review the screening images
first to confirm eligibility of study subject (no lytic lesions and/or ≤1 focal lesion with diameter
≥5 mm present unless proven benign/post-traumatic origin). After initial screening imaging
assessment by the site and confirming eligibility by the site, results of imaging studies
(ie, LDCT/CT/PET-CT/MRI) will be uploaded to a central repository and reviewed centrally. This
central review of screening images will be used to determine eligibility of subjects for study
participation (see Section 9.1.2). Presence of focal bone lesions will be evaluated by MRI, in
exceptional cases by PET-CT (see below). The presence of lytic bone lesions will be evaluated by
LDCT, PET-CT, or CT, including skull, entire vertebral column, pelvis, chest, humeri, femora,
and any other bones in which the investigator suspects involvement by disease radiography. Local
review will also be used to assess disease progression by evaluating the occurrence of bone disease.
During the Active Monitoring and Treatment Phases and before disease progression is confirmed,
imaging should be performed as indicated in the Time and Events Schedule (Table 1), to document
response or progression.
Lytic bone lesions (LDCT, PET-CT or CT)
The preferred method of assessment for osteolytic lesions is LDCT scan. Depending on local
practice, PET-CT or CT may be used as an alternative. Bone lesion assessments will be performed
at Screening and every 12 months until PD.
Focal Bone lesions (MRI)
MRI (spine and pelvis) will be performed to assess focal lesions at Screening and regularly during
the study, as indicated in the Time and Events Schedule. Positron emission tomography-computed
tomography (PET-CT) may be used as an alternative for those subjects for whom MRI is
contraindicated. However, the medical monitor is to be informed upfront about the reason why
MRI is contraindicated.
Disease Progression
Identification of >1 focal lesions on MRI is considered a Myeloma Defining Event (MDE). One
or more sites of osteolytic bone destruction (≥5 mm in size) seen on CT (including LDCT) or PET-
CT are considered an MDE. Increased uptake on PET-CT alone in >1 location without underlying
lytic lesions (focal lesions) is considered adequate for the diagnosis of MM only in subjects in
whom MRI is contraindicated (other reasons for increased PET signal, such as infection, should
be excluded); in all other subjects evidence of underlying osteolytic bone destruction is needed on
the CT portion of the examination. If the diagnosis of disease progression is obvious by imaging
investigations (LDCT, PET-CT, 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.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
65
Approved, Date: 23 September 2024
The suggested window for imaging studies is ±1 months. Studies triggered by biochemical
progression or suspected PD may replace a scheduled imaging study visit if the triggering event
occurs <1 month from the suggested window. If the triggering event occurs >1 month from the
suggested window for the next scheduled imaging study, then a dedicated study should be
performed. The suggested minimum interval between imaging studies of the same type is
3 months.
9.2.8. 
Best Response to First-line Multiple Myeloma Treatment
Best response to first-line MM treatment will be assessed by the investigator at 6-month intervals.
The investigator will assess response based on the IMWG response criteria for MM using local
lab evaluations.
9.3. 
Pharmacokinetics and Immunogenicity
Per protocol Amendment 6, no further Pharmacokinetics and Immunogenicity samples will be
collected.
9.3.1. 
Evaluations
Samples to assess both the serum concentration (PK) of daratumumab and the generation of
anti-daratumumab antibodies (immunogenicity) will be obtained from all subjects in the
daratumumab group according to the Time and Events Schedule (Table 2). Samples will also be
collected from all subjects in the daratumumab group to evaluate the immunogenicity of rHuPH20
according to the Time and Events Schedule (Table 2).
The exact dates and times of blood sampling must be documented. Refer to the Laboratory Manual
or equivalent document for sample collection requirements. Collected samples must be stored
under the specified and controlled conditions for the temperatures indicated in the laboratory
manual. Samples collected for determining serum concentrations/immunogenicity of
daratumumab or immunogenicity of rHuPH20 in this study may be retained to address questions
about drug characteristics that may arise at a later time point.
9.3.2. 
Analytical Procedures
Samples will be analyzed to determine concentrations of daratumumab or generation of antibodies
to daratumumab or rHuPH20 using validated immunoassay methods by or under the supervision
of the sponsor. For the daratumumab immunogenicity assessments, serum samples will be
screened for antibodies binding to daratumumab and serum titer will also be determined from
confirmed positive samples. Other immunogenicity analyses (eg, assessment of neutralizing
capabilities) may be performed to further characterize the immune responses that are generated.
For the rHuPH20 immunogenicity assessments, plasma samples will be screened for antibodies
binding to rHuPH20 and will be assessed in confirmatory and titer assays as necessary.
Neutralizing antibody assessments may also be performed to further characterize immune
responses that are generated.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
66
Approved, Date: 23 September 2024
9.3.3. 
Pharmacokinetic Parameters
Pharmacokinetic samples to determine serum concentration of daratumumab will be obtained from
subjects in the daratumumab group. The PK parameters are defined as:
Cmax  
Maximum observed serum concentration
Cmin  
Minimum observed serum concentration
If sufficient data are available, other PK parameters may be calculated. The Cmin  and Cmax will be
determined based on the assigned collection timepoints. If there are sufficient data, population-PK
analysis of serum concentration-time data of daratumumab may be performed using nonlinear
mixed-effects modeling and may 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 in the daratumumab group will be
assessed for the generation of anti-daratumumab antibodies (immunogenicity) according to the
Time and Events Schedule. Daratumumab concentration will be evaluated at all immunogenicity
time points to ensure appropriate interpretation of immunogenicity data. When both daratumumab
serum  concentration and immunogenicity analyses are specified, they will be performed on
aliquots from the same blood draw and no additional sampling is required. Plasma samples will
also be collected from all subjects in the daratumumab group  and assessed for antibodies to
rHuPH20.
When an IRR occurs associated with the second daratumumab administration or beyond, 2 blood
samples should be obtained, if possible, for determination of both antibodies to daratumumab and
antibodies to rHuPH20. No unscheduled samples need to be collected for IRRs associated with the
first administration of daratumumab. Daratumumab serum concentration will also be determined
from the daratumumab IRR sample for the purpose of interpreting immunogenicity data. These
samples will be stored and evaluated if deemed necessary. If an IRR results in treatment
discontinuation, then a subject should undergo all scheduled safety and efficacy evaluations.
Procedures for sample collection, preparation, identification, storage, and shipment will be
provided in the Laboratory Manual or equivalent document. Samples collected for the analysis of
daratumumab immunogenicity/serum concentration or rHuPH20 immunogenicity may
additionally be used to evaluate safety or efficacy aspects that address concerns arising during or
after the study period or for the evaluation of relevant biomarkers by the sponsor or sponsor’s
designee.
Subjects who discontinue treatment or withdraw from the study before confirmation of PD should
have samples collected at the time of early discontinuation. Subjects who discontinue treatment
will also be asked to return for immunogenicity evaluation during the Follow-up Phase.
9.4. 
Biomarkers
Per protocol Amendment 6, biomarker assessments by central laboratory will be discontinued.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
67
Approved, Date: 23 September 2024
Biomarker assessments will focus on 3 main objectives: determining the clinical benefit
(ORR, PFS, and OS) of daratumumab in subjects with genetic modifications (del(17p13),
amp(1q21), t(4;14), t(14:16), or other risk-associated molecular subtypes), depth of response by
the absence of MRD, and to evaluate the immunophenotype of subjects with SMM for potential
immune cell contributions to daratumumab response. All biomarker assessments will be performed
centrally.
Bone marrow aspirates may be collected at screening and following treatment as outlined in the
Time and Events Schedule. Bone marrow aspirates may be used for DNA/RNA sequencing in
subjects with genetic modifications (del(17p13), amp(1q21), t(4;14), t(14:16), or other
risk-associated molecular subtypes) and to monitor for potential predictive biomarkers of response
or resistance such as changes in CD38, complement inhibitor protein expression, and changes in
expression patterns of genes associated with ADCC, CDC, or other mechanisms of action of
daratumumab.
In addition, baseline bone marrow aspirates may be subjected to DNA sequencing in order to
establish the myeloma clone for MRD monitoring. A fresh bone marrow aspirate at Screening for
all subjects is required, if possible, for MRD assessments. If a fresh bone marrow aspirate will not
be performed at Screening because a sample is available within 56 days prior to randomization,
then non-decalcified diagnostic tissue (bone marrow aspirate slides, touch-prep from biopsy
[rolled biopsy] slides, or clot specimen slides) should be collected for MRD assessment. For
subjects who achieve a sCR or CR, additional bone marrow aspirate may be used for assessment
of MRD by next generation sequencing (NGS) of immunoglobulin heavy and light chains (Vij
201435). For subjects that maintain a sCR/CR, MRD may also be assessed at 12 months after date
of initial sCR/CR in bone marrow aspirate. All MRD samples will be stored and analyzed if ORR
data support testing. 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 SIFE and preventing determination of CR, subjects with VGPR may
also be evaluated for MRD by NGS.
A whole blood sample will be drawn at time points indicated in the Time and Events Schedule to
evaluate immune cell populations by methodologies such as cytometry by time of flight, and to
reserve plasma for potential biomarker 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. Plasma-based
analyses may also be used to evaluate changes in factors such as cytokines, complement proteins,
soluble CD38, soluble CD59, IFNγ, granzyme, perforin, and/or tumor associated DNA in
circulation to evaluate potential biomarkers of response and resistance.  Stool samples may be
collected at time points indicated in the Time and Events Schedule and DNA sequencing may be
performed to evaluate the gut microbiome.
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

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
68
Approved, Date: 23 September 2024
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 (Table 1).
9.5. 
Patient-reported Outcomes
The EORTC QLQ-C30, select items from the EORTC QLQ-MY20, and the EQ-5D-5L are
included to assess subject’s report of symptoms, functioning, and HRQoL.
The EORTC QLQ-C30 includes functional scales (physical functioning, role functioning,
emotional functioning, cognitive functioning, and social functioning), symptom scales
(fatigue, nausea and vomiting, and pain), and a Global Health Status scale (Attachment 8).
Reliability, validity, and clinically meaningful change have been demonstrated among patients
with MM (Wisloff 199637, Wisloff 199738). The EORTC Multiple Myeloma Module
(QLQ-MY20) has been designed to use alongside the EORTC QLQ-C30 as a validated
MM measure (Cocks 20074). Only the 3 questions in the future perspective scale and the 6
questions in the disease symptoms scales will be administered (Attachment 9). The EQ-5D-5L is
a generic preference-based measure of health status (Attachment 10). The 5-item questionnaire
assesses mobility, self-care, usual activities, pain/discomfort and anxiety/depression to compute a
single utility score plus a visual analog scale rating “health today” (Herdman 201110).
PRO endpoints are to be assessed during the screening window, the Active Monitoring/study
treatment phase, during pre-PD follow-up, at the time of disease progression, and during post-PD
phases. PRO data collection during the Screening Phase will serve as the baseline score, to be
collected after the subject signs informed consent. PRO assessments should be administered prior
to any interventions that could influence subject perceptions of their health state, scheduled for the
same day as PRO assessments are collected. The goal of data collection during the Active
Monitoring/study treatment phase is to measure changes in emotional functioning due to receiving
or not receiving treatment and to measure the impact of adverse events from daratumumab
treatment on HRQoL. The goal of data collection during the pre-PD phase is to measure HRQoL
after treatment and the value of potentially being in a pre-PD state longer because of treatment.
The goal of data collection during the post-PD phase is to measure the onset and severity of
symptoms associated with MM. Subject burden related to completion of PRO measures was a key
consideration in determining the number of assessments as well as the timepoints likely to observe
potential change in scores. If no in-person visit is scheduled, PROs can be
interviewer-administered during tele-health (conducted via phone or video conference) visits.
9.6. 
Medical Resource Utilization
Medical resource utilization data associated with medical encounters (including tele-health visits
[conducted via phone or video conference]), will be collected in the eCRF by the investigator and
study-site personnel for all subjects at the disease assessment visits and at Months 3 and 6, post-
PD. Protocol mandated procedures, tests, and encounters are excluded. The data collected will be

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
69
Approved, Date: 23 September 2024
used to conduct exploratory analyses that may be used to support the value story and cost-
effectiveness modelling for market access. The data collected include:
Number and characteristic of diagnostic and therapeutic tests procedures (inpatient and
outpatient)
Number and duration of hospitalization (total length of stay [days], including duration by each
hospital unit (intensive care unit)
Outpatient medical encounters (including physician, nurse practitioner or emergency room
visits, tests and procedures)
Please see eCRF completion guidelines for more details.
9.7. 
Safety Evaluations
Details regarding the IDMC are provided in Section 11.12. Safety will be measured by adverse
events, physical examinations, ECGs, SC injection-site evaluations, clinical laboratory test results
(hematology and chemistry), and ECOG performance status. All toxicities will be graded
according to the NCI-CTCAE Version 4.03. Any clinically relevant changes occurring during the
study must be recorded on the Adverse Event section of the eCRF. Any clinically significant
abnormalities persisting at the end of the study/early withdrawal will be followed by the
investigator until resolution or until a clinically stable endpoint is reached.
Based on the previous human experience with daratumumab, in vitro studies, and animal
toxicological findings, IRRs/allergic reactions, hemolysis, and thrombocytopenia will be closely
monitored. As a biologic agent, immunogenicity also will be monitored. Any of the safety
monitoring assessments may be performed more frequently, and adverse events should be
evaluated by the investigator according to the standard practice, if clinically indicated.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Time and Events.
Adverse Events
Adverse events (with the exception of progression to MM) will be reported by the subject (or,
when appropriate, by a caregiver, surrogate, or the subject's legally designated representative) as
specified in the Time and Events Schedule (Table 1). Adverse events will be followed by the
investigator as specified in Section 12, Adverse Event Reporting.
Clinical Laboratory Tests
As per protocol Amendment 6, central laboratory assessments will be discontinued.
Local Laboratory Testing
For subjects in the daratumumab arm, blood samples for serum chemistry and hematology will be
collected as outlined in the Time and Events Schedule and analyzed by the local laboratory before
each dosing to determine if the subject meets daratumumab treatment criteria described in
Section 6.5. The investigator must review the laboratory results, document this review, and record

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
70
Approved, Date: 23 September 2024
any clinically relevant changes occurring during the study in the adverse event section of the eCRF.
The laboratory reports must be filed with the source documents. Local laboratory data must be
entered in the eCRF for safety evaluation.
The following tests will be performed by the local laboratory:
Hematology Panel
-hemoglobin
- White blood cell count, absolute neutrophil count, and absolute lymphocyte count
-platelet count
Serum Chemistry Panel
- AST  
-potassium
- ALT  
-creatinine
-total bilirubina 
-glucose
-alkaline phosphatase 
- blood urea nitrogen or urea
-sodium  
-calcium and albumin-adjusted calcium
a if Gilbert’s disease, assessment of direct bilirubin
Hepatitis B Virus (HBV) serology and DNA Tests
- HBsAg, Anti-HBs, and Anti-HBc;
- HBV DNA by PCR for patients with serologic evidence of past HBV infection (all patients
during screening, arm B patients only Q12W during treatment, at the End of Treatment
Visit, and Q12W for up to 6 months after the last dose of study treatment)
Serum or Urine Pregnancy Testing
Serum or urine pregnancy testing at screening, and as clinically indicated, for women of
childbearing potential only
HBV Serology
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface
antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) at Screening. Additionally,
subjects ongoing in the Treatment Phase (arm B only) who are within 6 months of starting study
treatment when Protocol Amendment 3 is implemented will be required to have HBV serology
performed locally upon signing the updated ICF. (Refer to Appendix 18.1 for specific
requirements for France.)
HBV serology is not required at Screening or for subjects ongoing in the Treatment Phase (arm B
only) who are within 6 months of starting study treatment if this was performed as part ofstandard
of care within 3 months prior to first dose. For patients on treatment >6 months, testing is at
investigator discretion.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
71
Approved, Date: 23 September 2024
HBV DNA Tests
Subjects who are positive for Anti-HBc or Anti-HBs will undergo testing for hepatitis B DNA by
PCR. Subjects with serologic findings suggestive of HBV vaccination (Anti-HBs positivity as the
only serologic marker) and a known history of prior HBV vaccination do not need to be tested for
HBV DNA by PCR. During and following study treatment, subjects who have history of HBV
infection (positive for Anti-HBc and/or Anti-HBs, have a negative HBV DNA PCR at baseline
based on local laboratory assessments, and are randomized to Arm B) 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.
Indirect Antiglobulin Test (IAT)
Blood Type, Rh, and indirect antiglobulin test (IAT) should be done before the first dose of
daratumumab. Red blood cell (RBC) phenotyping (standard or extended) is an alternative to the
IAT test, if required by a local standard.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to identify
a subject’s antibodies to minor antigens so that suitable donor blood can be given for transfusion.
Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very low levels on
erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT
(Indirect Coombs Test). This positive result masks the detection of antibodies to minor antigens
and may prevent or delay blood banks from issuing donor blood for transfusion. This effect occurs
during daratumumab treatment and for up to 6 months after treatment ends. Subjects will receive
a patient identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT
or phenotyping) determined before the first administration of daratumumab along with information
on the IAT interference for healthcare providers/blood banks. Subjects are to carry this card
throughout the treatment period and for at least 6 months after treatment ends. Blood banks can
eliminate the daratumumab interference with IAT by treating reagent RBCs with dithiothreitol
(DTT) (Chapuy 20153).
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving
daratumumab include:
Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or
genotypically matched units
Providing ABO/RhD  compatible, K-negative units after ruling out or identifying
alloantibodies using DTT-treated reagent RBCs.
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is needed
emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant
hemolysis has been observed in daratumumab studies. For additional details, refer to the
Daratumumab Investigator Brochure.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
72
Approved, Date: 23 September 2024
Electrocardiogram (ECG)
A 12-lead ECG will be performed as specified in the Time and Events Schedule. During the
collection of ECGs, subjects should be in a quiet setting without distractions (eg, television, cell
phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection and
should refrain from talking or moving arms or legs. If blood sampling is scheduled for the same
time point as ECG recording, the procedures should be performed in the following order: ECG,
blood draw.
Physical Examination and ECOG Performance Status
A complete physical examination (including neurological examination) should be performed
during the Screening Phase. Thereafter, only a symptom-directed physical examination is required.
Abnormalities will be recorded in the appropriate section of the eCRF. ECOG performance status
will be used to evaluate the effect of the disease status on the activities of daily living. Height, and
weight should be measured as clinically necessary and will be recorded in the eCRF at screening
only. Vital signs should be monitored as clinically necessary. Only abnormal vital signs will be
recorded in the eCRF, as part of AE reporting in the AE reporting page.
Pulmonary Function Test
Subjects with known or suspected COPD must have a FEV1 test, as specified in the Time and
Events Schedule (Table 1). Refer to Section 6.3.2 of the protocol for details on subjects with higher
risk of respiratory complications.
9.8. 
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. Refer to the Time and Events Schedule for the timing and frequency of all sample
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
73
Approved, Date: 23 September 2024
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY TREATMENT/
WITHDRAWAL FROM THE STUDY
10.1. Completion
In the Active Monitoring group, a subject will be considered to have completed the study treatment
if the subject has completed 36 months of Active Monitoring. In the daratumumab group, a subject
will be considered to have completed study treatment if the subject has completed 39 cycles of
therapy or 36 months of daratumumab, whichever occurs first. A subject will be considered to
have completed the study (study completion defined in Section 17.9.1) if he or she has been
followed to the end of the study or has died before the end of the study. Subjects who have been
lost to follow-up, or have withdrawn consent for study participation before the end of the study,
will not be considered to have completed the study.
10.2. Discontinuation of Active Monitoring (Arm A) or Study Treatment (Arm B)
Discontinuation of Active Monitoring (Arm A) or Study Treatment (Arm B)
A subject will not be automatically withdrawn from the study if he or she has to discontinue active
monitoring or treatment before the end of the Active Monitoring or Treatment Phase. The End-of-
Active Monitoring/End-of-Treatment Visit and Follow-up Visit assessments should continue as
specified in the Time and Events Schedule (Table 1).
A subject must be discontinued from active monitoring or daratumumab treatment if:
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the subject to discontinue study treatment
A subject randomized to Arm B becomes pregnant unless the subject (or the subject's legally
acceptable representative), investigator, and sponsor agree the benefits outweigh the risks to
the fetus and continuation of study treatment is in the best interest of the subject. A subject
randomized to Arm A who becomes pregnant may remain on the study (refer to Section 4.3).
For a pregnant subject who remains on the study, any study procedures deemed by the
investigator to be potentially harmful to the fetus (eg, CT scans) may be deferred until the
subject is no longer 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
The subject’s daratumumab dose is held for more than 28 days due to treatment-related
adverse events (Arm B only)
The subject experiences disease progression (definition see Section 9.2.2). [Biochemical
progression without meeting IMWG diagnostic criteria for MM requiring therapy (Table 9)
does not constitute a reason for discontinuation of therapy.]
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
may be cured surgically may continue to receive active monitoring (Arm A) or the assigned

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
74
Approved, Date: 23 September 2024
study treatment (Arm B) and should continue to be followed for subsequent progression of
MM.
Before subjects discontinue active monitoring (Arm A) or study treatment (Arm B) due to
disease progression, sites will document disease progression by completing a disease progression
form as soon as possible and within 48 hours of disease progression assessment. The medical
monitor will confirm that treatment should be discontinued. After confirmation from the sponsor,
active monitoring (Arm A) or study treatment (Arm B) will be discontinued and the subject will
enter into Follow-up after completion of the End-of-Active Monitoring Visit or End-of-Treatment
Visit.
The primary reason for discontinuation of active monitoring or study treatment is to be recorded
in the eCRF.
10.3. Withdrawal from the Study (Arm A and Arm B)
A subject will be withdrawn from the study for any of the following reasons:
Lost to follow-up
Withdrawal of consent
Death
The study investigator, for any reason, stops the subject’s participation in the study
Sponsor terminates the study
If a subject discontinues active monitoring or study drug and withdraws from the study before the
end of the active monitoring or treatment phase, End-of-Active Monitoring or End-of-Treatment
Visit assessments should be obtained.
If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel
to contact the subject and determine the reason for discontinuation/withdrawal. The measures
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be
documented in the eCRF and in the source document. Study drug assigned to the withdrawn subject
may not be assigned to another subject. Subjects who withdraw will not be replaced. Additional
subjects will not be enrolled. If a subject withdraws from the study, assessments in the End-of-
Active Monitoring or the End-of-Treatment Visit should be obtained. If the reason for withdrawal
from the study is withdrawal of consent, no additional assessments are allowed. Public record
searches will be conducted, if permitted by local law.
10.4. Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5,
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will be
destroyed after they are no longer needed for the clinical study. Details of the sample retention for
research are presented in the main ICF.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
75
Approved, Date: 23 September 2024
11. 
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
11.1. Subject Information
The main analysis populations are:
Intent-to treat population, defined as all randomized subjects
Safety population, defined as all randomized subjects for subjects randomized to active
monitoring or all randomized subjects who received at least one dose of daratumumab for
subjects randomized to daratumumab
The intent-to-treat 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
The sample size calculation assumes that the median PFS for Arm A (active monitoring) is
30 months. The longer projected median PFS compared to the published 24 months was chosen to
account for the fact that ultra-high risk SMM subjects, who were included in earlier studies, are
now considered to have symptomatic MM according to the updated IMWG criteria, and to account
for the additional risk factors included to identify high-risk SMM for this study. It was further
assumed that daratumumab treatment will reduce the risk of the disease progression or death by
37.5%, ie, assuming a HR (daratumumab vs active monitoring) of 0.625, which translates to a
median PFS of 48 months for daratumumab. Taking into account the interim analysis, 165 PFS
events are needed to achieve a power of at least 85% to detect this hazard ratio with a log-rank test
(one sided alpha=0.025). With a 24-month accrual period and an additional 24 months of follow-
up, the sample size needed for the study is approximately 360 (180 in active monitoring, 180 in
daratumumab) subjects. Sample size calculations were performed using ADDPLAN v6.1.1.
At the end of study, approximately 134 PFS2 events are expected in both arms (81 at the time of
the primary analysis of PFS). With 134 PFS2 events, the probability ofshowing a positive trend,
ie, estimated HR<1, is more than 95% assuming the true HR=0.75 (median PFS2: 72 vs
96 months). Note that in the hierarchical testing procedure, only superiority will be tested for this
endpoint.
At the end of study, approximately 107 OS events are expected in both arms (64 at the time of the
primary analysis of PFS). With 107 OS events, the probability of showing a positive trend,
ie, estimated HR<1, is more than 85% assuming the true HR=0.80 (median OS: 100 vs
125 months).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
76
Approved, Date: 23 September 2024
11.3. Efficacy Analyses
The primary efficacy analysis will occur when approximately 165 PFS events have been observed.
This is expected to occur approximately 2 years after the last subject has been randomized.
Descriptive statistics will be used to summarize data. For continuous parameters, number of
observations, mean, SD, 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 Endpoint
For the primary endpoint of PFS, the primary analysis will consist of a stratified log-rank test for
the comparison of the PFS distribution among the 2 groups (daratumumab vs active monitoring).
The Kaplan-Meier method will be used to estimate the distribution of overall PFS for each group.
The treatment effect (HR) and its 2-sided 95% confidence intervals are to be estimated using a
stratified Cox regression model with treatment as the sole explanatory variable. These analyses
will be stratified by the stratification factor, number of risk factors associated with progression to
MM (<3 vs ≥3).
11.3.2. 
Secondary Endpoints
Time to biochemical or SLiM-CRAB progression (BOD-PFS): The median time to BOD-PFS
and 95% CI in each group will be estimated using the Kaplan-Meier method. The BOD-PFS
distributions between the 2 groups will be compared using the stratified log-rank test. The
treatment effect (HR) and its 2-sided 95% CI will be estimated using a stratified Cox
regression model with treatment as the sole explanatory variable.
ORR: The proportion of subjects who have an OR and the 95% CI will be calculated for each
treatment group. The rate of OR will be compared between the 2 groups using the stratified
Cochran-Mantel-Haenszel test. The Mantel-Haenszel odds ratio will be provided along with
its 2-sided 95% CI.
CR rate: The proportion of subjects who have a CR or better and the 95% CI will be calculated
for each group. The rate of CR or better will be compared between the 2 groups using the
stratified Cochran-Mantel-Haenszel test. The Mantel-Haenszel odds ratio will be provided
along with its 2-sided 95% CI.
Time to first-line treatment for MM: The median time to first-line treatment for active MM
and 95% CI in each group will be estimated using the Kaplan-Meier method. The time to first-
line treatment for MM distributions between the 2 groups will be compared using the stratified
log-rank test. The treatment effect (HR) and its 2-sided 95% CI will be estimated using a
stratified Cox regression model with treatment as the sole explanatory variable.
PFS2: The median PFS2 and 95% CI in each group will be estimated using the Kaplan-Meier
method. The PFS2 distributions between the 2 groups will be compared using the stratified
log-rank test. The treatment effect (HR) and its 2-sided 95% CI will be estimated using a
stratified Cox regression model with treatment as the sole explanatory variable.
OS: The median OS and 95% CI in each group will be estimated using the Kaplan-Meier
method. The OS distributions will be compared between the 2 groups using the stratified log-

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
77
Approved, Date: 23 September 2024
rank test. The treatment effect (HR) and its 2-sided 95% CI will be estimated using a stratified
Cox regression model with treatment as the sole explanatory variable.
Incidence of MM with adverse prognostic features: The proportion of subjects who progress
to MM with adverse prognostic features and the 95% CI will be calculated for each group.
Duration of response: A descriptive summary for duration of response will be provided. No
statistical comparison will be made.
Time to response: A descriptive summary for time to response will be provided. No statistical
comparison will be made.
In the event that the primary endpoint is statistically significant, details of the hierarchical testing
of the secondary endpoints will be provided in the Statistical Analysis Plan.
11.4. Pharmacokinetic Analyses
Pharmacokinetic analyses will be performed on the PK-evaluable population, defined as subjects
who have received at least 1 dose of daratumumab and have at least 1 postdose sample. All
concentrations below the lowest quantifiable concentration or missing data will be labeled as such
in the concentration database. Concentrations below the lowest quantifiable concentration will be
treated as zero in the summary statistics. The number of subjects and samples excluded from the
analysis will be clearly documented.
Descriptive statistics will be used to summarize daratumumab serum concentrations at each
sampling time point. Cmin  is defined as the minimum concentration observed immediately before
daratumumab administration and Cmax  is defined as the maximum concentration observed
following daratumumab administration, as presented in the summary of serum concentration by
sampling time point. Other PK parameters, if available, may also be summarized.
If sufficient data are available, population-PK analysis of serum concentration-time data of
daratumumab may be performed and may be combined with data from other studies. If the
population-PK analysis is conducted, details will be given in a population-PK analysis plan and
the results of the analysis will be presented in a separate report. Exposure-response analyses may
also be performed and may use data from other studies; if performed, details will be provided in a
separate analysis plan and report.
11.5. Immunogenicity Analyses
The incidence of anti-daratumumab antibodies will be summarized for all subjects who receive at
least 1 dose of daratumumab and have appropriate samples for detection of antibodies to
daratumumab (ie, subjects with at least 1 sample obtained after their first dose of daratumumab).
The incidence of anti-rHuPH20 antibodies will be summarized for all subjects who receive a dose
of daratumumab and have appropriate samples for detection of anti-rHuPH20 antibodies. A listing
of subjects who are positive for anti-daratumumab or anti-rHuPH20 antibodies will be provided.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
78
Approved, Date: 23 September 2024
11.6. 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, or survival analysis, depending on the endpoint). Correlation of baseline
expression levels or changes in expression levels with response to time-to-event endpoints will
identify responsive (or resistant) subgroups in addition to genes and pathways attenuated following
treatment with daratumumab.
Any pharmacodynamic measures will be listed, tabulated, and where appropriate, plotted. Subjects
may be grouped by cohort, dose schedule, or clinical response. As this is an open-label study with
an active monitoring control arm, 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.
11.7. Pharmacokinetic/Pharmacodynamic Analyses
If sufficient data are available, then other PK/pharmacodynamic modeling may be performed,
including exploring the relationship between serum concentrations of daratumumab and endpoints
of clinical efficacy and safety. If performed, details and results of the analysis will be presented in
a separate report.
11.8. Patient-reported Outcomes
The EORTC-QLQ-C30 (Attachment 8) and EORTC QLQ-MY20 (Attachment 9) scale scores and
EQ-5D-5L (Attachment 10) utility and visual analog scores will be descriptively summarized by
treatment group at each time point. Within-group and between-group treatment effects of the PRO
endpoints will be assessed by change from baseline using mixed models for repeated measures.
11.9. Medical Resource Utilization Analyses
Medical resource utilization will be summarized descriptively by treatment group. Additional
analyses may be conducted; details and results of any additional analyses will be presented in a
separate report.
11.10. Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded
using the Medical Dictionary for Regulatory Activities. Treatment-emergent adverse events are
adverse events with onset during the active monitoring or treatment phase or that are a consequence
of a pre-existing condition that has worsened since baseline. All reported adverse events will be
included in the analysis. For each adverse event, the percentage of subjects who experience at least

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
79
Approved, Date: 23 September 2024
1 occurrence of the given event will be summarized by treatment group. In addition, comparisons
between treatment groups will be provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline and
for observed values and changes from baseline at each scheduled time point. Changes from
baseline results will be presented in pre- versus posttreatment cross-tabulations (with classes for
below, within, and above normal ranges). Parameters with predefined NCI-CTCAE toxicity grades
will be summarized. Change from baseline to the worst adverse event grade experienced by the
subject during the study will be provided as shift tables. 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.
Electrocardiograms
Electrocardiogram data will be summarized based on categories of normal, abnormal either
clinically significant or not clinically significant and listed.
11.11. Interim Analysis
There will be one interim analysis for futility. This analysis will occur when approximately 60%
of the PFS events (99) have occurred. This is expected to occur approximately 8 months after the
last subject has been randomized. The purpose of this interim analysis is to evaluate cumulative
interim safety and efficacy data. The non-binding futility boundary at this interim analysis will be
determined using the Kim-Demets power spending function with parameter p=4.0. The beta spent
at this analysis will be 0.0194.
11.12. Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety
of the subjects enrolled in this study. The committee will meet periodically to review interim data.
After the review, the IDMC will make recommendations regarding the continuation of the study.
In addition, the IDMC will review cumulative safety data (ie, serious adverse events) after the first
60 subjects have been randomized and treated or observed for 8 weeks, 6 months later, and
thereafter every 12 months until the primary analysis. In addition, the IDMC will review the
efficacy data after 99 PFS events have occurred and will make recommendations regarding the
continuation of the study. The details will be provided in a separate IDMC charter.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
80
Approved, Date: 23 September 2024
The IDMC will consist of at least 2 medical experts in the relevant therapeutic area and
1 statistician. The IDMC responsibilities, authorities, and procedures will be documented in its
charter.
The IDMC will be discontinued once the primary analysis endpoint has been achieved.
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
Although no medicinal product is administered, adverse events and serious adverse events will be
reported for subjects in Arm A (active monitoring).
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a
medicinal (investigational or non-investigational/auxiliary) 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/auxiliary) product,
whether or not related to that medicinal (investigational or non-investigational/auxiliary) product.
(Definition per International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union 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.)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
81
Approved, Date: 23 September 2024
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 drug and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
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 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, Attribution Definitions.
12.1.2. 
Attribution Definitions
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s),
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation,
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is
reasonable; therefore, the causal relationship cannot be excluded.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
82
Approved, Date: 23 September 2024
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 4.03.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
12.2. Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety
evaluation include, but are not limited to:
Overdose of a sponsor study drug
Suspected abuse/misuse of a sponsor study drug
Accidental or occupational exposure to a sponsor study drug
Medication error involving a sponsor product (with or without subject/patient exposure to the
sponsor study drug, eg, name confusion)
Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of a serious adverse event should be recorded on the serious adverse event page
of the eCRF.
12.3. Procedures
12.3.1. 
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported
as specified in the Time and Events Schedule. Beyond the adverse event reporting period, only
adverse events that are considered to be possibly, probably, or very likely related to study drug
need to be reported.
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

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
83
Approved, Date: 23 September 2024
resulting from disease progression/lack of efficacy will be reported if they fulfill the serious
adverse event definition (refer to Section 12.1.1). For adverse events that result in death, death
should be recorded as an outcome of the adverse event and should not be recorded as an adverse
event or serious 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 drug,
must be recorded using medical terminology in the source document and the eCRF. Whenever
possible, diagnoses should be given when signs and symptoms are due to a common etiology
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
respiratory infection"). Investigators must record in the eCRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The
investigator (or sponsor where required) must report SUSARs to the appropriate Independent
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless
otherwise required and documented by the IEC/IRB. A SUSAR will be reported to regulatory
authorities unblinded. Participating investigators and IEC/IRB will receive a blinded SUSAR
summary, unless otherwise specified.
Subjects (or their designees, if appropriate) must be provided with a "wallet (study) card" and
instructed to carry this card with them for the duration of the study indicating the following, at a
minimum:
Study number
Statement, in the local language(s), that the subject is participating in a clinical study
Investigator's name and 24-hour contact telephone number
Local sponsor's name and 24-hour contact telephone number (for medical staff only)
Site number
Subject number
Blood type and IAT (as described in Section 9.7).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
84
Approved, Date: 23 September 2024
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 close observation following daratumumab administration, then the hospitalization
should not be reported as a serious adverse event
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility)
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be
considered serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
Expected progression of disease should not be considered an adverse event (or serious adverse
event). However, if determined by the investigator to be more likely related to the study treatment
than the underlying disease, the clinical signs or symptoms of progression and the possibility that
the study treatment is enhancing disease progression, should be reported per the usual reporting
requirements (see Section 12 Adverse Event Reporting).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
85
Approved, Date: 23 September 2024
12.3.3. 
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious
adverse events and must be reported using the Serious Adverse Event Form.  Any subject who
becomes pregnant during the study must be promptly withdrawn from the study and discontinue
further study treatment unless the subject (or the subject's legally acceptable representative),
investigator, and sponsor agree the benefits outweigh the risks to the fetus and continuation of
study treatment is in the best interests of the subject. A subject randomized to Arm A who becomes
pregnant may remain on the study (refer to Section 4.3). For a pregnant subject who remains on
the study, any study procedures deemed by the investigator to be potentially harmful to the fetus
(eg, CT scans) may be deferred until the subject is no longer pregnant. Because the effect of the
study drug on sperm is unknown, pregnancies in partners of male subjects included in the study
will be reported, as noted above. Follow-up information regarding the outcome of the pregnancy
and any postnatal sequelae in the infant will be required.
12.4. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
13. 
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, investigators,
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
13.1. Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
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.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
86
Approved, Date: 23 September 2024
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
14. 
STUDY DRUG INFORMATION
14.1. Physical Description of Study Drug
The daratumumab supplied for this study 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
Investigator's Brochure11 for a list of excipients.
14.2. Packaging
Daratumumab is supplied in glass vials containing daratumumab at a concentration of 120 mg/mL
and rHuPH20 at a concentration of 2000 U/mL (~20 g/mL). It will be supplied to the
site/pharmacy as open-label supply.
14.3. Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. Each
vial will contain a study-specific label with a unique identification number.
14.4. Preparation, Handling, and Storage
Daratumumab 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. Study drug must not be used after
the expiry date printed on the label. The product 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 Site Investigational Product Procedures Manual 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

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
87
Approved, Date: 23 September 2024
study site is an authorized destruction unit and study drug supplies are destroyed on-site, this must
also be documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for drug accountability purposes.
Study drug should be dispensed under the supervision of the investigator or a qualified member of
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to
subjects participating in the study. Returned study drug must not be dispensed again, even to the
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the
study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
Investigator's Brochure for daratumumab (and rHuPH20, where required per local
regulations)
Investigational Product Preparation Instructions
Investigational Product and Procedures Manual
Laboratory manual
PRO questionnaires and PRO completion guidelines
IWRS Manual
eCRF completion guidelines
Sample ICF
Subject diaries for recording predose and postdose medications that are administered at home
(Section 6.3)
Subject identification wallet card indicting blood type and IAT result
Other manuals and guidance documents as needed.
16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
The current standard of care for patients with SMM is observation. The QuiRedex study has
provided some evidence that therapeutic intervention administering therapy designed for MM in
SMM is beneficial. However, changes in the disease definition and concerns that QuiRedex may
have, in fact, included some subjects with fully developed MM have contributed to ongoing
questions in the field. These deliberations support the presence of clinical equipoise in this trial.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
88
Approved, Date: 23 September 2024
An argument for the early treatment of myeloma at the pre-symptomatic SMM stage is the
prevention of organ damage, especially with regards to bone fractures and kidney failure. Both
treatment arms in this study are aiming to accomplish this goal, either by active monitoring with
frequent disease evaluations or with pre-emptive therapy. It is truly unknown if one approach is
superior (clinical equipoise); however, both study arms have a reasonable likelihood of benefitting
the subjects enrolled.
The primary safety profile of daratumumab is predominantly characterized by IRRs; see
Section 6.2, 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.
In a previous study with SC administration of daratumumab (MMY1004), a lower incidence of
IRRs was observed compared to IRR rate reported from studies with IV administration of
daratumumab. However, IRRs may still occur and may develop at a later time point than
previously observed with IV administration due to the more gradual absorption. Subjects will
therefore be observed for at least 6 hours on their first day of SC daratumumab administration.
Apart from IRRs, a similar toxicity profile has been shown for SC versus IV administration for
anemia, thrombocytopenia, and other toxicities. During this study local tolerability at the
SC injection site will be closely monitored as well.
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The total blood volume to be collected is outlined in Section 9.1.1. A total volume corresponding to
1 to 2 blood donations will be collected over the entire study duration. The blood volumes collected
are not burdensome.
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.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
89
Approved, Date: 23 September 2024
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
16.2.2. 
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
Final protocol and, if applicable, amendments
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
Investigator's Brochure (or equivalent information) and amendments/addenda
Sponsor-approved subject recruiting materials
Information on compensation for study-related injuries or payment to subjects for
participation in the study, if applicable
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for subjects
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and subject compensation programs, and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct)
Revision(s) to ICF and any other written materials to be provided to subjects
If applicable, new or revised subject recruiting materials approved by the sponsor
Revisions to compensation for study-related injuries or payment to subjects for participation
in the study, if applicable
New edition(s) of the Investigator's Brochure and amendments/addenda

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
90
Approved, Date: 23 September 2024
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).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
16.2.3. 
Informed Consent
Each subject (or a legally acceptable representative) must give written consent according to local
requirements after the nature of the study has been fully explained. The ICF(s) must be signed
before performance of any study-related activity. The ICF(s) that is/are used must be approved by
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and
understand. The informed consent should be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential subjects or their legally acceptable representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Subjects will be informed that their participation is voluntary
and that they may withdraw consent to participate at any time. They will be informed that choosing
not to participate will not affect the care the subject will receive for the treatment of his or her
disease. Subjects will be told that alternative treatments are available if they refuse to take part and
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator
will maintain a subject identification register for the purposes of long-term follow up if needed
and that their records may be accessed by health authorities and authorized sponsor personnel

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
91
Approved, Date: 23 September 2024
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s)
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing
such access, which includes permission to obtain information about his or her survival status. It
also denotes that the subject agrees to allow his or her study physician to recontact the subject for
the purpose of obtaining consent for additional safety evaluations, and subsequent disease-related
treatments, if needed, 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/territories.
The subject has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete or make requests
concerning his or her personal data in accordance with applicable data protection law. Reasonable
steps will be taken to respond to such a request, taking into consideration the nature of the request,
the conditions of the study, and the applicable laws and regulations.
In the event of a data security breach, the sponsor will apply measures to adequately manage and
mitigate possible adverse effects taking into consideration the nature of the data security breach as

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
92
Approved, Date: 23 September 2024
necessary to address other obligations such as notifying appropriate authorities in accordance with
applicable data protection law.
Exploratory pharmacodynamic, biomarker, PK, and immunogenicity research is not conducted
under standards appropriate for the return of data to subjects. In addition, the sponsor cannot make
decisions as to the significance of any findings resulting from exploratory research. Therefore,
exploratory research data will not be returned to subjects or investigators, unless required by law
or local regulations. Privacy and confidentiality of data generated in the future on stored samples
will be protected by the same standards applicable to all other clinical data.
16.2.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand daratumumab, to understand
SMM, to understand differential drug responders, and to develop tests/assays related to
daratumumab and SMM. 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 10.2, Withdrawal From the Use of Samples in Future
Research).
16.2.6. 
Country/TerritorySelection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 16.1, Study-Specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be
promptly submitted to the IEC/IRB  and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involves only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
93
Approved, Date: 23 September 2024
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
17.2. Regulatory Documentation
17.2.1. 
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
17.2.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the
study site:
Protocol and amendment(s), if any, signed and dated by the principal investigator
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, subject compensation programs. This approval must clearly identify the specific
protocol by title and number and must be signed (or sealed, where appropriate per local
regulations) by the chairman or authorized designee.
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
Regulatory authority approval or notification, if applicable
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
Documentation of investigator qualifications (eg, curriculum vitae)
Completed investigator financial disclosure form from the principal investigator, where
required
Signed and dated clinical trial agreement, which includes the financial agreement
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:
Completed investigator financial disclosure forms from all subinvestigators

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
94
Approved, Date: 23 September 2024
Documentation of subinvestigator qualifications (eg, curriculum vitae)
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and date of birth (as allowed by local regulations). In cases where the subject is not enrolled into
the study, the date seen and date of birth (as allowed by local regulations) will be used.
The investigator must also complete a subject screening log, which reports on all subjects who
were seen to determine eligibility for inclusion in the study.
17.4. Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
subject identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all adverse events and follow-up of adverse events; concomitant medication;
drug receipt/dispensing/return records; study drug administration information; and date of study
completion and reason for early discontinuation of study drug or withdrawal from the study, if
applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as follows:
Referral letter from treating physician or
Complete history of medical notes at the site
Discharge summaries

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
95
Approved, Date: 23 September 2024
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by subject interview or other protocol required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An electronic source system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. This data is electronically
extracted for use by the sponsor. If the electronic source system is utilized, references made to the
eCRF in the protocol include the electronic source system but information collected through the
electronic source system may not be limited to that found in the eCRF. Data in this system may be
considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
All eCRF entries, corrections, and alterations must be made by the investigator or authorized
study-site personnel. Electronic Data Capture (eDC) will be used for this study. Study site
personnel must log into eDC via a secure manner (ie, using a personal password). The individual
password must be kept confidential for personal use). The investigator must verify that all data
entries in the eCRF are accurate and correct. The study data will be transcribed by study-site
personnel from the source documents onto an eCRF, if applicable. Study-specific data will be
transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the subject's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, pain scale information or other questionnaires) will be completed
by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
17.6. Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, and periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
96
Approved, Date: 23 September 2024
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before
the start of the study. The sponsor will review eCRF for accuracy and completeness during on-site
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with the
investigator or designee, as appropriate. After upload of the data into the study database they will
be verified for accuracy and consistency with the data sources.
17.7. Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each subject, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
17.8. Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring) to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
97
Approved, Date: 23 September 2024
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
17.9. Study Completion/Termination
17.9.1. 
Study Completion/End of Study
The study is considered completed approximately 8 years after the first subject is randomized or
when the sponsor decides to stop the study. 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. 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.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
98
Approved, Date: 23 September 2024
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding daratumumab or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study, and will not use it for other purposes without the sponsor's prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of daratumumab, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of 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 (ICMJE) 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

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
99
Approved, Date: 23 September 2024
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, 18 months after study end date, or the sponsor confirms there will be no
multicenter study publication. Authorship of publications resulting from this study will be based
on the guidelines on authorship, such as those described in the ICMJE Recommendations for the
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which state
that the named authors must have made a significant contribution to the conception or design of
the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
100
Approved, Date: 23 September 2024
18. 
COUNTRY/TERRITORY-SPECIFIC REQUIREMENTS
18.1. Requirements for France
Requirements for France
Section 
Requirement 
Amendment
Number
Time and Events 
Schedule 
Table 1: Active 
Monitoring (Arm 
A) and
Daratumumab
(Arm B): Active
Monitoring/Treatm
ent Phase, End-of-
Active
Monitoring/End-of-
Treatment, Pre-PD
Follow-up, and
Post-PD
Follow-up;
9.7 Safety
Evaluations
HBV Serology
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (Anti-HBs), and 
hepatitis B core antibody (Anti-HBc) at Screening. Additionally, subjects ongoing in the Treatment Phase (arm B only) 
with unknown hepatitis B serologic status, HBsAg, Anti-HBs, and Anti-HBc testing is recommended if the subject is
still receiving daratumumab (or is within 6 months after the last dose).
Amendment 3/FRA-2
(12 June 2019)
4.2 Exclusion 
Criteria (1d); 9.2.3 
CRAB Criteria-
related Laboratory 
Assessments 
Anemia, defined as hemoglobin <10 g/dL or >2 g/dL below lower limit of normal or both; transfusion support or 
concurrent treatment with erythropoietin stimulating agents is not permitted. 
The following is not relevant for France: Subjects who have clinically stable anemia attributable to a disease other than
multiple myeloma (eg, thalassemia, vitamin B12 deficiency, iron deficiency) may be considered for inclusion after a
case by case review by the medical monitor (see Section 9.2.3).
Amendment 2/FRA-1
(14 November 2018)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
101
Approved, Date: 23 September 2024
19. 
PROTOCOL AMENDMENT HISTORY
This protocol has been amended 5 times globally and 2 times for France (prior to creation of the
consolidated protocol amendment [Amendment 5/EEA-1]). The Protocol Amendment Summary
of Changes Table for the current amendment is located directly before the Table of Contents
(TOC).
Amendment 5/EEA-1 (14 August 2023)
Overall Rationale for the Amendment
The overall reason for the amendment is to update the protocol to comply with EU CTR requirements. In
addition, country-specific requirements for France from 2 prior country-specific amendments to the
protocol have been consolidated within a country/territory-specific appendix.
Applicable Section(s) 
Description of Change(s)
Rationale: To conform with EU CTR and indicate which country/territories are affected by each protocol
amendment.
Protocol 
Amendments 
Converted the Protocol version table to a Document History table with a
Country/Territory Affected column.
Rationale: To conform with EU CTR by describing the Benefit and Risks of this study
Synopsis; 1.3. 
Benefit-Risk
Assessment
Added Sections 1.3, 1.3.1, and 1.3.2 to describe benefits and risks.
Rationale: To clarify medicinal product designations and conform with the definitions under EU CTR.
5. Treatment 
Allocation; 12.1.1. 
Adverse Event 
Definitions and 
Classifications
Revised Section 5 to include a table (Table 6) providing designations of the study
medicinal products (IMP, non-IMP/AxMP).
Amended text in Section 12.1.1. as follows: (investigational or non-
investigational/auxiliary).
Rationale: To conform with EU CTR concerning data privacy.
16.2.4. Privacy of 
Personal Data 
Amended text on privacy of personal data and included the sponsor’s responsibilities in
the event of a data security breach, based on EU CTR.
Added pharmacodynamic to the list of types of exploratory research that are not
appropriate for the return of data to subjects/
Rationale: To consolidate country/territory-specific requirements per current sponsor protocol template and in
line with EU CTR requirements.
18. Country/ 
Territory-specific
Requirements
New appendix added.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
102
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Rationale: To align with the current sponsor protocol template requirement to list all changes pertaining to a
country or territory in an appendix.
Throughout the 
protocol 
Added cross-references within the body of the document to country-specific
requirements listed in Appendix 18 (Country/Territory-specific Requirements).
Rationale: To align with the current sponsor protocol template.
Throughout the 
protocol
Added country/territory and countries/territories.
Rationale: To update protocol with current sponsor template.
Protocol 
Amendments; 19. 
Protocol Amendment
History
New appendix added and the protocol history transferred from the Protocol
Amendments section to there.
Amendment 5 (14 January 2021)
The overall reason for the amendment: The overall reason for the amendment is to indicate that only the
futility analysis will be performed during the interim analysis. The superiority analysis will not be conducted
during the interim analysis to ensure data are sufficiently mature prior to unblinding per feedback from Health
Authorities.
Applicable Section(s) 
Description of Change(s)
Rationale: Text regarding the interim analysis was updated to remove the superiority analysis to ensure data are
sufficiently mature prior to unblinding.
Synopsis Statistical 
Methods;
3.1. Overview of
Study Design;
11.11. Interim
Analysis
Text regarding the interim superiority analysis was removed.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 4 (22 June 2020)
The overall reason for the amendment: The overall reason for the amendment is to permit home health care
and tele-health (conducted via phone or video conference) visits. Home health care and tele-health visits may be
implemented per the clinical judgement of the investigator, in consultation with the sponsor, and where feasible
and permissible by local policy and regulations.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
103
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Rationale: To specify that home health care and tele-health (conducted via phone or video conference) visits are
permitted for subjects with no safety concerns per the clinical judgement of the investigator, in consultation with
the sponsor, and where feasible and permissible by local policy and regulations.
Synopsis; Time and 
Events Schedule
(Tables 1 and 2); 9.1.1.
Overview
Text was added to indicate that home health care and tele-health visits are permitted.
3.1. Overview of Study 
Design 
The following text was modified to permit home health care and tele-health visits:
For subjects randomized to active monitoring (Arm A), no disease-specific
treatment will be given and subjects will return to the study are to be evaluated
every 12 weeks.
9.2. Efficacy 
Evaluations; 9.3.2. 
Analytical Procedures; 
9.4. Biomarkers
Information was added to indicate that samples for protocol-specified assessments
may be collected during home health care visits per the clinical judgement of the
investigator.
Information was provided regarding sample processing, shipment to the central
laboratory, and sample handling.
9.5. Patient-reported 
Outcomes 
Home health care and tele-health visits were added as a means by which PROs can be
administered.
9.6. Medical Resource 
Utilization
Specified that medical encounters include home health care and tele-health visits.
Rationale: To specify assessments that should be performed at the study site or designated facilities.
Time and Events 
Schedule (Table 1)
Footnote m was added.
Time and Events 
Schedule (Table 2)
Footnote g was added.
Rationale: To specify that data from the central laboratory remain the primary source for efficacy assessment and
progressive disease identification.
9.2. Efficacy 
Evaluations 
The following text was added: Data from the central laboratory remain the primary
source for efficacy assessment and progressive disease identification.
9.2.2. Assessment of 
Disease Progression to
Multiple Myeloma
(Table 7)
Footnote f was added.
Rationale: The definition of the baseline value that will be used in the study analysis was clarified.
9.2.4. Myeloma Protein 
Measurements in 
Serum and Urine 
The following text was added: Baseline value is defined as the last value prior to
initiating treatment (Arm B) or prior to randomization for active monitoring subjects
(Arm A).
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 
Eliminated definitions of severity criteria; the definitions are specified in NCI-CTCAE
version 4.03.
Rationale: Alignment of text with recent protocol template changes.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
104
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
12.3.1. All Adverse 
Events
Revised text related to sponsor's responsibility for reporting anticipated events.
Rationale: Text was added for clarity.
Time and Events 
Schedule (Table 1) 
Footnote n was added to indicate that if the end of active monitoring/end-of-treatment
visit is performed due to PD, the PRO assessments do not need to be performed twice
if the visits take place on the same day.
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3/FRA-2 (12 June 2019)
The overall reason for the amendment: The overall reason for the amendment is to incorporate feedback from
the Agence nationale de sécurité du medicament et des produits de santé (ANSM), who requested to add further
guidance on testing for hepatitis B in subjects with unknown serology status.
Applicable Section(s) 
Description of Change(s)
Rationale: The text for hepatitis B serology testing for any subject in the daratumumab arm (Arm B) with
unknown hepatitis B serology and monitoring and managing of hepatitis B virus (HBV) reactivation was added
in response to a request from ANSM.
Time and Events 
Schedule 
Table 1: Active 
Monitoring (Arm A) 
and Daratumumab 
(Arm B): Active 
Monitoring/Treatment 
Phase, End-of-Active 
Monitoring/End-of- 
Treatment, Pre-PD
Follow-up, and Post-
PD Follow-up;
9.7 Safety
Evaluations
HBV Serology
Added the following information detailing the conduct of HBV serology testing:
All subjects will be tested locally for hepatitis B surface antigen (HBsAg), hepatitis B
surface antibody (Anti-HBs), and hepatitis B core antibody (Anti-HBc) at Screening.
Additionally, subjects ongoing in the Treatment Phase (arm B only) who are within 6
months of starting study treatment when Protocol Amendment 3 is implemented will
be required to have HBV serology performed locally upon signing the updated ICF.
with unknown hepatitis B serologic status, HBsAg, Anti-HBs, and Anti-HBc
testing is recommended if the subject is still receiving daratumumab (or is within
6 months after the last dose)’.
Applicable Section(s) 
Description of Change(s)
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 3 (25 January 2019)
The overall reason for the amendment: The overall reason for the amendment is in response to identification
of a new important risk (hepatitis B virus [HBV] reactivation).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
105
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Rationale: The text for identification of HBV reactivation, testing, and management of subjects with the
potential for HBV reactivation was added or modified in response to identification of a new important risk (HBV
reactivation).
Time and Events 
Schedule –Table 1 
Added row for HBV serology, modified text for HBV DNA test, and identified the
timepoints at which HBV serology and HBV DNA test would be conducted.
Time and Events 
Schedule –Table 2 
Deleted the row for HBV DNA test as this assessment is now elaborately covered
under Table 1 Time and Events Schedule.
Section 4.2 Exclusion 
Criteria
(Criterion # 6.2) 
Clarified language to exclude subjects who are seropositive for hepatitis B.
Modified the following sentence: Subjects with resolved infection (ie, subjects who
are HBsAg negative but positive for antibodies to hepatitis B core antigen [Anti-
HBc] and/or antibodies to hepatitis B surface antigen [Anti-HBs]) must be screened
using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus
(HBV) DNA levels.
Section 8.4 Management 
of Hepatitis B Virus 
Reactivation
Added a new section for information for the management of Hepatitis B virus
reactivation.
Section 9.1.1 Overview  
Corrected the maximum blood volume to be collected during screening to
approximately 55 mL, thus accounting for HBV serology.
Section 9.7 Safety 
Evaluations 
Mentioned Hepatitis B Screening (for HBsAg, Anti-HBc, and Anti-HBs) and HBV
DNA tests under local laboratory testing. Added information detailing the conduct
of HBV serology and updated information on HBV DNA tests.
References 
Deleted reference # 7 and renumbered and updated the numbering of other
references.
Rationale: Minor errors were noted
Table 1 Time and 
Events Schedule 
Clarified that the frequency for whole blood and stool collection for biomarker
assessments during Cycle 1 –Cycle 39 is every 12 months from C1D1 (±1 month with
disease evaluations) and at Week 24 and at suspected CR (±1 month with disease
evaluations), respectively.
Table 2 Time and 
Events Schedule 
Corrected the End of Treatment as 30 (±3) days after the last Daratumumab dose instead
of 28 (±3) days after the last Daratumumab dose so as to be consistent with Table 1 of
the Time and Events Schedule
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment 2/FRA-1 (14 November 2018)
The overall reason for the amendment: The overall reason for the amendment is to address specific concerns
from the Health Authority in France.
Applicable Section(s) 
Description of Change(s)
Rationale: The Health Authority in France recommended modification of the Exclusion Criterion 1.d in order
to prevent subjects with anemia (hemoglobin <8g/dL) to be treated with daratumumab, given its known safety
profile.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
106
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
4.2 Exclusion 
Criteria (1d); 9.2.3 
CRAB Criteria- 
related Laboratory 
Assessments 
Removed text describing exceptions to the limitations on allowed hemoglobin levels:
Anemia, defined as hemoglobin <10 g/dL or >2 g/dL below lower limit of normal or
both; transfusion support or concurrent treatment with erythropoietin stimulating
agents is not permitted. Subjects who have clinically stable anemia attributable to a
disease other than multiple myeloma (eg, thalassemia, vitamin B12 deficiency, iron
deficiency) may be considered for inclusion after a case by case review by the medical
monitor (see Section 9.2.3).
Amendment 2 (19 September 2018)
The overall reason for the amendment: To implement a central review of screening images in order to confirm
subject eligibility. Updates to the inclusion and exclusion criteria and study assessments were also made for
clarity.
Applicable Section(s) 
Description of Change(s)
Rationale: A central review of screening images is being implemented to confirm subject eligibility.
Table 1 Active 
Monitoring (Arm A) and 
Daratumumab (Arm B): 
Active Monitoring/ 
Treatment Phase, End-of- 
Active Monitoring/End- 
of-Treatment, Pre-PD 
Follow-up, and Post-PD 
Follow-up, 
Demography/Medical 
History/benign/post- 
traumatic pre-existing 
bone lesions row, 
footnote d; 
3.1 Overview of Study
Design;
9.1.2 Screening Phase 
Confirmation of eligibility will be based on central disease, hematology, and
chemistry laboratory assessments and will also include assessment of ECG, ECOG,
medical history, concomitant medications, adverse events, and screening images.
Bone lesions assessment at screening will be done by an independent reviewer after
subject eligibility is confirmed by the site (no lytic lesions and/or ≤ 1 focal lesion
with diameter ≥5 mm present unless proven benign/post-traumatic origin). This
central review of screening images will be used to determine the subject’s
eligibility. For optimal assessment of the screening images by the independent
reviewers, additional clinical data, including benign/post-traumatic pre-existing
bone lesions, data of recent bone marrow procedures, and general medical history,
will be included in the independent review.  Details (diagnosis, location, duration)
on benign/post-traumatic pre-existing bone lesions that can be seen on the screening
images (eg, old fractures) and were also present on previous imaging are to be
reported in the CRF (see also Sections 9.1.2 and section 9.2.7).
Imaging from routine standard of care assessments can be used only if these meet
the minimum requirements as set by the current version of the Image Acquisition
Guidelines.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
107
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
9.2.7 Assessment of Bone 
Disease 
The presence of bone lesions will be evaluated both locally and centrally. Imaging
studies should be performed per Imaging Acquisition Guidelines provided by the
central imaging provider and will be read centrally in addition to the local read (see
IRC Charter). The site will review the screening images first to confirm
eligibility of study subject (no lytic lesions and/or ≤1 focal lesion with diameter
≥5 mm present unless proven benign/post-traumatic origin). After initial
screening imaging assessment by the site and confirming eligibility by the site,
results of imaging studies (ie, LDCT/CT/PET-CT/MRI) will be uploaded to a
central repository and reviewed centrally. This central review of screening images
will be used to determine eligibility of subjects for study participation (see
Section 9.1.2). Presence of focal bone lesions will be evaluated by MRI, in
exceptional cases by PET-CT (see below). The presence of lytic bone lesions will be
evaluated by LDCT, PET-CT, or CT, including skull, entire vertebral column,
pelvis, chest, humeri, femora, and any other bones in which the investigator suspects
involvement by disease radiography. Central review will also be used to assess
disease progression by evaluating the occurrence of bone disease. During the
Active Monitoring and Treatment Phases and before disease progression is
confirmed, imaging should be performed as indicated in the Time and Events
Schedule (Table 1), to document response or progression.
Rationale: The screening window has been increased from 28 days to 35 days to ensure there is enough time to
complete all screening assessments within the screening period.
Table 1; 
3.1 Overview of Study
Design;
4 Subject Population;
9.1.2 Screening Phase
Screening of subjects will be performed within 35 28 days before randomization.
Rationale: To include additional instructions for when a subject’s scheduled administration is delayed within 1
cycle.
Table 1; 
6 Dosage and 
Administration; 
6.5.2 Toxicity 
Management 
All subsequent days within that cycle and Day 1 of subsequent cycles should be
adjusted accordingly to maintain the 28-day cycle duration. In case of dose delays
affecting days other than Day 1, because of reasons other than toxicity,
administration should occur within the prespecified window. If an
administration does not commence within the prespecified window of the
scheduled administration date, then the dose will be considered a missed dose.
Administration may resume at the next planned dosing date. A missed dose will
not be made up. Every effort should be made to avoid dose delays because of
reasons other than toxicity (refer to Section 6.5.3 for details on interrupted or
missed doses).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
108
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Rationale: To clarify the End-of-Active-Monitoring and End-of-Treatment visit timing.
Table 1, footnote c; 
9.1.3 Active Monitoring 
Phase or Treatment Phase 
For subjects in the Active Monitoring (Arm A), the End-of-Active Monitoring
visit is to be performed within 30 days (±3 days) of confirmation of disease
progression by investigator.  If disease progression is confirmed in a subject in the
daratumumab arm, then the subject will discontinue study treatment, complete the
End-of-Treatment Visit (30 days ±3 days after the last dose of daratumumab, or
before starting subsequent therapy, if earlier), and enter the Follow-up Phase.
For subjects in Arm A, the End-of Active Monitoring Visit is to occur after 36
months (±3 days) (from the date of randomization) of active monitoring if disease
progression was not yet confirmed earlier, or if the subject did not meet other
criteria for discontinuation prior to 36 months (refer to Section 10.2). In case of
discontinuation because of reasons other than disease progression, the End-of-
Active Monitoring/End-of-Treatment Visit is to be performed within 30 days
(±3 days) after notification that the subject will discontinue Active
Monitoring/treatment. For subjects in the Arm B, the End-of-Treatment Visit is to
occur 28 30 (±3) days after the last dose of daratumumab.
Rationale: To update biomarker assessment timepoints, add a new microbiome assessment, and clarify the
handling samples for FISH analysis.
Table 1, Biomarker 
Assessments subsection  
Updated the assessment timepoints for cytometry, PBMCs, and plasma, and added a
new microbiome (stool sample) assessment.  Also, as it’s exploratory, moved the
cytogenetics by FISH assessment row from its prior location as part of “morphology
and additional diagnostic tests” subsection so it is now included as part of the
biomarker assessments subsection.
Table 1, footnote k; 
9.2.6 Bone Marrow 
Examination; 
Table 8 Bone Marrow 
Testing 
Samples for FISH are required to be sent to the central laboratory for further
analysis. For sites in China, every effort should be made to collect fresh samples for
FISH to be sent to central laboratory. If the subject had a routine bone marrow
aspirate performed prior to screening, and no additional aspirate is performed,
(formalin-fixed paraffin-embedded (FFPE) samples are the only available sample
for FISH) these samples can be analyzed by the local site laboratory.
Synopsis, Other 
Evaluations; 
3.2 Study Design 
Rationale; 
9.4 Biomarkers;
References
As a new microbiome (stool sample) has been added to the biomarker assessments,
an introduction to the potential role of the gut microbiome in influencing clinical
outcomes has been added.  Two new reference citations supporting the addition of
the microbiome assessment have been added.
Attachment 7: 
Interpretation of the 
SEBIA Hydrashift 2/4 
Daratumumab IFE
Interference test
An attachment describing the new SEBIA Hydrashift 2/4 Daratumumab IFE
Interference test has been added to replace the prior Daratumumab Interference
Reflex Assay.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
109
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Rationale: To clarify that it is acceptable for the screening FEV1 test to be performed as part of the standard of
care as long as it is performed within 35 days before randomization.  Also, to clarify that specific postdose
medications are to be considered for subjects with higher risk of respiratory complications, as per investigator
discretion.
Table 1, FEV1 test row  
Added a statement indicating that it’s acceptable to be considered as a screening
assessment if performed as part of the standard of care within 35 days before
randomization.
6.3.2 Postdose 
Medication  
For subjects with higher risk of respiratory complications (eg, subjects with COPD
who have a FEV1 <80% and subjects with asthma), the following postdose
medications should be considered, as per investigator discretion.
9.7 Safety Evaluations 
In the Pulmonary Function Test subsection, deleted the reference to FEV1 test
having to be done at screening and added a cross-reference to the Time and Events
Schedule (Table 1).
Rationale: Clarification on the timing of PRO collection during screening, and related ECOG wording has been
revised to increase operational flexibility.
Table 1, Patient Reported 
Outcomes row; 
9.1.1 Overview; 
9.5 Patient-Reported 
Outcomes
Added text to clarify that PRO collection should be completed after informed
consent forms are signed, but before any tests, procedures, or other consultations
that may influence subject perception scheduled for the same day as the PRO
assessments are collected.
9.7 Safety Evaluations 
Revised ECOG wording to remove text indicating that ECOG assessments should
occur prior to any other study procedures planned for the same day.
Rationale: To clarify the approach on lowering pre- and postdose steroid dose in case of an occurrence of an
IRR. Also, additional wording was added to emphasize the use of conversion rules when a different steroid than
methylprednisolone is used for this purpose.
6.3.1 Predose Medication  
A corticosteroid: methylprednisolone 100 mg PO or IV or equivalent for the first 2
doses and 60 mg for all subsequent doses (in the absence of IRR adverse events in
the first 2 doses). This reduction in steroid dose can only be done in the absence
of IRR adverse events in both of the first 2 doses. Substitutions for
methylprednisolone are allowed, but conversion rules have to be taken into
account (refer to Attachment 5).
6.3.2 Postdose 
Medication  
In the absence ofOnly when no IRR adverse events occurred during after the first
3 doses, postdose corticosteroids should be administered per investigator discretion.
Rationale: Text added, as per the algorithm, to clarify the process for confirming disease progression to align
with the IMWG criteria to confirm disease progression.
9.2 Efficacy Evaluations 
A repeated investigation for confirmation of disease progression does not need to
occur within a specified timeframe and could potentially occur on the same date (at
a later timepoint). However, the original value meeting disease progression and the
confirmation value must be consecutive (ie, no intermediate values that do not meet
the definition of disease progression). It is not a requirement to have a repeat
investigation if disease progression is based on at least 2 of the laboratory tests of
Hb, calcium, renal function and FLC at the same assessment date (eg, when Hb <10
g/dL and creatinine clearance <40 mL/min are present on the same day).

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
110
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Table 6 International 
Uniform Response 
Criteria Consensus 
Recommendations, new
footnote a
Subjects will continue in the last confirmed response category until there is
confirmation of progression or improvement to a higher response status; subjects
cannot move to a lower response category.
Table 7 Diagnostic 
Criteria for Progression to 
Multiple Myeloma, 
footnote a 
A clarifier regarding collection of a bone marrow aspirate was added to align with
the current study conduct: Bone marrow plasma cell percentage should preferably
be estimated from a core biopsy specimen (per IMWG criteria; however, bone
marrow aspirate only is acceptable for this study); in case of a disparity between
the aspirate and the core biopsy, the highest value should be used.
new footnote d 
New footnote to state that the determination of progression will be based on
modified FLC criteria combining IMWG progression criteria with IMWG FLC ratio
criteria.
Rationale: To ensure that sites use PET-CT appropriately as an alternative for subjects whom MRI is
contraindicated, as MRI is the preferred method of assessment.
9.2.7 Assessment of Bone 
Disease 
MRI (spine and pelvis) will be performed to assess focal lesions at Screening and
regularly during the study, as indicated in the Time and Events Schedule. Positron
emission tomography-computed tomography (PET-CT) may be used as an
alternative for those subjects for whom MRI is contraindicated. However, the
medical monitor is to be informed upfront about the reason why MRI is
contraindicated.
Rationale: Minor, miscellaneous edits made throughout the protocol for clarity and consistency.
3.1 Overview of Study 
Design; 
11.12 Date Monitoring
Committee
An additional IDMC Data Review Meeting will be scheduled 6 months
(approximately March 2019) after the first IDMC Data Review.
4.1 Inclusion Criteria, 
Criterion #2.1 
Clarified that the diagnosis of SMM (per IMWG criteria) for ≤5 years with
measurable disease is to be as of the time of randomization.
Criterion #3.1 
Clarified the immunoparesis risk factor definition to align with IMWG criteria in
that only IgA, IgM, and IgG should be considered in determination for
immunoparesis and that IgD and IgE are not considered in this assessment.
4.2 Exclusion Criteria, 
Criteria #1.1a to 1.1d 
Provided expanded details relating to the requirements that must be met for
inclusion in the study as it pertains to the definition of multiple myeloma;
specifically, for bone lesions, hypercalcemia, renal insufficiency, and anemia.
Criterion #3.1b; 
8 Prestudy and 
Concomitant Therapy; 
8.2 Permitted Therapies
Added reference to “denosumab”, as applicable, as denosumab is an approved
treatment for osteoporosis, and treatment with denosumab is to be handled the same
way as bisphosphonates.
New Criterion #3.1e; 
8.3 Prohibited Therapies 
As the sponsor has received several questions from sites regarding the allowability
of certain monoclonal antibodies and immunomodulators, a new exclusion criterion
has been added: Ongoing treatment with other monoclonal antibodies (eg,
infliximab, rituximab), immunomodulators (eg, abatacept, methotrexate,
azathioprine, cyclosporine) or other treatments that are likely to interfere with
the study procedures or results

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
111
Approved, Date: 23 September 2024
Applicable Section(s) 
Description of Change(s)
Criterion #7; 
To avoid unnecessary screening, the criterion wording was clarified to provide a
more specific exclusion of subjects with active system disease, as follows: Medical
or psychiatric condition or disease (eg, active systemic disease [including presence
of auto-antibodies], uncontrolled diabetes) 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.
Criteria #4, #9.1, #13 
Very minor updates added for clarity and increased understanding of requirements.
9.1.1 Overview  
Updates have been made to the blood volume paragraph to reflect the additional
blood collection being implement with this protocol amendment.
9.2.2 Assessment of 
Disease Progression to 
Multiple Myeloma
Updated the subsection heading for specificity to: Assessment of Progression to
Multiple Myeloma (diagnostic progression).
9.2.2 Assessment of 
Disease Progression to 
Multiple Myeloma 
Added statement that biochemical progression is to be considered as an important
risk factor to evolve to diagnostic progression and those subjects should be
monitored closely.
9.2.3 CRAB Criteria- 
related Laboratory 
Assessments 
Text updated to allow consideration of subjects who, at screening, have clinically
stable hypercalcemia, renal insufficiency, or anemia that has existed for several
years and did not show any deterioration during the prior year, on a case-by-case
basis after discussion with the medical monitor.
9.7 Safety Evaluations 
Updated the HBV DNA Test wording to clarify that the assessment is based on local
laboratory assessments
10.2 Discontinuation of 
Active Monitoring (Arm 
A) or Study Treatment 
(Arm B) 
As discontinuation in IWRS will only happen after the sponsor’s confirmation of
PD, text has been revised as follows: Before subjects discontinue active monitoring
(Arm A) or study treatment (Arm B) due to disease progression, sites will document
disease progression by completing a disease progression form or by contacting the
IWRS as soon as possible and within 48 hours of disease progression assessment.
12.3.2 Serious Adverse 
Events 
Updated the definition of expected progression of disease to align with the current
protocol template wording.
12.3.3 Pregnancy  
In alignment with other protocols across the daratumumab compound, provided
details on the requirements if a subject becomes pregnant during the study.
Rationale: Minor errors were noted.
3.2 Study Design 
Rationale 
Removed erroneous language specifying that certain high-risk cytogenetic
modifications will be used for stratification in the study.
4.2 Exclusion Criteria, 
Criterion #6.1 
Updated erroneous numbering of Criterion #6.1, which had previously been
numbered as #6.b.1 when updated at Amendment 1. The content remains
unchanged.
9.7 Safety Evaluations 
Deleted the erroneous statement indicating that the central laboratory results will be
recorded in the eCRF and clarified that local laboratory data must be entered into
the eCRF
Attachment 2: Modified 
Diet in Renal Disease
Formula
Updated an error in the formula for creatinine in µmol/L.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
112
Approved, Date: 23 September 2024
Amendment 1 (30 January 2018)
This amendment is considered to be nonsubstantial 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, in that it does not significantly
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to address feedback from
Health Authorities from the original protocol submission.
Applicable Section(s) 
Description of Change(s)
Rationale: To clarify that daratumumab administered subcutaneously contains rHuPH20, which is considered an
active agent by some Health Authorities.
Synopsis, Dosage and 
Administration; 3.1. Overview 
of Study Design; 6. Dosage and
Administration; 6.2. Treatment
Schedule and Administration
Added rHuPH20 (2000 U/mL) to daratumumab SC description (daratumumab
1800 mg + rHuPH20 [2000 U/mL]).
Rationale: To clarify the management of HBV infection to align with other daratumumab protocols.
Table 1; Table 2; 4.2 Exclusion 
Criteria, Criterion #6.b.1; 
9.7. Safety Evaluations –HBV
DNA Tests 
Added text to clarify which subjects need to be tested and/or followed for
HBV infection.
Timepoints for HBV DNA tests for subjects, if necessary, added at Screening,
every 12 weeks during the Treatment Phase, and at the End-of-Treatment
Phase.
Rationale: To clarify duration for Active Monitoring (Arm A) and Treatment Phase (Arm B).
Synopsis, Dosage and 
Administration; Table 1; 
3.1. Overview of Study Design;
6.2 Treatment Schedule and 
Administration;
10.1. Completion  
Added text to clarify that subjects could complete 39 cycles or up to
36 months of treatment, whichever occurs first.
Added text to clarify Arm A disease evaluations were every 12 weeks.
Added text to clarify that 36 months of adverse event and concomitant
medication monitoring should occur for Arm A.
Rationale: To update the data available for infusion-related reactions from the current Investigator’s Brochure.
3.1. Overview of Study Design  
Updated the date of the data available to reflect the current Investigator’s
Brochure (Edition 14, October 2017).
Rationale: Daratumumab SC formulation includes recombinant human hyaluronidase (rHuPH20).
4.2. Exclusion Criteria, 
Criterion #9.1. 
Added hyaluronidase to list of possible items that a patient might be intolerant
to.
Rationale: To clarify if both treatment arms needed to have repeat laboratory studies in cases where screening
values were obtained >14 days from Cycle 1 Day 1 (C1D1).
Table 1; 
9.2.4. Myeloma Protein 
Measurements in Serum and 
Urine
In the event that central laboratory screening values are ≤14 days from C1D1,
subjects randomized to the active monitoring arm (Arm A) would not be
required to return to the clinic for their C1D1 visit.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
113
Approved, Date: 23 September 2024
Rationale: Change the time of the baseline PRO assessment to prevent mixed modes data collection (telephone
and in-person PRO assessments) at baseline and to prevent missing data in Arm A, if scheduled at the C1D1 visit.
Table 1; 9.5. Patient-reported 
Outcomes 
Table 1 
Updated the baseline PRO assessment for all subjects to occur in-person
during the Screening visit and not at C1D1.
A time point at screening was added and it was noted that it will serve as the
baseline score. It was clarified that the PRO assessments will be collected
during Active Monitoring as well as during study treatment.
Added text to clarify that the PRO assessments during Active
Monitoring/study treatment should be performed with disease evaluations and
administered before any other study procedures for that visit.
Rationale: Clarification made for the sake of completeness and clarity.
9.1.1. Overview  
Added statement that reason for not completing PRO assessments is now to
be documented.
Rationale: To clarify how dose delays resulting from toxicity management should be handled and to clarify how
to handle subjects with missed doses.
6.5.2. Toxicity Management; 
Table 5 
Added guidance for dose delays affecting Day 1 of a cycle and dose delays
affecting days other than Day 1.
6.5.3. Interruption or Missed 
Doses 
Specified that subjects missing ≥3 consecutive planned doses of
daratumumab for reasons other than daratumumab-related toxicity should be
withdrawn from treatment.
Rationale: To clarify when use of a local laboratory is acceptable for efficacy and safety evaluations.
9.2. Efficacy Evaluations 
Addition of statement clarifying that if central laboratory evaluations fail, the
test should be performed again at the central laboratory; local laboratory
results should only be used in exceptional cases after discussion with the
medical monitor.
9.7. Safety Evaluations – 
Central Laboratory Testing 
Addition of statement clarifying that if central laboratory tests fail, it will be
acceptable to substitute local laboratory results for safety monitoring purposes
Rationale: To ensure that disease progression to multiple myeloma is not over-represented.
3.1. Overview of Study Design; 
9.2.2. Assessment of Disease 
Progression to Multiple
Myeloma
Changed progression determination from IRC adjudication to IMWG FLC
progression criteria combined with IMWG FLC ratio criteria.
Rationale: Clarification made to prevent false positive diagnosis of progression to multiple myeloma.
9.2.3. CRAB Criteria-related 
Laboratory Assessments, Serum
Calcium Corrected for Albumin
Added text to determine reason for elevation in calcium.
Creatinine Clearance 
Added text to determine reason for decrease in glomerular filtration rates.
Hemoglobin  
Added text to clarify the diagnosis of anemia before progression to MM can
be diagnosed.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
114
Approved, Date: 23 September 2024
Rationale: To clarify the timing of bone lesion assessments.
Table 1; 9.2.7. Assessment of 
Bone Disease 
Lytic bone lesions (LDCT, 
PET-CT or CT)
Clarified that bone lesion assessments will be performed at Screening and
every 12 months until PD. Deleted Figure 4, Schedule for Lytic Lesion
Assessments.
Added text to clarify that MRI should be performed per Imaging Acquisition
Guidelines provided by the central imaging provider.
Disease Progression  
Added information regarding reasons for an increased PET signal other than
markers of disease progression has been added.
Rationale: To clarify laboratory assessments for UPEP.
Table 1; 9.2.4. Myeloma Protein 
Measurements in Serum and 
Urine
Added text to clarify level of measurable disease and clarified when UPEP
analysis is performed.
Rationale: To clarify study completion for Arm A.
10.1 Completion  
Added a definition for study completer for Arm A.
Rationale: Added to address a Health Authority request.
3.2. Study Design Rationale 
Added summary of benefits and risks.
4.1. Inclusion Criteria, 
Criterion #2.1.
Clarified the basis for diagnosis of SMM by adding ‘per IMWG criteria’.
4.1. Inclusion Criteria, 
Criterion #3.1.
Added clarification of ‘clonal’ to BMPCs.
11.3.1 Primary Endpoint 
Added text to clarify stratification by number of risk factors associated with
progression to MM (<3 vs ≥3).
Table 1; 9.1.4. Follow-up Phase 
Survival will be followed until the end of the study and at a frequency of at
least every 12 weeks until PD. After PD, survival is to be followed at least
every 6 months.
8.1. Recommended Therapies 
Prophylaxis for pneumocystis carini/jirovecci pneumonia, according to
institutional guidelines, should be considered for subjects in Arm B
(daratumumab).
Rationale: To add an antihistamine that may be used for daratumumab predose medication.
Attachment 4 Antihistamine 
Medications 
Added chlorphenamine as an antihistamine that may be used for
daratumumab predose medication.
Rationale: Alignment of text with recent protocol template changes.
10.3. Withdrawal from the 
Study (Arm A and Arm B) 
Revised text related to subjects withdrawing from the study and added text
regarding public record searches.
12.3.1. All Adverse Events 
Added text related to sponsor's responsibility for reporting anticipated events
and about reporting a SUSAR.
12.3.3 Pregnancy  
Deleted text related to the unknown effect of study drug on sperm.
17.3 Subject Identification, 
Enrollment, and Screening Logs 
Added ‘(as allowed by local regulations)’ following 2 instances of ‘date of
birth’.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
115
Approved, Date: 23 September 2024
17.11 Use of Information and 
Publication  
Changed the time for submitting study results for publication from ‘within
12 months of the availability of the final data (tables, listings, graphs)…’ to
‘18 months after study end date…’.
Changed authorship guidelines from Uniform Requirements for Manuscripts
Submitted to Biomedical Journals to ICMJE Recommendations for the
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical
Journals.
Rationale: For clarity and consistency, minor grammatical and formatting changes were made throughout the
protocol.
Synopsis, Other Evaluations; 
Table 1 and Table 2; 
3.1. Overview of Study Design; 
6.2. Treatment Schedule and
Administration; 9.7. Safety
Evaluations; 11.10. Safety
Analysis
Height and weight assessments updated to be performed at screening only. In
some sections, this meant that text describing vital signs assessments was
deleted.
9.2.6. Bone Marrow 
Examination, Table 8 
Added text to clarify bone marrow tissue for MRD testing when taken from
archive tissue.
9.2.8 Best Response to First-line 
Multiple Myeloma Treatment 
Updated text to reflect using local lab evaluations to assess best response to
first-line MM.
4. Subject Population  
Added text to clarify randomized subjects are considered enrolled subjects.
4.1. Inclusion Criteria, 
Criterion #7.1.; Attachment 11
Added definition of women of childbearing potential
Table 1; 6. Dosage and 
Administration
Added text to clarify minimal interval of days between daratumumab doses.
Synopsis; 6. Dosage and 
Administration
Added text to clarify that all doses should be administered at outpatient visits.
Attachment 2 Modified Diet in 
Renal Disease Formula
Updated the modified diet in renal disease formulas.
Throughout the protocol 
Minor grammatical, formatting, or spelling changes were made.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
116
Approved, Date: 23 September 2024
REFERENCES
1. 
Agarwal A, Ghorbial I. Monoclonal gammopathy of undetermined significance and smoldering multiple
myeloma: A review of the current understanding of epidemiology, biology, risk stratification, and management
of myeloma precursor disease. Clin Can Res. 2012;19(5)985-994.
2. 
Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 3rd Edition. Philadelphia; WB Saunders, 1998.
3. 
Chapuy C, Nicholson R, Aguad MD, et al. Resolving the daratumumab interference with blood compatibility
testing. Transfusion. 2015;55:1545-1554.
4. 
Cocks K, Cohen D, Wisloff F, et al. An international field study of the reliability and validity of a
disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with
multiple myeloma. European J of Cancer. 2007;43:1670-1678.
5. 
de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal
antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol.
2011;186:1840-1848.
6. 
Dispenzieri A, Stewart AK, Chanan-Khan A, et al. Smoldering multiple myeloma requiring treatment: time for
a new definition? Blood. 2013;122:4172-4181.
7. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma.
Leukemia. 2006;20:1467-1473. Corrigenda/Erratum in: Leukemia. 2007;21:1134-1135.
8. 
Ghosh N, Tucker N, Zahurak M, et al. Addition of clarithromycin to lenalidomide and dexamethasone (BiRd)
is effective in MM after progression on lenalidomide and dexamethasone. Session 653. Myeloma: Therapy,
excluding Transplantation. American Society of Hematology (ASH) 2013 meeting. Abstract 1960.
9. 
Goodman B, Gardner H. The microbiome and cancer. J of Pathol. 2018;244:667-676.
10. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new five-level version of
the EQ-5D (EQ-5D-5L). Qual Lif Res. 2011;20:1727-1736.
11. Investigator's Brochure: JNJ-54767414 (daratumumab), Edition 14; Janssen Research & Development
(05 Oct 2017).
12. Korde N, Roschewski M, Zingone A, et al. Treatment with carfilzomib-lenalidomide-dexamethasone with
lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol.
2015;1(6):746-754. doi:10.1001/jamaoncol.2015.2010.
13. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cll
expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384-394.
14. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response
and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-46.
15. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and
smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and
guidelines for monitoring and management. Leukemia. 2010;24(6):1121-1127.
16. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk and response assessment of multiple myeloma.
Leukemia. 2009;23(1):3-9.
17. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS)
consistently precedes multiple myeloma: a prospective study. Blood. 2009;113(22):5412-5417.
18. Landgren O. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma:
biological insights and early treatment strategies. Hematology Am Soc Hemtaol Educ Program. 2013: 478-487.
19. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in
renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-254.
20. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple
myeloma. N Engl J Med. 2015;373:1207-1219.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
117
Approved, Date: 23 September 2024
21. Lonial S, Weiss BM , Usmani SZ ,et al. Daratumumab monotherapy in patients with treatment-refractory
multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet.2016;387(10027):1551-1560.
22. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal
residual disease detection in multiple myeloma. Blood. 2014;123(20):3073-3079.
23. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering
multiple myeloma. N Engl J Med. 2013;369:438-447.
24. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone versus observation with
high-risk smouldering multiple myeloma (QuiReDex): long-term follow-up of a randomized controlled,
phase 3 trial. Lancet Oncol. 2016;17(8):1127-1136.
25. McCudden C, Axel A, Slaets D, et al. Assessing clinical response in multiple myeloma (MM) patients treated
with monoclonal antibodies (mAbs): Validation of a daratumumab IFE reflex assay (DIRA) to distinguish
malignant M-protein from therapeutic antibody. J Clin Oncol. 2015 (suppl; abstr 8590).
26. Meisel M, Hinterleitner R, Pacis A, et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-
deficient host. Nature. 2018 May;557(7706):580-584.
27. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology
Group. Am J Clin Oncol 1982;5(6):649-655.
28. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor
activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. Accepted for
publication in Monoclonal Antibodies. 2015;7:311-321.
29. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for
the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548.
30. Rajkumar SV, Gupta V, Fonseca R, et al. Impact of primary molecular cytogenetic abnormalities and risk of
progression in smoldering multiple myeloma. Leukemia. 2013;27(8):1738-1744.
31. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of
clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695.
32. Rajkumar SV, Landgren O, Mateos M-V. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075.
33. Rios-Tamayo R. Smoldering Multiple Myeloma: Changing the Management Paradigm or Just the Definition.
J Leuk. 2014,2:1.
34. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with
heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016. DOI: 10.1182/blood-2016-03-
705210
35. Vij R, Mazumder A, Klinger M, et al. Deep sequencing reveals myeloma cells in peripheral blood in majority
of multiple myeloma patients. Clin Lymphoma Myeloma Leuk. 2014;14(2):131-139.
36. Weiss BM, Abadie J, Verma P, Howard RS, Kuehl WM. A monoclonal gammopathy precedes multiple
myeloma in most patients. Blood. 2009;113(22):5418-5422.
37. Wisloff F, Eika S, Hippe E, et al. Measurement of health-related quality of life in multiple myeloma. Nordic
Myeloma Study Group. Br J Haematol. 1996;92:604-613.
38. Wisloff F, Hjorth M. Health-related quality of life assessed before and during chemotherapy predicts for
survival in multiple myeloma. Nordic Myeloma Study Group. Br J Haematol. 1997;97:29-37.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
118
Approved, Date: 23 September 2024
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 198227

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
119
Approved, Date: 23 September 2024
Attachment 2: Modified Diet in Renal Disease Formula
For creatinine in mg/dL, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal
disease (MDRD) formulas is:
e-GFR (MDRD) mL/min per 1.73 m2= 175 × [serum creatinine mg/dL]-1.154 × [age]-0.203 ×
[1.212 if black] × [0.742 if female]
For creatinine in µmol/L, the estimated glomerular filtration rate (e-GFR) for the modified diet in renal
disease (MDRD) formulas is:
e-GFR (MDRD) mL/min per 1.73 m2= 175 × [serum creatinine µmol/L/88.4]-1.154 × [age]-0.203
× [1.212 if black] × [0.742 if female]
(Levey 200619)

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
120
Approved, Date: 23 September 2024
Attachment 3: Asthma Guidelines
Components of
Severity
Classification ofAsthma Severity
Intermittent
Persistent
Mild 
Moderate 
Severe
0-4 yrs 5-11 yrs 
12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs
Impairment
Normal
FEV1/FVC :
8-19yr 85%
20-39yr 80%
40-59yr 75%
60-80yr 70%
Symptoms
≤2 days/week  
≥2 days/week but not daily 
Daily
Throughout the day
Nighttime
awakenings
0
≤2x/month  
1-2x/
month  
3-4x/month
3-4x/
month
> 1x/week but not
nightly
> 1x/
month  
Often 7x/week
SABA use for
symptom control
(not prevention
of EIB)
≤2 days/week
≤2 days/week but not daily
>2 days/
week but
not daily,
and
not more
than 1x
Daily 
Several time per day
Interference with
normal activity
None 
Minor limitation  
Some limitation  
Extremelylimited
Lung function
FEV1
FEV1/FVC
N/A
Normal FEV1
between
exacerbations
> 80%
> 85%
Normal FEV1
between
exacerbations
> 80%
Normal
N/A  
> 80%
> 80%
> 80%
Normal
N/A
60-80%
75-80%
60-80%
Reduced5%
N/A  
< 60%
< 75%
< 60%
Reduced
Risk
Exacerbations
requiring oral
systemic
corticosteroids
0-1/year
≥2 exacerbations in 6
months requiring oral
steroids or >4 wheezing
episodes/1 year lasting
>1 dayandrisk factors
for persistent asthma
≥ 2/year 
Relative 
annual risk 
maybe 
relatedto 
FEV1. 
≥ 2/year
Relative
annual risk
maybe
relatedto
FEV1.
≥ 2 exacerbations in 6
months requiring oral
steroids or >4 wheezing
episodes/1 year lasting
>1 dayandrisk factors
for persistent asthma
≥ 2/year
Relative
annual risk
maybe
relatedto
FEV1.
≥ 2/year
Relative
annual risk
maybe
relatedto
FEV1.
≥ 2 exacerbations in
6months requiring oral
steroids or >4 wheezing
episodes/1 year lasting
>1 dayand risk factors
for persistent asthma
≥ 2/year
Relative
annual risk
maybe
relatedto
FEV1.
≥ 2/year
Relative
annual risk
maybe
related
to FEV1.
Considerseverityandinterval since last exacerbation. Frequencyandseveritymayfluctuate over time for patients in anyseveritycategory.
Recommended
Step for
Initiating Treatment
Step 1 
Step 2
Step 3 and consider
short course of oral
steroids
Step 3: 
medium  
dose ICS  
and 
consider 
short
course of
Step 3 and 
consider 
short course 
of oral
steroids
Step 3 and consider
short course of oral
steroids
Step 3:
medium dose
ICS OR Step 4
and consider
short course of
oral steroids
Step 4 or 5
and
consider
short
course
of oral
steroids
In 2-6 weeks, evaluate level of asthma control that is achieved.
0-4 years: If no clear benefit is observedin 4-6weeks, stop treatment andconsider alternate diagnosis or adjusting therapy. 5-11 and12+ years: adjust therapyaccordingly.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
121
Approved, Date: 23 September 2024
Components of
Control
Classification of Asthma Control
Well Controlled 
Not Well Controlled 
Very Poorly Controlled
0-4 yrs 5-11 yrs 12 + yrs 0-4 yrs 5-11 
12 + yrs 0-4 yrs 5-11 yrs 12 + yrs
Symptoms
≤ 2 days/week but not
more than once on
each day
≤ 2 days/
week
> 2 days/week or
multiple times on
≤2 days/week
> 2 days/
week
Throughout the day
Impairment
Nighttime
awakenings 
≤ 1x/month  
≤ 2x/month  > 1x/month  ≥ 2x/month  1-3x/week > 1x/week ≥ 2x/week ≥ 4x/week
Interference with
normal activity 
None 
Some limitation  
Extremely limited
SABA use for symptom
control (not prevention of 
EIB)
≤2 days/week  
> 2 days/week  
Several times per day
Lung function  
FEV1 or peak flow  
FEV1/FVC 
N/A  
> 80% 
> 80% 
> 80% 
N/A  
60-80% 
75-80% 
60-80% 
N/A
< 60% 
< 75%
< 60%
Validated questionnaires 
ATAQ  
ACQ
ACT 
0 
≤ 0.75 
≥ 20 
1-2 
≥ 1.5 
16-19 
3-4
N/A
≤ 15
Risk
Exacerbations requiring oral
systemic corticosteroids
0-1/year
≥2/year
Consider severity and interval since last exacerbation
Reduction in lung growth/
Progressive loss of lung
function
Evaluation requires long-term follow-up
Recommended Action
for
Treatment
• Maintain current step
• Regular follow-up every
1-6 months
• Consider step down if well
controlledfor 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
• Considershort 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 therapyaccordingly.
• 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 therapyaccordingly.
• For side effects, consider
alternative treatment options.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
122
Approved, Date: 23 September 2024
Attachment 4: Antihistamine Medications
The following antihistamines may be used for daratumumab predose medication (including, but
not limited to):
Diphenhydramine
Cetirizine
Fexofenadine
Loratadine
Clemastine
Dexchlorpheniramine
Chlorphenamine
Promethazine*
* The IV use of promethazine should be avoided.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
123
Approved, Date: 23 September 2024
Attachment 5: 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

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
124
Approved, Date: 23 September 2024
Attachment 6: Serum Calcium Corrected for Albumin
If calcium is expressed in mg/dL and albumin is expressed in g/dL:
Corrected calcium (mg/dL) =
serum calcium (mg/dL) + 0.8•(4 - serum albumin [g/dL])
If calcium is expressed in mmol/L and albumin is expressed in g/L:
Corrected calcium (mmol/L) =
serum calcium (mmol/L) + 0.02•(40 - serum albumin [g/L])
Source: Burtis 19982

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
125
Approved, Date: 23 September 2024
Attachment 7: Interpretation of the SEBIA Hydrashift 2/4 Daratumumab IFE Interference test
Background: Clinical response assessment in myeloma relies on serum protein electrophoresis
(SPEP) and immunofixation electrophoresis (IFE). As daratumumab is a monoclonal IgG kappa
antibody, the SPEP and IFE can be positive for daratumumab at the serum levels anticipated
during this protocol.
Implementation: To mitigate this interference, the sponsor will use the SEBIA Hydrashift 2/4
Daratumumab IFE Interference test to distinguish a positive SPEP/IFE due to the presence of
daratumumab versus the presence of the underlying (endogenous) monoclonal protein.  The
SEBIA Hydrashift 2/4 Daratumumab IFE Interference test will be sent automatically to the
central laboratory if a subject with IgG kappa multiple myeloma has an SPEP at or below 0.2
g/dL on 2 or more consecutive cycles. In addition, the SEBIA Hydrashift 2/4 Daratumumab IFE
Interference test will be sent automatically to the central laboratory if a subject has an SPEP of
zero, but persistently positive IFE for IgG kappa on 2 or more occasions.
Interpretation of results:
The results will be available to the investigator via the central laboratory interface and will be
reported as follows:
DARAHydra Impress1:  result defined as “DARA detected”, “DARA not detected”, OR
“DARA indeterminate”
DARAHydra Impress2:  result defined as “M-protein not detected” OR the specific
protein detected (i.e. “IgG,k” or “IgA”)
DARAHydra Impress3: result defined as “M-protein not detected” OR the specific
protein detected (i.e. “IgG,k” or “IgA”)
– 
If Impress1 result is “DARA detected” and Impress2 and 3 results are “M-protein not
detected”, the patient may be in complete response (CR) if the other criteria for CR (including
negative bone marrow aspirate/biopsy) are achieved.
– 
If Impress1 result is “DARA not detected” or “DARA indeterminate”, the patient is still
positive for underlying (endogenous) monoclonal protein and Impress2 and 3 can inform as to
the type of endogenous protein still present.  Therefore, this patient is not in a complete response
(CR), because the CR response criteria requires a negative SPEP and serum IFE.
– 
If Impress1 result is “DARA detected” but there is also protein present and reported by
Impress2 or 3, the patient is still positive for underlying (endogenous) monoclonal protein and
Impress2 and 3 can inform as to the type of endogenous protein still present.  Therefore, this patient
is not in a complete response (CR), because the CR response criteria requires a negative SPEP and
serum IFE.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
126
Approved, Date: 23 September 2024
Attachment 8: EORTC QLQ-C30
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
127
Approved, Date: 23 September 2024
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
128
Approved, Date: 23 September 2024
Attachment 9: EORTC QLQ-MY20
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
129
Approved, Date: 23 September 2024
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
130
Approved, Date: 23 September 2024
Attachment 10: 
EQ-5D-5L
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
131
Approved, Date: 23 September 2024
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
132
Approved, Date: 23 September 2024
CCI

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
133
Approved, Date: 23 September 2024
Attachment 11: 
Women of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Women Not of Childbearing Potential:
Premenarchal:
A premenarchal state is one in which menarche has not yet occurred.
Postmenopausal:
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy, however in the absence of 12 months
of amenorrhea, a single FSH measurement is insufficient.
Permanently sterile:
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria. If reproductive status is questionable, additional
evaluation should be considered.

JNJ-54767414 (daratumumab)
Clinical Protocol 54767414SMM3001; Amendment 6/EEA-1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
134
Approved, Date: 23 September 2024
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD

Signature
User 
Date 
Reason
 
24-Sep-2024
11:13:45
(GMT)
Document Approval
PPD